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α-Amylase- and Redox-Responsive Nanoparticles for Tumor-Targeted Drug Delivery
Abstract
Paclitaxel (PTX) is an effective antineoplastic agent and shows potent anti-tumor activity against wide spectrum of cancers. Yet, the wide clinical use of paclitaxel (PTX) is limited by its poor aqueous solubility and side effects associated with current therapeutic formulation. To tackle these obstacles, we, for the first time, report an α-amylase- and redox- responsive nanoparticles based on hydroxyethyl starch (HES) for tumor targeted delivery of PTX. PTX is conjugated onto HES by redox-sensitive disulfide bond to form HES-SS-PTX, which is confirmed with NMR, HPLC-MS, and FT-IR. HES-SS-PTX conjugates assemble into stable and monodispersed nanoparticles (NPs), as characterized with DLS, TEM, and AFM. In blood, α-amylase will degrade the HES shell and thus decrease the size of HES-SS-PTX NPs, facilitating NPs extravasation and penetration in tumor. Pharmacokinetic study demonstrates HES-SS-PTX NPs have longer half-life than that of the commercial PTX formulation (Taxol). As a consequence, HES-SS-PTX NPs accumulate more in tumor compared with Taxol in in vivo imaging study. Under reductive conditions, HES-SS-PTX NPs could disassemble quickly as evidenced by their triggered-collapse, burst drug-release, and enhanced cytotoxicity against 4T1 tumor cell in the presence of reducing agent. Collectively, HES-SS-PTX NPs shows improved in vivo antitumor efficacy (63.6% vs 52.4%) and reduced toxicity in 4T1 tumor-bearing mice than Taxol. These results highlight the advantages of HES-based α-amylase- and redox- responsive nanoparticles, showing great clinical translation potential for cancer chemotherapy.
Supplementary resource (1)
... Paclitaxel (PTX) is a highly potent antineoplastic agent that shows broad-spectrum antitumor activity in cancer therapy [109]. However, its clinical application is limited due to its hydrophobic nature and poor aqueous solubility, which leads to undesired neurotoxic side effects, such as hypersensitivity, peripheral neuropathy, and neutropenia. ...
... The HES−SS-PTX conjugates have the ability to form monodispersed nanoparticles that are degraded by α-amylase in plasma, leading to the release of active drug at the tumor site. The redox-sensitive disulfide bond facilitates the extravasation and penetration of the HES−SS-PTX nanoparticles into the tumor microenvironment (as shown in Figure 13) [109]. These α-amylase and redox-responsive nanoparticles offer significant advantages in cancer chemotherapy and have great potential for clinical translation. ...
... The fate of HES−SS-PTX NP in vivo[109]. Copyright 2017; reproduced with permission from American Chemical Society. ...
Cancer is a genetic disorder and its treatment usually requires a long time and expensive diagnosis. While chemotherapy is the most conventional approach in treating most cancers, patients often suffer from undesired side effects due to various pharmacokinetic aspects. To address this issue, target-oriented drug-delivery systems (DDS) or pulsatile drug-delivery systems (PDDS) have recently been developed as an alternative tool that takes care of the entire pharmacodynamic activities of drug action. Hydroxyethyl starch (HES) has emerged as an effective clinical tool for delivering anticancer agents into target cells. These systems have demonstrated significant potential as anticancer drug carrier conjugates through their innate pharmacokinetic properties with their safety profile. This review focuses primarily on the structural aspect during the use of HES or HES-based polymers as carriers for delivering well-known anticancer drugs. This review also indicates a perspective on the long-term research needed for the sake of improving modern drug-delivery systems based on HES polymers and in the form of nanocarriers.
... Further, the survival time of the virus-infected mice increased and their lung index improved with intravenous administration of fucoidan [57]. In another study, the influence of Fucus evanescens fucoidan on inhibition of hepatitis B virus (HBV) was investigated in an HBV-infected mouse model [114]. In this study, fucoidan acted as an adjuvant to suppress HBV DNA, HBV surface antigen (HBsAG) and active HBV proteins implicated in viral replication, namely HBeAg and HBcAg [114]. ...
... In another study, the influence of Fucus evanescens fucoidan on inhibition of hepatitis B virus (HBV) was investigated in an HBV-infected mouse model [114]. In this study, fucoidan acted as an adjuvant to suppress HBV DNA, HBV surface antigen (HBsAG) and active HBV proteins implicated in viral replication, namely HBeAg and HBcAg [114]. The treatment of HBV-infected mice with 100 mg of fucoidan upregulated the expression of interferon-α (INF-α) via activation of mitogen-activated protein kinase (MAPK-ERK1/2) pathway, which reduced DNA production and viral replication [114]. ...
... In this study, fucoidan acted as an adjuvant to suppress HBV DNA, HBV surface antigen (HBsAG) and active HBV proteins implicated in viral replication, namely HBeAg and HBcAg [114]. The treatment of HBV-infected mice with 100 mg of fucoidan upregulated the expression of interferon-α (INF-α) via activation of mitogen-activated protein kinase (MAPK-ERK1/2) pathway, which reduced DNA production and viral replication [114]. Despite numerous studies demonstrating the therapeutic potential of fucoidan for treating HBV infections, further research is needed to validate the results in large animal models prior to translation to clinical practice. ...
Polymers, due to their high molecular weight, tunable architecture, functionality, and buffering effect for endosomal escape, possess unique properties as a carrier or prophylactic agent in preventing pandemic outbreak of new viruses. Polymers are used as a carrier to reduce the minimum required dose, bioavailability, and therapeutic effectiveness of antiviral agents. Polymers are also used as multifunctional nanomaterials to, directly or indirectly, inhibit viral infections. Multifunctional polymers can interact directly with envelope glycoproteins on the viral surface to block fusion and entry of the virus in the host cell. Polymers can indirectly mobilize the immune system by activating macrophages and natural killer cells against the invading virus. This review covers natural and synthetic polymers that possess antiviral activity, their mechanism of action, and the effect of material properties like chemical composition, molecular weight, functional groups, and charge density on antiviral activity. Natural polymers like carrageenan, chitosan, fucoidan, and phosphorothioate oligonucleotides, and synthetic polymers like dendrimers and sialylated polymers are reviewed. This review discusses the steps in the viral replication cycle from binding to cell surface receptors to viral-cell fusion, replication, assembly, and release of the virus from the host cell that antiviral polymers interfere with to block viral infections.
... 15,44 Previous studies on HESbased NPs indicate that the molecular weight and hydroxyethyl substitution degree of HES are two key parameters for regulating the size and α-amylase-mediated degradation of HES-based NPs. 18,45,46 In this study, based on many comparative trials, HES with its molecular weight of 130 kDa and hydroxyethyl molar substitution of 0.4 was selected as the carrier for DOX conjugation since it has a suitable ability to resist fast degradation, and concomitantly, the resulting NPs could have their sizes suited for intravenous administration and the tumor accumulation. A multi-step synthesis method, for the first time, was developed for synthesizing HES-SS-hyd-DOX to achieve a high DOX load, and meanwhile, to link DOX with HES through a hydrazone bond, as explicated in Scheme 2. ...
... Some other signals in the spectrum of HES-PDP are attributed to the HES backbone. 45,46 The other two intermediates, MP-hyd and HES-SShyd, were also synthesized in advance, and their 1 H NMR spectra were presented in Figures S3 and 1A, respectively. In the 1 H NMR spectrum of MP-hyd, signals for the protons of hydrazide groups are observed at 4.18 and 9.00 ppm, whilst the signals for the protons of methylene groups can be seen at 2.27 and 2.66 ppm. ...
... The significantly higher anti-cancer cytotoxicity of HES-SS-hyd-DOX can be attributed to its enhanced intratumoral accumulation ( Figure 4C), and fast DOX release (Figure 2A). It is worth mentioning that the initial tumor volume before treatment in the current study was between 170-190 mm 3 , which is considerably larger than that mentioned in some previous studies, 19,45,46,50 and can be considered as advanced tumor models. Therefore, the presently achieved results corroborate that these HES-SS-hyd-DOX NPs have significantly higher antitumor efficacy because they can inhibit the growth of advanced tumors. ...
Background:
Chemotherapeutic drugs used for tumor treatments often show limited efficiency due to their short lifetime, nonspecific delivery, and slow or insufficient intracellular drug release, and also, they can cause severe system or organ toxicity. The development of chemotherapeutic nanomedicines with high efficacy and satisfactory safety still remains a challenge for current tumor chemotherapy.
Methods:
A novel type of conjugate was synthesized using hydroxyethyl starch (HES) as a carrier while binding doxorubicin (DOX) onto HES backbone through a pH/redox responsive linker containing both disulfide and hydrazone bonds in series. The built conjugates were self-assembled into nanoparticles (NPs) (HES-SS-hyd-DOX NPs) for achieving enhanced antitumor therapy and adequate safety.
Results:
HES-SS-hyd-DOX NPs had a certain ability for the tumor-orientated drug accumulation and were capable of releasing DOX itself rather than DOX derivatives. It was found that the pH/redox responsive linkage enabled the NPs to achieve fast and sufficient intracellular drug release. Based on the tumor-bearing mouse model, antitumor results demonstrated that these NPs were able to inhibit the growth of the advanced tumors with significantly enhanced efficacy when compared to free DOX, and to those conjugate NPs containing only a single responsive or unresponsive bond. Besides, HES-SS-hyd-DOX NPs also showed adequate safety to the normal organs of the treated mice.
Conclusion:
The pH/redox responsive linkage in HES-SS-hyd-DOX was found to play a critical role in mediating the drug accumulation and the fast and sufficient intracellular drug release. The HES-exposed surface of HES-SS-hyd-DOX NPs endowed the NPs with long circulation capability and remarkably reduced the DOX-induced side effects.
... Figure 1 shows the 1 H NMR spectrum of HES in DMSO-d6 including the chemical structure and the signal assignments. In Figure 1, significant peak overlapping is observed, making it challenging to identify and assign all the peaks in the spectrum [33][34][35][36]. The anomeric proton resonances of H-1 at α-1,4 unsubstituted (peak 1), H-1 at α-1,4 substituted at C-2 position by hydroxyethyl group (peak 1 at (2s)), and H-1 at α-1,6 branching points (peak 1 at (6b)) are also difficult to resolve due to signal overlapping with the hydroxyl group (-OH) peaks from the anhydroglucose unit (AGU) of HES in the region of δH 4.44−5.70 ...
... To determine the peaks raised from anomeric protons, 1 H NMR measurements ( Figure 2) were carried out in D2O and D2O/DMSO-d6 mixture 1:9 ratio so that the protons of the hydroxyl groups of HES can rapidly exchange with labile deuterium. In Figure 1, significant peak overlapping is observed, making it challenging to identify and assign all the peaks in the spectrum [33][34][35][36]. The anomeric proton resonances of H-1 at α-1,4 unsubstituted (peak 1), H-1 at α-1,4 substituted at C-2 position by hydroxyethyl group (peak 1 at (2s)), and H-1 at α-1,6 branching points (peak 1 at (6b)) are also difficult to resolve due to signal overlapping with the hydroxyl group (-OH) peaks from the anhydroglucose unit (AGU) of HES in the region of δ H 4.44−5.70 ...
Polysaccharide-based nanoformulations with tailored hydrophobic properties have become a frontier in nanomedicine applications. Herein, highly hydrophobicized hydroxyethyl starch (HES) conjugates were synthesized by grafting stearic acid (SA) with HES via a carbodiimide-mediated reaction. A detailed NMR characterization of HES and the conjugates was studied to obtain structural information. The grafting ratio of the stearate-HES (St-HES) conjugates was determined from 1H NMR spectra as 29.4% (St-HES29.4) and 60.3% (St-HES60.3). Thermal analyses and X-ray diffractograms suggested an entire transition from amorphous HES to a semicrystalline (St-HES60.3) character upon increasing the degree of grafting. Both conjugates, St-HES29.4 and St-HES60.3, were able to form self-assembled particles with a diameter of 130.7 nm and 152.5 nm, respectively. SEM images showed that the self-aggregates were mostly spherical in shape. These conjugates can be employed to entrap highly hydrophobic drugs with an increased encapsulation efficiency and loading capacity.
... S1 and S2) to afford CuET@PH NPs [72,73]. Consistent with previous studies [74,75], HES 200/0.5 with a molecular weight of 200 kDa and hydroxy ethyl substitution degree of 50% exhibits a colloidal diameter around 20 nm in dynamic laser light scattering (DLS) measurement. Figure 2B also demonstrates that CuET@PH NPs have a hydrodynamic diameter around 122 nm, which is slightly bigger than CuET@HES NPs, suggesting that PDA and HES-SH have been successfully decorated on the surface of CuET@HES NPs. ...
... This indicates that PDA can interact with the copper elements in CuET, thereby augmenting the stability of CuET. Figure 2H illustrates that CuET@PH NPs are stable in 10% fetal bovine serum (FBS) solution for at least 7 days. Considering that the outer layer of CuET@ PH NPs is functionalized with HES, this result is reasonable, as HES is highly hydrophilic and can withstand protein adsorption [71][72][73][74][75]. Therefore, CuET@PH NPs have the potential for systemic administration. ...
Cuproptosis-based cancer nanomedicine has received widespread attention recently. However, cuproptosis nanomedicine against pancreatic ductal adenocarcinoma (PDAC) is severely limited by cancer stem cells (CSCs), which reside in the hypoxic stroma and adopt glycolysis metabolism accordingly to resist cuproptosis-induced mitochondria damage. Here, we leverage hyperbaric oxygen (HBO) to regulate CSC metabolism by overcoming tumor hypoxia and to augment CSC elimination efficacy of polydopamine and hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanoparticles (CuET@PH NPs). Mechanistically, while HBO and CuET@PH NPs inhibit glycolysis and oxidative phosphorylation, respectively, the combination of HBO and CuET@PH NPs potently suppresses energy metabolism of CSCs, thereby achieving robust tumor inhibition of PDAC and elongating mice survival importantly. This study reveals novel insights into the effects of cuproptosis nanomedicine on PDAC CSC metabolism and suggests that the combination of HBO with cuproptosis nanomedicine holds significant clinical translation potential for PDAC patients.
... This combination of redox and enzyme agents could not only enhance the accumulation of bioactives and drugs inside the target cells such as tumor cytoplasm, but also augment the permeation via changing the particle size due to the cleavage by extracellular enzymes [114]. For instance, Li et al. [115] reduced the hydroxyethyl starch (HES) NPs size using α-amylase. They also conjugated Paclitaxel (PTX) to HES by a disulfide bond to exhibit the redox responsive property. ...
... Furthermore, no drug leakage was observed after degrading NPs with α-amylase. This study proposed a successful strategy of redox responsive and changing particle size by enzyme reaction to improve internalization in tumor tissues and get a better anticancer effect [115]. ...
Recent advances in emerging nanocarriers and stimuli-responsive (SR) delivery systems have brought about a revolution in the food and pharmaceutical industries. SR carriers are able to release the encapsulated bioactive compounds (bioactives) upon an external trigger. The potential of releasing the loaded bioactives in site-specific is of great importance for the pharmaceutical industry and medicine that can deliver the cargo in an appropriate condition. For the food industry, release of encapsulated bioactives is considerably important in processing or storage of food products and can be used in their formulation or packaging. There are various stimuli to control the favorite release of bioactives. In this review, we will shed light on the effect of different stimuli such as temperature, humidity, pH, light, enzymatic hydrolysis, redox, and also multiple stimuli on the release of encapsulated cargo and their potential applications in the food and pharmaceutical industries. An overview of cargo release mechanisms is also discussed. Furthermore, various alternatives to manipulate the controlled release of bioactives from carriers and the perspective of more progress in these SR carriers are highlighted.
... Our previous work has demonstrated that hydroxyethyl starch (HES), a clinical used plasma volume expander with excellent biocompatibility, biodegradability and well-defined in vivo safety, can greatly improve the stability of PDA in physiological environment [36]. In addition, to overcome the side effects of chemotherapeutic drugs, many HES-based, TME-responsive prodrugs have been prepared by our lab [37,38]. We assume that some of these HES prodrugs can also stabilize PDA while achieve tumor-specific chemotherapeutic effects which is a decent complement to CDT. ...
... The relatively low H 2 O 2 content in normal tissues enables the slowly degradation of P(HSD-Cu-DA) NPs. Coincidentally, HES can be degraded in vivo by serum α-amylase [38]. These characters guarantee the biodegradability of P(HSD-Cu-DA) NPs. ...
Rationale: Chemodynamic therapy (CDT) is an emerging tumor-specific therapeutic strategy. However, the anticancer activity of CDT is impeded by the insufficient Fenton catalytic efficiency and the high concentration of glutathione (GSH) in the tumor cells. Also, it is challenging to eliminate tumors with CDT alone. Thus, simple strategies aimed at constructing well-designed nanomedicines that can improve therapeutic efficiency of CDT and simultaneously incorporate extra therapeutic modes as helper are meaningful and highly required.
Method: Tailored to specific features of tumor microenvironment (TME), in this study, we developed a biosafe, stable and TME-activated theranostic nanoplatform (P(HSD-Cu-DA)) for photoacoustic imaging (PAI) and self-amplified cooperative therapy. This intelligent nanoplatform was fabricated following a simple one-pot coordination and polymerization strategy by using dopamine and Cu²⁺ as precursors and redox-responsive hydroxyethyl starch prodrugs (HES-SS-DOX) as stabilizer.
Results: Interestingly, the pre-doped Cu²⁺ in polydopamine (PDA) framework can endow P(HSD-Cu-DA) NPs with tumor-specific CDT ability and remarkably enhance NIR absorption of PDA. PAI and biodistribution tests proved such nanoplatform can effectively accumulate in tumor tissues. Following enrichment, massive amounts of toxic hydroxyl radicals (·OH, for CDT) and free DOX (for chemotherapy) were generated by the stimulation of TME, which was further boosted by local hyperthermia. Concomitantly, in the process of activating these therapeutic functions, GSH depletion triggered by disulfide bond (-SS-) breakage and Cu²⁺ reduction within tumor cells occurred, further amplifying intratumoral oxidative stress. Importantly, the framework structure dominated by bioinspired polydopamine and clinical-used HES guaranteed the long-term biosafety of in vivo treatment. As a result, the mutual promotion among different components yields a potent tumor suppression outcome and minimized systemic toxicity, with one dosage of drug administration and laser irradiation, respectively.
Conclusion: This work provides novel insights into designing efficient and tumor-specific activatable nanotherapeutics with significant clinical translational potential for cancer therapy.
... Difficulty of formulation, limited bioavailability, and unfeasibility of rout of administration are among other issues correlated with high hydrophobicity of drug [2]. Important anticancer drugs such as Doxorubicin, Paclitaxel, Docetaxel, Camptothecine and Vinblastine are among highly hydrophobic drugs, limiting their clinical application due to nonspecific biodistribution, rapid metabolism, clearance, and drug resistance [3][4][5]. Advances in nanoparticle (NP) design as a drug carrier has attracted tremendous attention during last two decade [6]. Capability of drug delivery systems has been enhanced through nanoparticle technology for delivery of hydrophobic drugs, for which pharmacokinetic and pharmacodynamics are subject to improvement [4,7]. ...
... Advances in nanoparticle (NP) design as a drug carrier has attracted tremendous attention during last two decade [6]. Capability of drug delivery systems has been enhanced through nanoparticle technology for delivery of hydrophobic drugs, for which pharmacokinetic and pharmacodynamics are subject to improvement [4,7]. ...
Poor water solubility, off-target toxicity, and small therapeutic window are among major obstacles for the development of drug products. Redox-responsive drug delivery nanoplatforms not only overcome the delivery and pharmacokinetic pitfalls observed in conventional drug delivery, but also leverage the site-specific delivery properties. Cleavable diselenide and disulfide bonds in the presence of elevated reactive oxygen species (ROS) and glutathione concentration are among widely used stimuli-responsive bonds to design nanocarriers. This review covers a wide range of redox-responsive chemical structures and their properties for designing nanoparticles
aiming controlled loading, delivery, and release of hydrophobic anticancer drugs at tumor site.
... In this work, PTX was conjugated to HES through a redox-active disulfide bond (HES-SS-PTX) in the NPs andα-amylase was used in the formulation to degrade the NPs via the cleavage of α-1,4 glycosidic bonds. The NPs' degradation decreased the NPs' size which enhanced the penetration of PTX in the tumor tissue and improved the antitumor efficacy of the HES-based NPs [69]. ...
Paclitaxel (PTX) as the most important member of the taxane family is used against a wide range of cancers including breast, ovarian and lung cancers. However, the effectiveness of PTX in clinical practice is limited by its low water solubility and permeability in biological tissues. To address these limitations, PTX is formulated with Cremophor EL and dehydrated ethanol, known as Taxol®. Due to the adverse side effects of the formulation, efforts have been made in recent years to develop alternative PTX formulations. Polysaccharides, due to their low toxicity and biocompatibility, biodegradability, and ease of chemical modification are an excellent alternative to Cremophor EL for formulating PTX. This review focuses on recent advances to develop PTX formulations based on polysaccharides.
... LY/ICG were loaded into HES-PCL using Pickering emulsion solvent evaporation method [34]. As shown in Table S1, the ICG entrapment efficiency (EE%) of ICG@HES-PCL and LY/ICG@HES-PCL was above 90%, the ICG loading content of ICG@HES-PCL nanoparticles (ICG: 5.0%) are very close to those of LY/ICG@HES-PCL nanoparticles (LY: 5.1%, ICG: 4.7%) and the weight ratio of LY to ICG are close to 1:1 for both nanoparticles. ...
TGF-β is widely existed in tumor microenvironment, taking part in tumorigenesis process including angiogenesis, cancer associated fibroblast (CAF) proliferation, and immunosuppression. It inhibited the activation, proliferation, migration and differentiation of T cells, in which way caused a limited therapeutic effects of chimeric antigen receptor T (CAR-T) towards solid tumor such as lymphoma. To targeted block TGF-β at tumor site, we take advantages of nano-techniques to deliver TGF-β inhibitors LY2157299 (LY) towards the tumor sites, in order to help achieve a improved and long-term functions of CAR-T towards lymphoma. Based on amphipathic hydroxyethyl starch-polycaprolactone (HES-PCL), LY and photosensitizer indocyanine green (ICG) were co-loaded in HES-PCL to achieve LY/ICG@HES-PCL nanoparticle. The enhanced function of CAR-T benefited from LY/ICG@HES-PCL were verified through lymphoma Raji cells in vitro and Nod scid gamma mice engrafted with the Raji cells in vivo. LY was targeted transported to tumor site and accelerated release by mild ICG photothermal. Chemokines CXCL9/10/11 at the tumor site relevant to CAR-T migration and chemokines receptor CXCR3 of CAR-T could be up-regulated by LY, thus facilitated the enhanced accumulation of CAR-T at lymphoma site. T effector memory cells differentiation could also be accelerated by LY/ICG@HES-PCL. Combined therapy of LY/ICG@HES-PCL and CAR-T achieved 2.4 times higher antitumor activity and 2.7 times higher relapse inhibiting rates than CAR-T alone within 15 days and 11 days, respectively. The results suggested that LY/ICG@HES-PCL facilitated the enhanced therapeutic index of CAR-T cells towards lymphoma simply and safely, it may be further potentiated applied for other solid tumors.
... Several disulfide bond-bridged HES conjugates were used to build drug-loaded NPs with redox sensitivity for anti-tumor therapy (Hu et al., 2016;Li et al., 2017;Li et al., 2019;Tan et al., 2021). These NPs can release the conjugated drugs in response to the stimulation of GSH. ...
A novel type of diselenide bond-bridged hydroxyethyl starch-doxorubicin conjugate, HES-SeSe-DOX, was synthesized via a specially designed multistep synthetic route. The optimally achieved HES-SeSe-DOX was further combined with photosensitizer, chlorin E6 (Ce6), to self-assemble into HES-SeSe-DOX/Ce6 nanoparticles (NPs) for potentiating chemo-photodynamic anti-tumor therapy via diselenide-triggered cascade actions. HES-SeSe-DOX/Ce6 NPs were observed to disintegrate through the cleavage or oxidation of diselenide-bridged linkages in response to the stimuli arising from glutathione (GSH), hydrogen peroxide and Ce6-induced singlet oxygen, respectively, as evidenced by the enlarged size with irregular shapes and cascade drug release. In vitro cell studies exhibited that HES-SeSe-DOX/Ce6 NPs in combination with laser irradiation effectively consumed intracellular GSH and promoted a large rise in levels of reactive oxygen species in tumor cells, actuating the disruption of intracellular redox balance and the enhanced chemo-photodynamic cytotoxicity against tumor cells. The in vivo investigations revealed that HES-SeSe-DOX/Ce6 NPs were inclined to accumulate in tumors with persistent fluorescence emission, inhibited tumor growth with high efficacy and had good safety. These findings demonstrate the potential of HES-SeSe-DOX/Ce6 NPs for use in chemo-photodynamic tumor therapy and suggest their viability for clinical translation.
... In the present study, biocompatible hydroxyl ethyl starch nanocapsules (HES-NCs) prepared by a miniemulsion process were utilized for this approach. HES is well suited for translation into the clinical routine due to its biodegradability and high biocompatibility which is comparable to native starch [30,31]. Furthermore, it is known for its presence of modifiable chemical groups as well as tailorability [32]. ...
Hair follicles constitute important drug delivery targets for skin antisepsis since they contain ≈25% of the skin microbiome. Nanoparticles are known to penetrate deeply into hair follicles. By massaging the skin, the follicular penetration process is enhanced based on a ratchet effect. Subsequently, an intrafollicular drug release can be initiated by various trigger mechanisms. Here, we present novel ultraviolet A (UVA)-responsive nanocapsules (NCs) with a size between 400 and 600 nm containing hydroxyethyl starch (HES) functionalized by an o-nitrobenzyl linker. A phase transfer into phosphate-buffered saline (PBS) and ethanol was carried out, during which an aggregation of the particles was observed by means of dynamic light scattering (DLS). The highest stabilization for the target medium ethanol as well as UVA-dependent release of ethanol from the HES-NCs was achieved by adding 0.1% betaine monohydrate. Furthermore, sufficient cytocompatibility of the HES-NCs was demonstrated. On ex vivo porcine ear skin, a strong UVA-induced release of the model drug sulforhodamine 101 (SR101) could be demonstrated after application of the NCs in cyclohexane using laser scanning microscopy. In a final experiment, a microbial reduction comparable to that of an ethanol control was demonstrated on ex vivo porcine ear skin using a novel UVA-LED lamp for triggering the release of ethanol from HES-NCs. Our study provides first indications that an advanced skin antisepsis based on the eradication of intrafollicular microorganisms could be achieved by the topical application of UVA-responsive NCs.
... Starch is a safe and biodegradable material that is widely used in the food industry and as a drug delivery system. 27,30,31 Additionally, starch can be degraded by various enzymes such as amylases, glucoamylases, glucosidases, and other debranching enzymes. These degradation products are absorbed by the body. ...
Introduction:
Compared to intravenous administration, intratumoral drug administration enables the direct delivery of drugs to tumors and mitigates the systemic absorption of drugs and associated drug-induced side effects. However, intratumoral drug administration presents several challenges. The high interstitial fluid pressure (IFP) of the tumor prevents the retention of drugs within the tumor; thus, significant amounts of the drugs are absorbed systemically through the bloodstream or delivered to non-target sites. To solve this problem, in this study, a drug-enclosed needle-type starch implant was developed that can overcome IFP and remain in the tumor.
Methods:
Injectable needle-type starch implants (NS implants) were prepared by starch gelatinization and drying. The structure, cytotoxicity, and anticancer effects of the NS implants were evaluated. Biodistribution of NS implants was evaluated in pork (in vitro), dissected liver (ex vivo), and 4T1 tumors in mice (in vivo) using a fluorescence imaging device.
Results:
The prepared NS implants exhibited a hydrogel structure after water absorption. NS implants showed effective cytotoxicity and anticancer effects by photothermal therapy (PTT). The NS implant itself has sufficient strength and can be easily injected into a desired area. In vivo, the NS implant continuously delivered drugs to the tumor more effectively and uniformly than conventional hydrogels and solutions.
Conclusion:
This study demonstrated the advantages of needle-type implants. An injectable NS implant can be a new formulation that can effectively deliver drugs and exhibit anticancer effects.
... Different nanocarriers have been designed upon this concept such as micelles (115), nanoparticles based on hydroxyethyl starch (116), gold-nanoparticle (117) and liposomes (118)(119)(120). Most of the materials used to obtain these nanosystems contain characteristic disulfide (S-S) bonds. ...
Since more than 40 years liposomes have being extensively studied for their potential as carriers of anticancer drugs. The basic principle behind their use for cancer treatment consists on the idea that they can take advantage of the leaky vasculature and poor lymphatic drainage present at the tumor tissue, passively accumulating in this region. Aiming to further improve their efficacy, different strategies have been employed such as PEGlation, which enables longer circulation times, or the attachment of ligands to liposomal surface for active targeting of cancer cells. A great challenge for drug delivery to cancer treatment now, is the possibility to trigger release from nanosystems at the tumor site, providing efficacious levels of drug in the tumor. Different strategies have been proposed to exploit the outer and inner tumor environment for triggering drug release from liposomes and are the focus of this review.
... A combination of active targeting with the two-step stimuli-responsive drug release achieved a good in vivo targeting with an efficient tumor therapy. Similarly, Li et al. [219] developed NPs composed of hydroxyethyl starch (HES) coupled to paclitaxel (PTX) through a redox-sensitive disulfide bond. During circulation particles underwent a size reduction due to HES degradation by α-amylase, which promoted their extravasation to tumors. ...
Viruses are nanomaterials with a number of properties that surpass those of many synthetic nanoparticles (NPs) for biomedical applications. They possess a rigorously ordered structure, come in a variety of shapes, and present unique surface elements, such as spikes. These attributes facilitate propitious biodistribution, the crossing of complex biological barriers and a minutely coordinated interaction with cells. Due to the orchestrated sequence of interactions of their stringently arranged particle corona with cellular surface receptors they effectively identify and infect their host cells with utmost specificity, while evading the immune system at the same time. Furthermore, their efficacy is enhanced by their response to stimuli and the ability to spread from cell to cell. Over the years, great efforts have been made to mimic distinct viral traits to improve biomedical nanomaterial performance. However, a closer look at the literature reveals that no comprehensive evaluation of the benefit of virus-mimetic material design on the targeting efficiency of nanomaterials exists. In this review we, therefore, elucidate the impact that viral properties had on fundamental advances in outfitting nanomaterials with the ability to interact specifically with their target cells. We give a comprehensive overview of the diverse design strategies and identify critical steps on the way to reducing them to practice. More so, we discuss the advantages and future perspectives of a virus-mimetic nanomaterial design and try to elucidate if viral mimicry holds the key for better NP targeting.
The advancement of numerous interdisciplinary fields of science, engineering, and medicine has been integrated into the rapid growth of nanomedicine (NM) over the past few decades. Many aspects of NM need to be investigated, even though a few clinical successes of nanomaterials have significantly altered the landscape of disease diagnosis and treatment. One such topic is the complex interactions between NM and its post-administration chemical, physical, and biological interactions and how these interactions impact NM biological performance. Because of the increased prevalence of metabolic disorders, neurological illnesses, heart diseases, and cancer, as well as the hunt for effective therapies for these and other diseases, there is a larger demand for unique, inventive, and drug-delivery systems that can transport medications to the desired place. The many cutting-edge drug delivery systems are becoming more and more dependent on nanotechnology. In this review, developments in the field and talk about how nanomedicine interacts with the physical, chemical, and biological material, with a focus on biological stimuli research. We also show how nano-bio interaction can create a variety of multifunctional platforms of biomedical applications with a wide range. The potential difficulties and opportunities in the study of nano-bio interactions are also discussed.
Poor tumor penetration is the most significant barrier to the clinical translation of nanomedicines. Despite numerous studies, little is known about how the physicochemical properties and tumor-associated environments impact liposome intratumoral penetration from a multi-factorial perspective. Thus, we developed a set of model liposomes to explore the laws of their intratumoral penetration. Our comprehensive analysis revealed that zeta potential, membrane fluidity, and size of liposomes could influence their penetration in the peripheral, intermediate, or central areas of the tumor, respectively. Moreover, protein corona and stromal cells primarily impeded liposome penetration in the tumor periphery, while the vascular vessels had a similar effect in the tumor center. Our results also revealed a non-monotonic relationship, indicating that the best condition for a single factor may not necessarily be the optimal choice when considering all the factors. The preferred size, zeta potential, and membrane fluidity for excellent tumor penetration are within the ranges of 52-72 nm, 16-24 mV, and 230-320 mp, respectively. Our study provides a comprehensive understanding of the influence of physicochemical properties and tumor-associated environments on liposome intratumoral penetration, offering explicit guidance for the precise design and rational optimization of anti-tumor liposomes.
Chemotherapy is recognized as one of the significant treatment methods for liver cancer. The compound celastrol (CSL) could effectively inhibit the proliferation, migration, and invasion of liver cancer cells, which is regarded as a promising candidate to become a mainstream anti-liver cancer drug. However, the application of CSL in liver cancer chemotherapy is limited due to its systemic toxicity, poor water solubility, multidrug resistance, premature degradation, and lack of tumor targeting. Meanwhile, in order to comply with the current concept of precision medicine, precisely targeted delivery of the anti-liver compound CSL was desired. This paper takes into account that liver cancer cells were equipped with hyaluronic acid (HA) receptors (CD44) on their surface and overexpressed. Hyaluronidase (HAase) capable of degrading HA, HAase-responsive nanocarriers (NCs), named HA/(MI)7-β-CD NCs, were prepared based on the electrostatic interaction between HA and imidazole moieties modified β-cyclodextrin (MI)7-β-CD. HA/(MI)7-β-CD NCs showed disassembly properties under HAase stimuli, which was utilized to trap, deliver, and the controllable release of the anti-liver cancer compound CSL. Furthermore, cytotoxicity assay experiments revealed that CSL-trapped HA/(MI)7-β-CD NCs not only reduced cytotoxicity for normal cells but also effectively inhibited the survival for five tumor cells, and even the apoptotic effect of CSL-trapped NCs with a concentration of 5 μg mL-1 on tumor cells (SMMC-7721) was consistent with free CSL. Cell uptake experiments demonstrated HA/(MI)7-β-CD NCs possessed the capability of targeted drug delivery to cancerous cells. HA/(MI)7-β-CD NCs exhibited site-specific and controllable release performance, which is anticipated to proceed further in precision-targeted drug delivery systems.
Now-a-days, the polysaccharides are extensively employed for the delivery of small-molecule drugs ascribed to their excellent biocompatibility, biodegradability and modifiability. An array of drug molecules is often chemically conjugated with different polysaccharides to augment their bio-performances. As compared to their therapeutic precursors, these conjugates could typically demonstrate an improved intrinsic solubility, stability, bioavailability and pharmacokinetic profiles of the drugs. In current years, various stimuli-responsive particularly pH and enzyme-sensitive linkers or pendants are also exploited to integrate the drug molecules into the polysaccharide backbone. The resulting conjugates could experience a rapid molecular conformational change upon exposure to the microenvironmental pH and enzyme changes of the diseased states, triggering the release of the bioactive cargos at the targeted sites and eventually minimize the systemic side effects. Herein, the recent advances in pH and enzyme -responsive polysaccharide-drug conjugates and their therapeutic benefits are systematically reviewed, following a brief description on the conjugation chemistry of the polysaccharides and drug molecules. The challenges and future perspectives of these conjugates are also precisely discussed.
Cancer stem cells (CSCs), enabled to self-renew, differentiate, and initiate the bulk tumor, are recognized as the culprit of treatment resistance, metastasis, and recurrence. Simultaneously eradicating CSCs and bulk cancer cells is crucial for successful cancer therapy. Herein, we reported that doxorubicin (Dox) and erastin co-loaded hydroxyethyl starch-polycaprolactone nanoparticles (DEPH NPs) eliminated CSCs and cancer cells by regulating redox status. We found that an excellently synergistic effect existed when Dox and erastin were co-delivered by DEPH NPs. Specifically, erastin could deplete intracellular glutathione (GSH), thereby inhibiting the efflux of intracellular Dox and boosting Dox-induced reactive oxygen species (ROS) to amplify redox imbalance and oxidative stress. The high ROS levels restrained CSCs self-renewal via downregulating Hedgehog pathways, promoted CSCs differentiation, and rendered differentiated cancer cells vulnerable to apoptosis. As such, DEPH NPs significantly eliminated not only cancer cells but more importantly CSCs, contributing to suppressed tumor growth, tumor-initiating capacity, and metastasis, in various tumor models of triple negative breast cancer. This study demonstrates that the combination of Dox and erastin is potent in elimination of both cancer cells and CSCs, and that DEPH NPs represent a promising treatment against CSCs-rich solid tumors.
Cancer stem cells (CSCs) have been recognized as the culprit for tumor progression, treatment resistance, metastasis, and recurrence while redox homeostasis represents the Achilles' Heel of CSCs. However, few drugs or formulations that are capable of elevating oxidative stress have achieved clinical success for eliminating CSCs. Here, we report hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanoparticles (CuET@HES NPs), which conspicuously suppress CSCs not only in vitro but also in numerous tumor models in vivo. Furthermore, CuET@HES NPs effectively inhibit CSCs in fresh tumor tissues surgically excised from hepatocellular carcinoma patients. Mechanistically, we uncover that hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanocrystals via copper‑oxygen coordination interactions, thereby promoting copper-diethyldithiocarbamate colloidal stability, cellular uptake, intracellular reactive oxygen species production, and CSCs apoptosis. As all components are widely used in clinics, CuET@HES NPs represent promising treatments for CSCs-rich solid malignancies and hold great clinical translational potentials. This study has critical implications for design of CSCs targeting nanomedicines.
Chemo-photodynamic therapy shows great potential for cancer treatment. However, the rational integration of chemotherapeutic agents and photosensitizers to construct an intelligent nanoplatform with synergistic therapeutic effect is still a great challenge. In this work, curcumin-loaded reduction-responsive prodrug nanoparticles of new indocyanine green ([email protected]) were developed for synergistic cancer chemo-photodynamic therapy. [email protected] exhibit high drug loading content and special worm-like morphology, contributing to their efficient cellular uptake. Due to the presence of the disulfide bond between IR820 and PEG, [email protected] display reduction responsive drug release behaviors. The efficient cellular uptake and reduction triggered drug release of [email protected] lead to their enhanced in vitro cytotoxicity against 4T1cells as compared to the mixture of IR820 and curcumin (IR820/Cur) under laser irradiation. Besides, [email protected] exhibit prolonged blood half-life time, better tumor accumulation and retention, enhanced tumor hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial cell growth factor (VEGF) suppression effect as compared to IR820/Cur. In vivo antitumor activity study, [email protected] effectively inhibit the tumor angiogenesis, which potentiates the PDT efficacy and leads to the best in vivo antitumor effect of [email protected] This work provides a novel and relatively simple strategy for synergistic cancer chemo-photodynamic therapy.
Gambogic acid (GA) has been approved to enter the phase III clinical trial. However, due to its short half-life, low water solubility, poor stability and inflammatory response, GA failed to pass the clinical superiority evaluation. Nano-preparations perform well in prolonging drug half-life, improving drug solubility, and enhancing drug stability etc. Therefore, a self-assembled nanoparticle (GA-HES/NPs) with long circulation and deep tumor penetration ability was designed, in which hydroxyethyl starch (HES) endowed GA-HES/NPs with longer circulation time as well as deep tumor penetration ability, and the simple synthesis method ensured the stability of GA structure. Experimental results showed that GA-HES/NPs owned a certain tumor targeting and deep tumor penetration ability, as well as longer circulation time, which could enhance the therapeutic effect of GA.
Chemotherapy is a conventional cancer treatment in clinical settings. Although numerous nano drug delivery systems have been developed, the chemotherapeutic effect is greatly limited by abnormal tumor mechanics in solid tumors. Tumor stiffening and accumulated solid stress compress blood vessels and inhibit drug delivery to tumor cells, becoming critical challenges for chemotherapy. By loading doxorubicin (DOX), tissue plasminogen activator (tPA), and fibrin targeting peptide CREKA (Cys-Arg-Glu-Lys-Ala) within pH responsive amphiphilic block polymers, pyridyldithio-hydroxyethyl starch-Schiff base-polylactic acid (PA-HES-pH-PLA), we report a smart nanomedicine, DOX@CREKA/tPA-HES-pH-PLA (DOX@CREKA/tPA-HP), which exhibits a potent antitumor efficacy. In triple-negative breast cancer (TNBC) 4T1 tumors, DOX@CREKA/tPA-HP precisely targeted and effectively decomposed fibrin matrix. By measuring Young's Modulus of tumor slices and quantifying tumor openings, we demonstrated that DOX@CREKA/tPA-HP remarkably reduced tumor stiffness and solid stress. Consequently, the alleviated tumor mechanics decompressed tumor blood vessels, promoted drug delivery, and led to amplified antitumor effect. Our work reveals that decomposing fibrin is a significant means for modulating tumor mechanics, and DOX@CREKA/tPA-HP is a promising smart nanomedicine for treating TNBC.
Recently, the role of starch-based carrier systems in anticancer drug delivery has gained considerable attention. Although there are same anticancer drugs, difference in their formulations account for unique therapeutic effects. However, the exploration on the effect-enhancing of anticancer drugs and their loading system by modified starch from the perspective of carrier regulation is still limited. Moreover, research on the reduced toxicity of the anticancer drugs due to modified starch as the drug carrier mediated by the intestinal microenvironment is lacking, but worth exploring. In this review, we examined the effect of modified starch on the loading and release properties of anticancer drugs, and the effect of resistant starch and its metabolites on intestinal microecology during inflammation. Particularly, the interactions between modified starch and drugs, and the effect of resistant starch on gene expression, protein secretion, and inflammatory factors were discussed. The findings of this review could serve as reference for the development of anticancer drug carriers in the future.
Microbial species are known to grow in diverse environmental conditions and have shown remarkable adaptability toward extreme conditions. Temperature plays a critical role in the survival and growth of such microorganisms and their presence varies widely on different parts of the biosphere ranging from subzero cold in Polar regions to very high-temperature ranges in hot springs, volcanic eruptions, and desert regions. It is evident that genetic variability and cellular adaptations under such extreme temperature ranges brings differences in microbial survival. A complete understanding of these adaptation mechanisms would decipher the molecular pathways involved in protecting the cell damage. As the discovery of thermostable polymerase revolutionized the field of genetic engineering, a similar interest could be envisaged with thermostable enzymes present within extremophiles which holds immense industrial applications. Cellulase and beta-glucosidase from thermophiles have been shown to be more efficient for second-generation biofuels production using agricultural or forestry residues in biorefineries. Further, extremophilic enzymes can be employed in other applications such as the production of lactose-free milk products or production of stonewashed jeans in textile industry. Thus this chapter focuses on a variety of microorganisms found in extreme temperature conditions, their molecular mechanisms for survival and the production of extremozymes that can be used for industrially relevant bioprocesses.
Genetic and protein engineering is an essential technology for understanding molecular physiology and for the design of novel functional proteins required to develop biotechnological applications in the fields of industry and medicine. In the last 40 years, this technology has developed in a vertiginous way, however, these advances have been more limited within the archaea domain, and specifically in haloarchaea. Halophilic archaea require high salt concentrations for their growth, the cell wall composition and their sensitivity to antibiotics is different from bacteria. As a consequence of these salinity requirements, halophilic proteins are also dependent on high salt concentration for both activity and stability. These differences have been determinant in the development of adequate molecular biology tools for the genetic modification of these microorganisms. This chapter summarizes the advances of gene technology and protein engineering and their applications in halophilic archaea.
The use of enzymes as biocatalysts is very well defined so far, but the role of these biomolecules in industrial chemical reactions is generally restricted to mild conditions of pH, temperature, pressure, ionic strength, etc. New advances in the understanding of haloarchaea physiology, metabolism, biochemistry, and molecular biology show that these kinds of microorganisms produce several enzymes with potential applications in industry and biotechnology. Among the main applications already described, the use of several dehydrogenases, amylases, agarases and reductases can be highlighted. The principal goal of the chapter is to present a review about the main characteristics of enzymes from haloarchaea, which are extremophilic enzymes, as well as their potential applications in industries related to cosmetics, textile, food production and processing and bioremediation-based processes. Advantages and disadvantages about their use at mid or large scale are also discussed.
Paclitaxel, a clinical chemotherapy drug commonly used in the past few years, is greatly limited by its low therapeutic index. Starch and its derivatives have gained wide interest from researchers owing to their unique hydrophilic and hydrophobic properties resulting from their various modifications, which exert the effect-enhancing and toxicity-reducing activity to paclitaxel in vivo and in vitro. This review summarizes the research progress toward different kinds of starch-based carriers, whether oral or injectable. In addition, we discuss the complex properties of starch derivatives toward physically complexed or chemically conjugated paclitaxel. The corresponding complex configurations are suggested. Starch-based carriers can act as permeability enhancers because they may interact with the unstirred water layer that separates hydrophobic drugs from biological membranes, even altering the barrier properties of the membrane. The information presented in this review may be used as a reference for future hydrophobic drug carrier studies.
Synthetic, semi-synthetic, and natural polymers make up the colloidal formations of polymeric nanoparticles. Because of their large surface area and nanoscale size, nanoparticles have unique physical and chemical capabilities. Their distinct size, shape, and structure influence their optical characteristics, reactivity, durability, and other attributes. Supercritical fluids, in which the fluid retains a single-phase regardless of pressure, are environmentally beneficial. It is in a state of minor criticality. Because the precipitate is solvent-free, this method is environmentally friendly. Due to their qualities, they are good candidates for various commercial and marital uses, including catalysis, imaging, pharmaceutical applications, energy-based research, and ecological applications. This review provides a supercritical fluid technology-based polymeric nanoparticles overview of various forms uses, synthesis, properties, and forthcoming prospects.
Introduction:
Compared with ordinary chemotherapeutic drugs, the variable-size nanoparticles (NPs) have better therapeutic effects and fewer side effects.
Areas covered:
This review mainly summarizes the strategies used to construct smart, size-tunable nanocarriers based on characteristic factors of tumor microenvironment (TME) to dramatically increase the penetration and retention of drugs within tumors.
Expert opinion:
Nanosystems with changeable sizes based on the TME have been extensively studied in the past decade, and their permeability and retention have been greatly improved, making them a very promising treatment for tumors.
The use of nanocarriers for the delivery of chemotherapeutic molecules has opened new avenues for the development of novel treatment strategies for various diseases, particularly in cancer. However, the use of bare or targeted nanocarriers still faces the hurdle of premature cargo release. As a result, such nanocarriers demonstrate side-effects. To overcome this hurdle, the research community has focused on developing nanocarriers with the ability to release the cargo under a specific stimulus only, viz. external stimuli like magnetic field, light, etc., and internal stimuli like pH, redox, enzyme, etc. The development of stimuli-responsive nanocarriers can be achieved by incorporating moieties sensitive to a specific type of stimuli. The present chapter deals with an in-depth discussion about such stimuli-sensitive nanocarriers, emphasizing the rationale behind the design and its application.
pH-Responsive nanoparticles (NPs) have emerged as an effective antitumor drug delivery system, promoting the drugs accumulation in the tumor and selectively releasing drugs in tumoral acidic microenvironment. Herein, we developed a new amphiphilic modified hydroxyethyl starch (HES) based pH-sensitive nanocarrier of antitumor drug delivery. HES was first modified by hydrophilic imidazole and hydrophobic cholesterol to obtain an amphiphilic polymer (IHC). Then IHC can self-assemble to encapsulate doxorubicin (DOX) and form doxorubicin-loaded nanoparticles (DOX/IHC NPs), which displayed good stability for one week storage and acidic sensitive long-term sustained release of DOX. As a result, cancer cell endocytosed DOX/IHC NPs could continuously release doxorubicin into cytoplasm and nucleus to effectively kill cancer cells. Additionally, DOX/IHC NPs could be effectively enriched in the tumor tissue, showing enhanced tumor growth inhibition effect compared to free doxorubicin. Overall, our amphiphilic modified HES-based NPs possess a great potential as drug delivery system for cancer chemotherapy.
This article provides a broad spectrum about the nanoprodrug fabrication advances co‐driven by prodrug and nanotechnology development to potentiate cancer treatment. The nanoprodrug inherits the features of both prodrug concept and nanomedicine know‐how, attempts to solve underexploited challenge in cancer treatment cooperatively. Prodrugs can release bioactive drugs on‐demand at specific sites to reduce systemic toxicity, this is done by using the special properties of the tumor microenvironment, such as pH value, glutathione concentration, and specific overexpressed enzymes; or by using exogenous stimulation, such as light, heat, and ultrasound. The nanotechnology, manipulating the matter within nanoscale, has high relevance to certain biological conditions, and has been widely utilized in cancer therapy. Together, the marriage of prodrug strategy which shield the side effects of parent drug and nanotechnology with pinpoint delivery capability has conceived highly camouflaged Trojan horse to maneuver cancerous threats.
Many types of drugs and agents used for cancer diagnosis and therapy
often have low bioavailability and insufficient efficacy, as well as causing
various side effects due to their nonspecific delivery. Nanocarriers with
purposely-designed compositions and structures have shown varying
degrees of abilities to deliver these compounds towards cancers in passive
or active manners. Despite the availability of a variety of materials for the
construction of nanocarriers, natural polymers with good biocompatibility
and biodegradability are preferable for such usage because of their high
in vivo safety as well as easy removal of degradation products. Among the
natural polymers intended for building nanocarriers, hydroxyethyl starch
and its derivatives have gained tremendous attention in the field of drug
delivery in the form of nanomedicines over the last decade. There is growing
optimism that ever more hydroxyethyl starch-based nanomedicines will be a
significant addition to the armoury currently used for cancer diagnosis and
therapy.
Although nanotechnology-driven drug delivery systems are relatively new, they are rapidly evolving since the nanomaterials are deployed as effective means of diagnosis and delivery of assorted therapeutic agents to targeted intracellular sites in a controlled release manner. Nanomedicine and nanoparticulate drug delivery systems are rapidly developing as they play crucial roles in the development of therapeutic strategies for various types of cancer and malignancy. Nevertheless, high costs, associated toxicity and production of complexities are some of the critical barriers for their applications. Green nanomedicines have continually been improved as one of the viable approaches towards tumor drug delivery, thus making a notable impact on which considerably affect cancer treatment. In this regard, the utilization of natural and renewable feedstocks as a starting point for the fabrication of nanosystems can considerably contribute to the development of green nanomedicines. Nanostructures and biopolymers derived from natural and biorenewable resources such as proteins, lipids, lignin, hyaluronic acid, starch, cellulose, gum, pectin, alginate, and chitosan play vital roles in the development of cancer nanotherapy, imaging and management. This review uncovers recent investigations on diverse nanoarchitectures fabricated from natural and renewable feedstocks for the controlled/sustained and targeted drug/gene delivery systems against cancers including an outlook on some of the scientific challenges and opportunities in this field. Various important natural biopolymers and nanomaterials for cancer nanotherapy are covered and the scientific challenges and opportunities in this field are reviewed.
In the past decades, the vigorous development of nanomedicine has opened up a new world for drug delivery. Hydroxyethyl starch (HES), a clinical plasma volume expander which has been widely used for years, is playing an attracting role as drug carriers. Compared with all other polysaccharides, HES has proven its unique characteristics for drug delivery platforms, including good manufacture practice, biodegradability, biocompatibility, abundant groups for chemical modification, excellent water solubility, and tailorability. In this review, an overview of various types of HES based drug delivery systems is provided, including HES–drug conjugates, HES-based nano-assemblies, HES-based nanocapsules, and HES-based hydrogels. In addition, the current challenges and future opportunities for design and application of HES based drug delivery systems are also discussed. The available studies show that HES based drug delivery systems has significant potential for clinical translation.
Objective
To reduce the toxicity and side effects of arsenic trioxide (ATO) and provide a new approach for the treatment of primary liver cancer, a folic acid-modified calcium arsenite liposomal “target-controlled” drug delivery system (FA-LP-CaAs) was fabricated using the reverse microemulsion method.
Methods
A Malvern particle size analyzer and a transmission electron microscope were employed to determine the particle size, distribution, zeta potential and morphology of FA-LP-CaAs. Further, inductively coupled plasma emission spectrometry was employed to determine the drug loading capacity, entrapment efficiency, and in vitro release behavior of FA-LP-CaAs. To determine its toxicity in human hepatoma cells (HepG2) and human normal hepatocytes (LO2) and its effect on HepG2 cell cycle and apoptosis, the MTT method was used. Laser confocal and flow cytometry were also employed to determine the uptake of FA-LP-CaAs by cells. After establishing a mouse liver cancer model, the in vivo distribution of the drug included in the formulation was investigated using in vivo fluorescence. To evaluate the liver cancer targeting and anti-tumor effects of FA-LP-CaAs in vivo, the distribution of ATO in tissues and changes in tumor volume and body weight after liposomal administration were investigated using hematoxylin-eosin (HE)-stained tumor sections.
Results
The particle size, zeta potential and PDI of FA-LP-CaAs were (122.67 ± 2.18) nm, (12.81 ± 0.75) mV and 0.22 ± 0.01, respectively, while its drug loading capacity was 18.49% ± 1.14%. In vitro experimental results revealed that FA-LP-CaAs had a strong killing effect on HepG2 cells. Further, the cell uptake capacity of this formulation was found to improve. Based on in vivo assessments, FA-LP-CaAs could significantly increase the distribution of ATO in tumor sites and inhibit tumor growth.
Conclusions
Herein, an FA-LP-CaAs formulation was successfully fabricated. This liposomal drug delivery system had a round appearance, uniform particle size, good polydispersity coeffi-cient, evident “core-shell” structure, high drug loading capacity and pH response, tumor targeted drug delivery and sustained drug release. These findings support further research and the application of ATO as an anti-liver cancer prodrug and provide a new method for the treatment of liver cancer.
In this study, novel redox-sensitive nanoparticles based on xylan-lipoic acid (Xyl-LA) conjugate were developed for tumour targeted delivery of niclosamide (Nic) in cancer therapy. The niclosamide loaded xylan-lipoic acid conjugate nanoparticles (Xyl-LA/Nic NPs) showed redox responsive behaviour in presence of reductive glutathione (GSH), which indicate their suitability for intracellular drug release. The obtained Xyl-LA/Nic NPs exhibited uniform particle size (196±1.64 nm), high loading capacity (∼28.6 wt %) and excellent blood compatibility. The anticancer activity of the Niclosamide and the Xyl-LA/Nic NPs against the colon carcinoma cell lines (HCT-15, Colo-320) were evaluated by MTT assay and the overall results indicate that the Xyl-LA/Nic NPs significantly enhanced the therapeutic efficiency of niclosamide in cancer therapy.
Glioma is the most typical malignant brain tumor, and the chemotherapy to glioma is limited by poor permeability for crossing blood-brain-barrier (BBB) and insufficient availability. In this study, angiopep-2 modified lipid-coated mesoporous silica nanoparticle loading paclitaxel (ANG-LP-MSN-PTX) was developed to transport paclitaxel (PTX) across BBB mediated by low-density lipoprotein receptor-related protein 1 (LRP1), which is over-expressed on both BBB and glioma cells. ANG-LP-MSN-PTX was characterized with homogeneous hydrodynamic size, high drug loading capacity (11.08%) and a sustained release. In vitro experiments demonstrated that the targeting efficiency of PTX was enhanced by ANG-LP-MSN-PTX with higher penetration ability (10.74%) and causing more C6 cell apoptosis. ANG-LP-MSN-PTX (20.6%) revealed higher targeting efficiency compared with LP-MSN-PTX (10.6%) via blood and intracerebral microdialysis method in the pharmacokinetic study. The therapy of intracranial C6 glioma bearing rats was increasingly efficient, and ANG-LP-MSN-PTX could prolong the survival time of model rats. Taken together, ANG-LP-MSN-PTX might hold great promise as a targeting delivery system for glioma treatment.
The size of nanostructures (NSs) strongly affects their chemical and physical properties and further impacts their actions in biological systems. Both small and large NSs possess respective advantages for disease theranostics, and this therefore presents a paradox when choosing NSs with suitable sizes. To overcome this challenge, size‐transformable NSs have emerged as a powerful tool, as they can be manipulated to possess the merits of both types of NSs. Herein, various strategies to construct size‐transformable NSs are summarized, and the recent research progress regarding their biomedical applications, particularly within the fields of cancer and bacterial theranostics, is highlighted. This review will inspire researchers to further develop various methods that can be used to construct size‐transformable NSs for use in novel applications within different fields. Size‐transformable nanostructures that can inherit the merits of both small and large ones are powerful platforms for enhanced disease theranostics with long‐term retention, deep penetration, and rapid clearance. Various strategies to realize the transformation between large and small nanostructures are introduced. The biomedical application potential of this kind of nanostructures is also discussed.
Doxorubicin (DOX) is one of the most potent anticancer agents in cancer chemotherapy, but the clinical use of DOX is restricted by its severe side effects caused by nonspecific delivery. To alleviate the side effects and improve the antitumor efficacy of DOX, a novel redox-sensitive hydroxyethyl starch-doxorubicin conjugate, HES-SS-DOX, with diameter of 19.9 ± 0.4 nm was successfully prepared for tumor targeted drug delivery and GSH-mediated intracellular drug release. HES-SS-DOX was relatively stable under extracellular GSH level (～2 µM) but released DOX quickly under intracellular GSH level (2-10 mM). In vitro cell study confirmed the GSH-mediated cytotoxicity of HES-SS-DOX. HES-SS-DOX exhibited prolonged plasma half-life time and enhanced tumor accumulation in comparison to free DOX. As a consequence, HES-SS-DOX exhibited better antitumor efficacy (81.0 ± 6.9 %) and reduced toxicity compared with free DOX (72.4 ± 11.0 %) in in vivo antitumor activity study. The redox-sensitive HES-SS-DOX was proved to be a promising prodrug of DOX, with clinical potentials, to achieve tumor targeted drug delivery and timely intracellular drug release for effective and safe cancer chemotherapy.
The conjugate of paclitaxel (PTX) and docosahexaenoic acid has entered into clinical trials. However, the most recent clinical outcomes fell short of expectations, due to the extremely slow drug release from the hydrophobic conjugates. Herein, a novel prodrug-based nanoplatform self-assembled by the disulfide bond linked conjugates of PTX and oleic acid for rapid and differential release of PTX in tumor cells is reported. This redox-responsive prodrug-nanosystem demonstrates multiple therapeutic advantages, including one-step facile fabrication, high drug-loading efficiency (56%, w/w), on-demand drug release responding to redox stimuli, as well as favorable cellular uptake and biodistribution. These advantages result in significantly enhanced antitumor efficacy in vivo, with the tumor almost completely disappearing in mice. Such a uniquely engineered prodrug-nanosystem has great potential to be used as potent chemotherapeutic nanomedicine in clinical cancer therapy.
Significance
Successively overcoming a series of biological barriers that cancer nanotherapeutics would encounter upon intravenous administration is required for achieving positive treatment outcomes. A hurdle to this goal is the inherently unfavorable tumor penetration of nanoparticles due to their relatively large sizes. We developed a stimuli-responsive clustered nanoparticle (iCluster) and justified that its adaptive alterations of physicochemical properties (e.g. size, zeta potential, and drug release rate) in accordance with the endogenous stimuli of the tumor microenvironment made possible the ultimate overcoming of these barriers, especially the bottleneck of tumor penetration. Results in varying intractable tumor models demonstrated significantly improved antitumor efficacy of iCluster than its control groups, demonstrating that overcoming these delivery barriers can be achieved by innovative nanoparticle design.
The aim of this study was to develop an alternative, more bio-available, better tolerated paclitaxel nanosuspension (PTXNS) for intravenous injection in comparison with commercially available Taxol® formulation. In this study, PTXNS was prepared by emulsification method through combination of high speed homogenizer and high pressure homogenization, followed by lyophilization process for intravenous administration. The main production parameters including volume ratio of organic phase in water and organic phase (Vo:Vw+o), concentration of PTX, content of PTX and emulsification time (Et), homogenization pressure (HP) and passes (Ps) for high pressure homogenization were optimized and their effects on mean particle size (MPS) and particle size distribution (PSD) of PTXNS were investigated. The characteristics of PTXNS, such as, surface morphology, physical status of paclitaxel (PTX) in PTXNS, redispersibility of PTXNS in purified water, in vitro dissolution study and bioavailability in vivo were all investigated. The PTXNS obtained under optimum conditions had an MPS of 186.8nm and a zeta potential (ZP) of -6.87mV. The PTX content in PTXNS was approximately 3.42%. Moreover, the residual amount of chloroform was lower than the International Conference on Harmonization limit (60ppm) for solvents. The dissolution study indicated PTXNS had merits including effect to fast at the side of raw PTX and sustained-dissolution character compared with Taxol® formulation. Moreover, the bioavailability of PTXNS increased 14.38 and 3.51 times respectively compared with raw PTX and Taxol® formulation.
Copyright © 2015. Published by Elsevier B.V.
Biosensor based on rugate PSi interferometer for the detection of avidin has been described. Rugate PSi
fabricated by applying a computer-generated pseudo-sinusoidal current waveform has been prepared for the
application as a label-free biosensor based on porous silicon interferometer. The fabrication, optical
characterization, and surface derivatization of a rugate PSi has been described. The method to fabricate biotinderivatized rugate PSi has been investigated. The surface and cross sectional morphology of rugate PSi are obtained with SEM. FT-IR spectroscopy is used to characterize the oxidation and functionalization reaction of rugate PSi sample. Binding of the avidin into the biotin-derivatized rugate PSi induces a change in refractive index. A red-shift of reflectivity by 18 nm in the reflectivity spectrum is observed, when the biotin-modified rugate PSi was exposed to a flow of avidin.
Cremophor EL (CrEL) is a formulation vehicle used for various poorly-water soluble drugs, including the anticancer agent paclitaxel (Taxol). In contrast to earlier reports, CrEL is not an inert vehicle, but exerts a range of biological effects, some of which have important clinical implications. Its use has been associated with severe anaphylactoid hypersensitivity reactions, hyperlipidaemia, abnormal lipoprotein patterns, aggregation of erythrocytes and peripheral neuropathy. The pharmacokinetic behaviour of CrEL is dose-independent, although its clearance is highly influenced by duration of the infusion. This is particularly important since CrEL can affect the disposition of various drugs by changing the unbound drug concentration through micellar encapsulation. In addition, it has been shown that CrEL, as an integral component of paclitaxel chemotherapy, modifies the toxicity profile of certain anticancer agents given concomitantly, by mechanisms other than kinetic interference. A clear understanding of the biological and pharmacological role of CrEL is essential to help oncologists avoid side-effects associated with the use of paclitaxel or other agents using this vehicle. With the present development of various new anticancer agents, it is recommended that alternative formulation approaches should be pursued to allow a better control of the toxicity of the treatment and the pharmacological interactions related to the use of CrEL.
The identification of stem-cell-like cancer cells through conventional methods that depend on stem cell markers is often unreliable. We developed a mechanical method for selecting tumorigenic cells by culturing single cancer cells in fibrin matrices of ~100 Pa in stiffness. When cultured within these gels, primary human cancer cells or single cancer cells from mouse or human cancer cell lines grew within a few days into individual round colonies that resembled embryonic stem cell colonies. Subcutaneous or intravenous injection of 10 or 100 fibrin-cultured cells in syngeneic or severe combined immunodeficiency mice led to the formation of solid tumours at the site of injection or at the distant lung organ much more efficiently than control cancer cells selected using conventional surface marker methods or cultured on conventional rigid dishes or on soft gels. Remarkably, as few as ten such cells were able to survive and form tumours in the lungs of wild-type non-syngeneic mice.
A nanoparticle toolset was created within the size limits of 10–150 nm for probing size-dependent nanoparticle distribution in solid tumors. By using multiphoton intravital microscopy, the particles were tracked both spatially and temporally in the same tumor grown in a transparent window model.
The enhanced permeability and retention (EPR) effect is a unique phenomenon of solid tumors related to their anatomical and pathophysiological differences from normal tissues. For example, angiogenesis leads to high vascular density in solid tumors, large gaps exist between endothelial cells in tumor blood vessels, and tumor tissues show selective extravasation and retention of macromolecular drugs. This EPR effect served as a basis for development of macromolecular anticancer therapy. We demonstrated methods to enhance this effect artificially in clinical settings. Of great importance was increasing systolic blood pressure via slow angiotensin II infusion. Another strategy involved utilization of NO-releasing agents such as topical nitroglycerin, which releases nitrite. Nitrite is converted to NO more selectively in the tumor tissues, which leads to a significantly increased EPR effect and enhanced antitumor drug effects as well. This review discusses molecular mechanisms of factors related to the EPR effect, the unique anatomy of tumor vessels, limitations and techniques to avoid such limitations, augmenting tumor drug delivery, and experimental and clinical findings.
We report biocompatible, cell-permeable core-shell-corona polymer micelles bearing glutathione-cleavable shell cross-links, which allow the facilitated release of entrapped anticancer drugs at cytoplasm in response to an intracellular glutathione level.
Taxol, a natural plant product that enhances the rate and extent of microtubule assembly in vitro and stabilizes microtubules in vitro and in cells, was labeled with tritium by catalytic exchange with (3)H(2)O. The binding of [(3)H]taxol to microtubule protein was studied by a sedimentation assay. Microtubules assembled in the presence of [(3)H]taxol bind drug specifically with an apparent binding constant, K(app), of 8.7 x 19(-7) M and binding saturates with a calculated maximal binding ration, B(max), of 0.6 mol taxol bound/mol tubulin dimer. [(3)H]Taxol also binds and assembles phosphocellulose-purified tubulin, and we suggest that taxol stabilizes interactions between dimers that lead to microtubule polymer formation. With both microtubule protein and phosphocellulose- purified tubulin, binding saturation occurs at approximate stoichiometry with the tubulin dimmer concentration. Under assembly conditions, podophyllotoxin and vinblastine inhibit the binding of [(3)H]taxol to microtubule protein in a complex manner which we believe reflects a competition between these drugs, not for a single binding site, but for different forms (dimer and polymer) of tubulin. Steady-state microtubules assembled with GTP or with 5'-guanylyl-alpha,beta-methylene diphosphonate (GPCPP), a GTP analog reported to inhibit microtubule treadmilling (I.V. Sandoval and K. Weber. 1980. J. Biol. Chem. 255:6966-6974), bind [(3)H]taxol with approximately the same stoichiometry as microtubules assembled in the presence of [(3)H]taxol. Such data indicate that a taxol binding site exists on the intact microtubule. Unlabeled taxol competitively displaces [(3)H]taxol from microtubules, while podophyllotoxin, vinblastine, and CaCl(2) do not. Podophyllotoxin and vinblastine, however, reduce the mass of sedimented taxol-stabilized microtubules, but the specific activity of bound [(3)H]taxol in the pellet remains constant. We conclude that taxol binds specifically and reversibly to a polymerized form of tubulin with a stoichiometry approaching unity.
Cremophor EL (CrEL) is a formulation vehicle used for various poorly-water soluble drugs, including the anticancer agent paclitaxel (Taxol). In contrast to earlier reports, CrEL is not an inert vehicle, but exerts a range of biological effects, some of which have important clinical implications. Its use has been associated with severe anaphylactoid hypersensitivity reactions, hyperlipidaemia, abnormal lipoprotein patterns, aggregation of erythrocytes and peripheral neuropathy. The pharmacokinetic behaviour of CrEL is dose-independent, although its clearance is highly influenced by duration of the infusion. This is particularly important since CrEL can affect the disposition of various drugs by changing the unbound drug concentration through micellar encapsulation. In addition, it has been shown that CrEL, as an integral component of paclitaxel chemotherapy, modifies the toxicity profile of certain anticancer agents given concomitantly, by mechanisms other than kinetic interference. A clear understanding of the biological and pharmacological role of CrEL is essential to help oncologists avoid side-effects associated with the use of paclitaxel or other agents using this vehicle. With the present development of various new anticancer agents, it is recommended that alternative formulation approaches should be pursued to allow a better control of the toxicity of the treatment and the pharmacological interactions related to the use of CrEL.
Three intracellular acid-degradable hydroxyethyl starch-doxorubicin (HESDOX) prodrugs with different drug binding rates (DBRs) were synthesized through the conjugation of oxidized HES and DOX with a pH-responsive Schiff base bond. The DBRs of HESDOX conjugates were determined to be 1.7, 3.3, and 5.9%, which could be facilely adjusted by the feeding molar amount of DOX. All HESDOX conjugates could spontaneously self-assemble into spherical micellar nanoparticles in phosphate-buffered saline. The hydrodynamic diameter decreased from 73.4 ± 5.3, 63.9 ± 5.5, to 51.9 ± 8.5 nm with the increase of the DBR from 1.7, 3.3, to 5.9%. The DOX release from HESDOX could be accelerated by the decrease of pH and the DBR, attributed to the acid-sensitive Schiff base bond and the loose core, respectively. Furthermore, the HESDOX micelle selectively released DOX in the endosome and/or lysosome after cellular uptake, and exhibited excellent proliferation inhibition toward murine melanoma B16F10 cells in vitro and in vivo. Furthermore, the antitumor efficacy was upregulated by the increase of the DBR, benefiting from the selective acidity-triggered DOX release in tumor cells. These results indicated that HESDOX exhibited great potential in the precise chemotherapy of malignancy.
The therapeutic efficacy of nanoscale anticancer drug delivery systems is severely truncated by their low tumor-targetability and inefficient drug release at the target site. Here, we report the design and development of novel endosomal pH-activatable paclitaxel prodrug micelles based on hyaluronic acid-b-dendritic oligoglycerol (HA-dOG-PTX-PM) for active targeting and effective treatment of CD44-overexpressing human breast cancer xenografts in nude mice. HA-dOG-PTX-PM had a high drug content of 20.6 wt.% and an average diameter of 155 nm. The release of PTX was slow at pH 7.4 but greatly accelerated at endosomal pH. MTT assays, flow cytometry and confocal experiments showed that HA-dOG-PTX-PM possessed a high targetability and antitumor activity toward CD44 receptor overexpressing MCF-7 human breast cancer cells. The in vivo pharmacokinetics and biodistribution studies showed that HA-dOG-PTX-PM had a prolonged circulation time in the nude mice and a remarkably high accumulation in the MCF-7 tumor (6.19 %ID/g at 12 h post injection). Interestingly, HA-dOG-PTX-PM could effectively treat mice bearing MCF-7 human breast tumor xenografts with little side effects, resulting in complete inhibition of tumor growth and a 100 % survival rate over an experimental period of 55 days. These results indicate that hyaluronic acid-shelled acid-activatable PTX prodrug micelles have a great potential for targeted chemotherapy of CD44-positive cancers.
Most anticancer drugs are poorly soluble and nonspecific, which restricts their clinical application. Drug conjugates, as a prodrug strategy, provide the possibility to overcome these shortcomings, especially combined with nanotechnology. Drug conjugate nanoparticles possess the advantages of high drug loading capacity and passive tumor targeting ability. Here, we prepared doxorubicin drug-drug conjugate nanoparticles (DOX-SS-DOX NPs) based on disulfide-linked doxorubicin drug-drug conjugate (DOX-SS-DOX). Dynamic light scattering (DLS) and transmission electron microscope (TEM) characterization indicated DOX-SS-DOX NPs were spherical with a uniform size distribution around 89nm. DLS and in vitro release experiment revealed DOX-SS-DOX NPs possessed reduction responsive activity. In vitro cellular uptake studies reflected that DOX-SS-DOX NPs could increase the uptake level substantially compared with DOX liposomes. Endocytosis mechanism assay demonstrated that DOX-SS-DOX NPs internalized into cells through clathrin-mediated endocytosis pathway in an energy-dependent manner. In this manner, the amidase in lysosomes could break the amide bond to release free DOX, which would be helpful to antitumor activity. The in vitro cytotoxicity of DOX-SS-DOX NPs was a bit weaker than that of DOX liposomes, which might be the result of the slow cleavage of the disulfide bridge. Even though, the antitumor efficacy of DOX-SS-DOX NPs evaluated in MCF-7 bearing mice demonstrated to be higher than that of DOX liposomes. This might because the long lasting effect resulted from the slow cleavage of the disulfide bond. In summary, DOX-SS-DOX NPs, prepared nearly totally with drug, provide a good strategy for cancer therapy.
Covalently linked amphiphilic polymer-paclitaxel (PTX) could self-assemble into micelles to overcome many drawbacks of existing delivery systems of PTX by virtue of tunable compositions, variable sizes, high drug loading content and zero burst release. Moreover, a reduction-responsive system based on glutathione (GSH) can be established by introducing disulfide bonds into the polymeric carriers to improve the selectivity for cancer cells. Herein, we reported a disulfide bond linked polymer-PTX, P(PEGMEA)-co-P(PDPHEMA)-g-PTX with a high PTX loading content of 43.7 wt.%. In vitro cell assay showed that the polymer carrier has almost no cytotoxicity. The half maximal inhibitory concentration (IC50) values of the polymer-PTX conjugate against HEK-293 cells was about 10 times higher than that of HeLa cells after incubation for 72 h. Such a dramatic selectivity for cancer and normal cells provides a promising strategy to improve the therapeutic efficacy and decrease the side effects of PTX in chemotherapy.
Objective: To investigate the pharmacokinetics and safety of a daily infusion of 500mL of hydroxyethyl starch (HES) [130/0.4] 10% solution on 10 consecutive days.
Study design and participants: An open, one-way, multiple-dose study was performed in 12 healthy male volunteers. Daily infusions over 30 minutes of 500mL of HES (130/0.4) 10% solution were performed on 10 consecutive days. Plasma and urine HES concentrations were determined repeatedly during the study until 72 hours after the last infusion.
Results: Maximum plasma HES concentrations, assessed with geometric means of 7.7 and 7.4 mg/mL, respectively, as well as the time courses of the plasma concentrations were similar on days 1 and 10 of treatment. Plasma HES concentrations 24 hours after the last infusion were 0.48 mg/mL (mean). Total plasma clearance was calculated as 23.7 and 21.8 mL/min on days 1 and 10, respectively. Urinary recoveries of 69% on day 1 and of 70% on day 10 were in good agreement.
Conclusion: The results clearly demonstrated that there is no relevant accumulation in plasma after repetitive infusion of the medium-molecular weight HES (130/0.4) solution, which exhibits a high renal excretion rate over 10 days. Local as well as systemic tolerability of 10 repeated doses was good.
Polymer-drug conjugates (PDCs) are drug delivery systems where one or more drug(s) are covalently attached to the functional groups of the polymer directly or through a spacer. Several anticancer drugs that have been used to synthesize PDCs are currently under clinical trials. PDCs have shown enhanced tumor accumulation, increased therapeutic index, and prolonged circulation, accompanied by a sustained release of the bound drug. Distinct cell uptake mechanisms make PDCs less sensitive to efflux pumps associated with the development of multi-drug resistance. However, the effectiveness of PDCs as a delivery system primarily depends on the drug, polymer, type of linkage, and presence of targeting groups. Due to the availability of different functional groups and spacers, it is possible to control drug release as well as multi-functionalize PDCs, thereby increasing their versatility as drug carriers. Furthermore, active tumor uptake may be achieved by using the concept of drug targeting. However, functionalization alters the in vivo behavior of the polymer, signifying the evaluation of safety and effectiveness of PDCs. Several PDCs are currently being tested in different phases of clinical trials. This review focuses on critical aspects in the design of PDCs when used in cancer drug delivery.
Nanomedicine is an interdisciplinary field of research at the interface of science, engineering, and medicine, with broad clinical applications ranging from molecular imaging to medical diagnostics, targeted therapy, and imageguided surgery. Despite major advances during the past 20 years, there are still major fundamental and technical barriers that need to be understood and overcome. In particular, the complex behaviors of nanoparticles under physiological conditions are poorly understood, and detailed kinetic and thermodynamic principles are still not available to guide the rational design and development of nanoparticle agents. Here we discuss the interactions of nanoparticles with proteins, cells, tissues, and organs from a quantitative physical chemistry point of view. We also discuss insights and strategies on how to minimize nonspecific protein binding, how to design multistage and activatable nanostructures for improved drug delivery, and how to use the enhanced permeability and retention effect to deliver imaging agents for image-guided cancer surgery. Expected final online publication date for the Annual Review of Physical Chemistry Volume 66 is March 31, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
The synthesis of polymer-drug conjugate (PDC) capable of convenient preparation and controlled release of therapeutic agents is still an urgent requirement in drug delivery field. Herein, we develop a novel anti-cancer PDC engineered with side groups of disulfide and ester bonds for on-demand delivery of paclitaxel (PTX) with redox and pH dual sensitive behaviors. A simple polymer, 3,3'-dithiodipropionic acid functionalized poly(ethylene glycol)-b-poly(L-lysine) (mPEG-b-P(LL-DTPA)), was synthesized and PTX was directly conjugated to the carboxyl groups of mPEG-b-P(LL-DTPA) to obtain the disulfide-containing polymer-PTX conjugate (P(L-SS-PTX)). Another structural similar polymer-PTX conjugate without disulfide bonds (P(L-PTX)) was also prepared to verify the function of disulfide linkages. The P(L-SS-PTX) micelles showed rapid drug release under tumor-relevant reductive conditions as designed. Interestingly, the PTX release from P(L-SS-PTX) micelles could also be promoted by the increased acidity (pH≈5). In vitro cytotoxicity study showed that the P(L-SS-PTX) micelles exhibited significantly enhanced cytotoxicity against a variety of tumor cells compared to the non-sensitive P(L-PTX) micelles. The in vivo studies on B16F1 melanoma bearing C57BL/6 mice demonstrated the superior antitumor activity of P(L-SS-PTX) over both free PTX and P(L-PTX). This dual-sensitive prodrug provides a useful strategy for anti-tumor drug delivery.
To address the obstacles of cancer chemotherapeutics, including toxicity, side effects, water insolubility, and lack of tumor selectivity, a novel stimuli-responsive drug-delivery system was developed based on paclitaxel-loaded poly(ethylene glycol)-disulfide-paclitaxel conjugate nanoparticles (PEG-SS-PTX/PTX NPs). The formulation emphasizes several benefits, including polymer-drug conjugates/prodrugs, self-assembled NPs, a high drug content, redox-responsibility, and programed drug release. The PTX-loaded, self-assembled NPs, with a uniform size of 103 nm, characterized by DLS, TEM, XRD, DSC and 1H-NMR, exhibited excellent drug-loading capacity (15.7%) and entrapment efficiency (93.3%). PEG-SS-PTX/PTX NPs were relatively stable under normal conditions but disassembled quickly under reductive conditions, indicated by the triggered-aggregation phenomena and drug-release profile in the presence of dithiothreitol (DTT), a reducing agent. What's more, by taking advantages of difference in drug releasing rates between physical-loaded and chemical-conjugated drugs, the "programmed drug release" phenomenon was observed, which attributed to higher concentration and longer action-time of drugs. The influence of PEG-SS-PTX/PTX NPs on in vitro cytotoxicity, the cell cycle, and cellular apoptosis was determined in MCF-7 cell lines, and the NPs demonstrated a superior anti-proliferation activity associated with PTX-induced cell arrest in the G2/M phase and apoptosis over their nonresponsive counterparts. Moreover, the redox-responsive NPs were more efficacious than both free PTX and the non-redox-responsive formulation at equivalent doses of PTX in the breast cancer xenograft mouse model. This redox-responsive PTX drug delivery system is promising and can be explored in effective intracellular drug delivery.
In cancer therapy nanocargos based on star-shaped polymer exhibit unique features such as better stability, smaller size distribution and higher drug capacity in comparison to linear polymeric micelles. In this study, we developed a multifunctional star-shaped micellar system by combination of active targeting ability and redox-responsive behavior. The star-shaped micelles with good stability were self-assembled from four-arm poly(ε-caprolactone)-poly(ethylene glycol) copolymer. The redox-responsive behaviors of these micelles triggered by glutathione were evaluated from the changes of micellar size, morphology and molecular weight. In vitro drug release profiles exhibited that in a stimulated normal physiological environment, the redox-responsive star-shaped micelles could maintain good stability, whereas in a reducing and acid environment similar with that of tumor cells, the encapsulated agent was promptly released. In vitro cellular uptake and subcellular localization of these micelles were further studied with confocal laser scanning microscopy and flow cytometry against the human cervical cancer cell line HeLa. In vivo and ex vivo DOX fluorescence imaging displayed that these FA-functionalized star-shaped micelles possessed much better specificity to target solid tumor. Both the qualitative and quantitative results of the antitumor effect in 4T1 tumor-bearing BALB/c mice demonstrated that these redox-responsive star-shaped micelles have a high therapeutic efficiency to artificial solid tumor. Therefore, the multifunctional star-shaped micelles are a potential platform for targeted anticancer drug delivery.
Abstract 10-hydroxy camptothecin (10-HCPT) is an antitumor agent effective in the treatment of several solid tumors but its use is hampered by poor water solubility, low lactone stability, short plasma half-life and dose-limiting toxicity. In this study, 10-HCPT-hydroxyethyl starch (HES) conjugate was prepared to overcome these limits of 10-HCPT. The solubility of 10-HCPT conjugate was 0.72 mg/ml, about 100 times to free 10-HCPT. The 10-HCPT conjugate showed good sustained release effect in phosphate-buffered saline (PBS), rat plasma and liver homogenate. Meanwhile, 10-HCPT-HES conjugate achieved much lower IC50 and higher cytotoxicity effects than the free 10-HCPT on Hep-3B liver cancer cells. The pharmacokinetics results of 10-HCPT-HES conjugate demonstrated that the biological half-life of 10-HCPT was increased from 10 min to 4.38 h and the bioavailability was 40 times higher than the commercial 10-HCPT injection. The pharmacodynamics results indicated that 10-HCPT-HES conjugate had a better antitumor efficiency against nude mouse with Hep-3B tumor than the commercial 10-HCPT injection, and the inhibition ratio of tumor was 83.9 and 27.8%, respectively, at the same administration dosage. These findings suggest that 10-HCPT-HES conjugate is a promising drug delivery system providing improved long circulating effect, greater stability and better antitumor effect.
Ideal "smart" nanoparticles for drug delivery should enhance therapeutic efficacy without introducing side effects. To achieve that, we developed a drug delivery system (HCN) based on a polymer-drug conjugate of poly[(2-(pyridin-2-yldisulfanyl)]-graft-polyethylene glycol (PDSG) and camptothecin with an intracellularly cleavable linker and human epidermal growth factor receptor 2 (HER2) targeting ligands. In vitro drug release study found that HCN was stable at physiological environment while supersensitive to the stimulus of intracellular elevated redox potential, releasing all payloads in less than 30 minutes. Furthermore, confocal microscopy revealed that HCN could specifically enter HER2-positive cancer cells. As a consequence, HCN could effectively kill HER2-positive cancer cells while not affecting HER2-negative cells.
To the Editor: The article by Von Hoff et al. (Oct. 31 issue)(1) is entitled Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine. This title strikes us as inappropriately rosy, given the modest benefits and substantial toxic effects observed. The addition of nab-paclitaxel increased the median survival by 1.8 months, or 55 days. The chance of being alive at 2 years was increased from 4% to 9%. Meanwhile, an additional 10% of patients had grade 3 (severe) fatigue. Grade 2 fatigue (moderate, not relieved by rest) and duration of fatigue are not mentioned. Grade 3 (severe) neuropathy was increased ...
With the extensive progress in nanotechnology-based drug delivery systems, pharmacokinetic evaluations have gained much attention from researchers as a central part of the study of these systems. Because the fulfillment of any therapeutic goal(s) by a novel drug delivery system requires that the absorption, distribution, metabolism, and excretion (ADME) be considered from the early stages of the system design to the final clinical evaluations, extensive knowledge of the pharmacokinetic aspects related to ADME is a crucial part of research in this field. The main objectives of the nanotechnology-based drug delivery systems from a pharmacokinetic viewpoint are (1) an improved drug-release profile in vivo, (2) enhanced drug absorption, (3) site-directed drug distribution, (4) a modified drug metabolism pattern, (5) prolonged drug residence time in body (e.g., in blood circulation), and (6) delayed and/or decreased renal excretion of the drug. Accordingly, the purpose of the current review is to present an insightful summary of pharmacokinetic analyses of nanotechnology-based drug delivery systems along with a critical review of recent findings.
The objective of this study was to develop a sustained-release drug delivery system for 5-fluorouracil (5-FU) to improve its short half-life. 5-Fluorouracil-1-acetic acid (FUAC) was prepared and then conjugated to hydroxyethyl starch (HES) through ester bonds. The conjugates were relatively stable in acidic buffer solution at pH 5.8 and slowly released FUAC but became more sensitive to hydrolysis with an increase in the pH and temperature. The conjugates were degraded to FUAC both in human and rat plasma with half-time life of 20.4 h and 24.6 h, respectively. Both 5-FU and FUAC were released in a rat liver homogenate following a 12 h incubation of the conjugates. The pharmacokinetic behavior was evaluated in rats after intravenous injection of 5-FU, FUAC and the conjugates. The drug release data in vitro and in vivo indicated that HES is a promising carrier for the sustained-release of antitumor drugs.
The therapeutic performance of biodegradable micellar drugs is far from optimal due to existing challenges like poor tumor cell uptake and intracellular drug release. Here, we report on ligand-directed reduction-sensitive shell-sheddable biodegradable micelles based on poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) copolymer actively delivering doxorubicin (DOX) into the nuclei of target cancer cells, inducing superb in vitro antitumor effects. The micelles were constructed from PEG-SS-PCL and galactose-PEG-PCL (Gal-PEG-PCL) block copolymers, in which Gal-PEG-PCL was designed with a longer PEG than that in PEG-SS-PCL (6.0 versus 5.0 kDa) to fully expose Gal ligands onto the surface of micelles for effective targeting to hepatocellular carcinoma cells. PEG-SS-PCL combining with 10 or 20 wt.% of Gal-PEG-PCL formed uniform micelles with average sizes of 56.1 and 58.2 nm (denoted as PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20, respectively). The in vitro release studies showed that ca. 81.1 % and 75.0 % DOX was released in 12 h from PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20 micelles under a reducing condition containing 10 mM dithiothreitol (DTT). In contrast, minimal DOX release (< 12 %) was observed for PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20 micelles under non-reducing conditions as well as for reduction-insensitive Gal-PEG-PCL and PEG-PCL/Gal20 micelles in the presence of 10 mM DTT. MTT assays in HeLa and HepG2 cells showed that DOX-loaded PEG-SS-PCL/Gal20 micelles exhibited apparent targetability and significantly enhanced anti-tumor efficacy toward asialoglycoprotein receptor (ASGP-R)-overexpressing HepG2 cells with a particularly low half maximal inhibitory concentration (IC50) of 1.58 mg DOX equiv./mL, which was comparable to free DOX and approximately 6 times lower than that for non-targeting PEG-SS-PCL counterparts under otherwise the same conditions. Interestingly, confocal microscopy observations using FITC-labeled PEG-SS-PCL/Gal20 micelles showed that DOX was efficiently delivered and released into the nuclei of HepG2 cells in 8 h. Flow cytometry revealed that cellular DOX level in HepG2 cells treated with DOX-loaded PEG-SS-PCL/Gal20 micelles was much greater than that with reduction-insensitive PEG-PCL/Gal20 and non-targeting PEG-SS-PCL controls, signifying the importance of combining shell-shedding and active targeting. Ligand-directed, reduction-sensitive, shell-sheddable, and biodegradable micelles have emerged as a versatile and potent platform for targeted cancer chemotherapy.
Taxanes are a key chemotherapy component for several malignancies, including metastatic breast cancer (MBC), ovarian cancer, and advanced non-small cell lung cancer (NSCLC). Despite the clinical benefit achieved with solvent-based (sb) taxanes, these agents can be associated with significant and severe toxicities. Albumin-bound paclitaxel (Abraxane; nab®-Paclitaxel), a novel solvent-free taxane, has demonstrated higher response rates and improved tolerability when compared with solvent-based formulations in patients with advanced MBC and NSCLC. The technology used to create nab-paclitaxel utilizes albumin to deliver paclitaxel, resulting in an advantageous pharmacokinetic (PK) profile. This review discusses the proposed mechanism of delivery of nab-paclitaxel, including an examination into a hypothesized greater ability to leverage albumin-based transport relative to sb-paclitaxel. An advantageous PK profile and the more efficient use of albumin-based transport may contribute to the preclinical finding that nab-paclitaxel achieves a 33% higher tumor uptake relative to sb-paclitaxel. Another possible contributing factor to the tumor accumulation of nab-paclitaxel is the binding of albumin to secreted protein acidic and rich in cysteine (SPARC), although the data supporting this relationship between SPARC and nab-paclitaxel remain largely correlative at this point. Recent data also suggest that nab-paclitaxel may enhance tumor accumulation of gemcitabine in pancreatic cancer treated with both agents. Additionally, a possible mechanistic synergy between nab-paclitaxel and capecitabine has been cited as the rationale to combine the two agents for MBC treatment. Thus, nab-paclitaxel appears to interact with tumors in a number of interesting, but not fully understood, ways. Continued preclinical and clinical research across a range of tumor types is warranted to answer the questions that remain on the mechanisms of delivery and antitumor activity of nab-paclitaxel.
This work is aimed at the development of a reduction-sensitive drug carrier for the delivery of the anti-cancer drug paclitaxel (PTX). N,N'-bis(acryloyl)cystamine (CBA) was reacted with ethanolamine (AEOL) via Michael addition to synthesize cationic poly(CBA-AEOL) (PCA) containing disulfide bonds. Subsequently, polycaprolactone (PCL) was grafted from PCA to form a novel reduction-sensitive copolymer (PCA-g-PCL). The PCA-g-PCL copolymer self-assembled as spherical micelles with a mean size of ca. 108nm. The disulfide bonds in the PCA-g-PCL copolymer contributed to the reduction-sensitivity of the micelles, observed as stepwise aggregation under simulated reduction conditions. To improve the stability of PCA-g-PCL micelles in aqueous media, carboxyl-terminated poly(ethylene glycol) methyl ether (mPEG-COOH) was conjugated with the PCA-g-PCL copolymer via electrostatic interaction to produce polyion complex micelles with a hydrophilic PEG surface. The in vitro release of PTX from the mPEG@PCA-g-PCL micelle showed a reduction sensitive profile, namely the rate of drug release strongly depended upon the concentration of the reducing agent. Leakage of PTX was limited to below 30% under normal conditions while almost all the drug was released in 9h under reduction conditions with 40mM DTT. In conclusion, the assembled mPEG@PCA-g-PCL micelle with reduction-sensitive controlled release shows great potential for improving the therapeutic effect of paclitaxel.
PEGylation is currently the gold-standard in shielding cationic DNA-polyplexes against non-specific interaction with blood components. However, it reduces cellular uptake and transfection, in what is known as the "PEG-dilemma". In an approach to solve this problem we developed hydroxyethyl starch (HES)-shielded polyplexes which get deshielded under the action of alpha amylase (AA). In this study, the effect of molar mass and degree of hydroxyethylation on the shielding and deshielding of the polyplexes as well as their in vivo performance were investigated. For this purpose, a battery of HES-polyethylenimine (PEI) conjugates was synthesized, and their rate and extent of biodegradation were investigated using asymmetric flow-field flow fractionation (AF4) and quartz-crystal microbalance with dissipation (QCM-D). Additionally, the transfection efficiency of the polyplexes was tested in Neuro2A cells and tumor-bearing mice. AF4 and QCM results show a rapid degradation for HES with lower degrees of hydroxyethylation. Meanwhile, in vitro transfection experiments showed a better shielding for higher HES molar masses, as well as deshielding with a significant boost in transfection upon addition of AA. Finally, in vivo experiments showed that the biodegradable HES markedly reduced the non-specific lung transcription of the polyplexes, but maintained gene expression in the tumor, contrary to the non-degradable HES and PEG controls, which reduced both tumor and lung expression. This study shows that by controlling the molecular characteristics of HES it is possible to engineer the shielding and deshielding properties of the polyplexes for more efficient gene delivery.
Redox and pH dual-responsive biodegradable micelles were developed based on poly(ethylene glycol)-SS-poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate) (PEG-SS-PTMBPEC) copolymer and investigated for intracellular doxorubicin (DOX) release. PEG-SS-PTMBPEC copolymer with an M(n) of 5.0-4.1 kg/mol formed micellar particles with an average diameter of 140 nm and a low polydispersity of 0.12. DOX was loaded into PEG-SS-PTMBPEC micelles with a decent drug loading content of 11.3 wt.%. The in vitro release studies showed that under physiological conditions only ca. 24.5 % DOX was released from DOX-loaded micelles in 21 h. The release of DOX was significantly accelerated at pH 5.0 or in the presence of 10 mM glutathione (GSH) at pH 7.4, in which 62.8 % and 74.3 % of DOX was released, respectively, in 21 h. The drug release was further boosted under 10 mM GSH and pH 5.0 conditions, with 94.2 % of DOX released in 10 h. Notably, DOX release was also facilitated by 2 or 4 h incubation at pH 5.0 and then at pH 7.4 with 10 mM GSH, which mimics the intracellular pathways of endocytosed micellar drugs. Confocal microscopy observation indicated that DOX was delivered and released into the nuclei of HeLa cells following 8 h incubation with DOX-loaded PEG-SS-PTMBPEC micelles, while DOX was mainly located in the cytoplasm for reduction-insensitive PEG-PTMBPEC controls. MTT assays revealed that DOX-loaded PEG-SS-PTMBPEC micelles had higher anti-tumor activity than reduction-insensitive controls, with low IC(50) of 0.75 and 0.60 μg/mL for HeLa and RAW 264.7 cells, respectively, following 48 h incubation. PEG-SS-PTMBPEC micelles displayed low cytotoxicity up to a concentration of 1.0 mg/mL. These redox and pH dual-bioresponsive degradable micelles have appeared as a promising platform for targeted intracellular anticancer drug release.
Drug delivery systems involve technology designed to maximize therapeutic efficacy of drugs by controlling their biodistribution profile. In order to optimize a function of the delivery systems, their biodistribution characteristics should be systematically understood. Pharmacokinetic analysis based on the clearance concepts provides quantitative information of the biodistribution, which can be related to physicochemical properties of the delivery system. Various delivery systems including macromolecular drug conjugates, chemically or genetically modified proteins, and particulate drug carriers have been designed and developed so far. In this article, we review physiological and pharmacokinetic implications of the delivery systems.
Block copolymer micelles are generally formed by self-assembly of amphiphilic copolymer molecules in an aqueous milieu. The hydrophobic blocks (or polyion complexes) form the micelle cores while the hydrophilic blocks form the micelle corona (or shells). Consequently, lipophilic drugs are solubilized in the hydrophobic micelle cores, which dramatically increases drug concentration in an aqueous environment. This offers new life to bioactive compounds abandoned due to low aqueous solubility. Polymeric micelles can be designed to avoid extravasation to normal tissues and recognition by the reticulo-endothelial system cells; this prolongs their circulation time after systemic injection. This in turn provides passive targeting to cancerous or inflamed tissues via the enhanced permeability and retention effect. Active tumor-targeting may be achieved by modifying the micelle surface with specific ligands to tumor cell receptors or creating “immunomicelles” by attaching monoclonal antibodies to specific antigens over-expressed on the cancerous cell surface. A different approach to active tumor targeting consists of developing stimuli-responsive micelles that release their drug load only in response to environmental or physical stimuli, such as the lower pH in tumor tissue, heat, sound, or light. Currently, a number of polymeric micelles are in various phases of pre-clinical and clinical development. Present paper reviews recent advances in the development of physical stimuli-responsive micelles with high targeting potentials and controlled on-demand drug release.
Many tumor cells specifically overexpress somatostatin receptors, in particular, subtype 2 (SSTR2). Lanreotide, a somatostatin analogue with high affinity for SSTR2, can be exploited as a ligand for tumor targeted therapy. In this study, lanreotide was first conjugated to poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) copolymer, and the active targeting micelles with paclitaxel (lanreotide-PM-PTX) or fluorescent agent were constructed and characterized with various analytical methods. Lanreotide-PM-PTX micelles were spherical in shape with a hydrodynamic diameter of 43.2 ± 0.4 nm, high drug encapsulation (87.1 ± 2.8%) and slow drug release rate. Two cancer cell lines (human lung cancer H446 and human breast cancer MCF-7 cells) with different expression levels of SSTR2 were used in this study. As observed by flow cytometry, confocal microscopy and cytotoxicity studies, lanreotide-encoded PEG-b-PCL micelles demonstrated more specific cell uptake and cytotoxicity in SSTR2-positive tumor cells via a receptor-mediated mechanism over the passive targeting micelles. The active targeting micelles showed higher accumulation in tumor tissue and tumor cells in tumor-bearing mice in vivo by near-infrared fluorescence (NIRF) imaging, high-performance liquid chromatography and confocal microscopy, respectively. Furthermore, treatment with lanreotide-PM-PTX micelles resulted in stronger tumor inhibition, increased life span and enhanced tumor cell apoptosis in SSTR2-overexpressing tumor model in athymic nude mice. The in vivo efficacy test with both H446 and MCF-7 tumor models further demonstrated the involvement of receptor-mediated interaction. Finally, the active targeting micelles exhibited less body weight loss, lower hemolysis and lower myelosuppression, as compared with the control groups. In conclusion, lanreotide can serve as an effective homing peptide, and the lanreotide-modified PEG-b-PCL micelles hold considerable promise in the treatment of SSTR2-overexpressing solid tumors.
The non-viral delivery of nucleic acids faces many extracellular and intracellular hurdles on the way from injection site to the site of action. Among these, aggregation in the blood stream and rapid elimination by the mononuclear phagocytic system (MPS) represent strong obstacles towards successful development of these promising therapeutic modalities. Even the state-of-the-art solutions using PEGylation show low transfection efficiency due to limited uptake and hindered endosomal escape. Engineering the carriers with sheddable coats reduces aggregation and phagocytosis due to the effective shielding, while the controlled deshielding at the desired site of action enhances the uptake and intracellular release. This work reports for the first time the use of hydroxyethyl starch (HES) for the controlled shielding/deshielding of polyplexes. HES, with different molar masses, was grafted to polyethylenimine (PEI) and characterized using (1)H NMR, colorimetric copper-assay, and SEC. HES-PEI conjugates were used to generate polyplexes with the luciferase-expressing plasmid DNA pCMVluc, and were characterized by DLS and zeta potential measurements. Deshielding was tested in vitro by zeta potential measurements and, erythrocyte aggregation assay upon addition of α-amylase (AA) to the HES-decorated particles. The addition of AA led to gradual increase in the zeta potential of the nanoparticles over 0.5 to 1h and to a higher aggregation tendency for erythrocytes due to the degradation of the HES-coat and exposure of the polyplexes' positive charge. In vitro transfection experiments were conducted in 2 cell-lines±AA in the culture medium. The amylase-treated HES-decorated complexes showed up to 2 orders of magnitude higher transfection levels compared to the untreated HES-shielded particles, while AA had no effect on the transfection of PEG-coated or uncoated polyplexes. Finally, flow cytometry showed that the addition of AA increased the amount of delivered DNA per cell for the HES-shielded polyplexes. This study shows that decorating nanoparticles with HES can be a promising tool for the controlled shielding/deshielding of polyplexes.
Introduction:
Docetaxel and paclitaxel are among the most active agents for the treatment of breast cancer. These first-generation taxanes are extremely hydrophobic; therefore, solvents are needed for its parenteral administration. Albumin nanoparticle technology allows for the transportation of such hydrophobic drugs without the need of potentially toxic solvents. Nab-paclitaxel can be administered without premedication, in a shorter infusion time and without the need for a special infusion set. Moreover, this technology allows the selective delivery of larger amounts of anticancer drug to tumors, by exploiting endogenous albumin pathways.
Areas covered:
An overview of the albumin nanoparticle technology, from a clinical perspective, is reported in this paper. The preclinical and clinical development of nab-paclitaxel is reviewed, in the context of available therapies for advanced breast cancer, with a focus on safety data. Preclinical and clinical data on the prognostic and predictive role of SPARC (secreted protein, acidic and rich in cysteine) are also reported.
Expert opinion:
Nab-paclitaxel is approved at present for the treatment of metastatic breast cancer, after the failure of first-line standard therapy, when anthracyclines are not indicated. Efficacy and safety data, along with a more convenient administration, confirm the potential for nab-paclitaxel to become a reference taxane in breast cancer treatment.
In order to realize the targeted delivery of paclitaxel (PTX) to tumor through an environment-sensitive mechanism, increase its solubility in water and reformulate without toxic excipients, a novel PTX conjugate, PEG-VC-PABC-PTX was designed and synthesized in this study, using p-aminobenzylcarbonyl (PABC), a spacer, and valine-citrulline (VC), a substrate of cathepsin B (C(B)), to link polyethylene glycol (PEG) and PTX. Pegylated PTX (PEG-PTX) which was synthesized and Taxol formulation were prepared as controls. The conjugates were purified and characterized by melting points, (1)H-NMR, ESI-MS or MALDI-TOF-MS. The two conjugates were similar in particle size, water solubility and their effects on MCF-7 cell line in vitro, and both of them induced no obvious toxicity in vivo. The release of PTX from PEG-PTX was faster due to its ester bond, while PEG-VC-PABC-PTX was proved to be C(B)-sensitive in terms of PTX release and its effect on cell cycle. Additionally, PEG-VC-PABC-PTX exhibited significant effects of antitumor, anti-angiogenesis and anti-proliferation in vivo, while the control conjugate was almost inefficacious at the same in vivo test. On the other hand, PTX conjugates demonstrated a thousand-time or more improvement in water solubility compared to PTX, suggesting a very easy way in the preparation and use of its injection. Without involvement of Cremophore EL and ethanol, the PTX conjugate will guarantee less adverse effects as frequently reported for Taxol formulation. Taxol formulation had a higher cytoxicity in vitro than PEG-VC-PABC-PTX likely because of toxic additives. Importantly, the C(B)-sensitive conjugate indicated a similar in vivo efficacy with the Taxol control, but much lower in vivo toxicity at the same doses evidenced by body weight, animal status, liver toxicity and blood count. Moreover, at the tolerant dose, this novel conjugate exhibited significantly better antitumor effect than that of Taxol formulation. In general, the PEG-VC-PABC-PTX conjugate designed in this study demonstrated significant advantages in terms of high water solubility, no toxic surfactant or organic solvent, tumor environment-sensitivity and high therapeutic index.
Polymer therapeutics have shown promise as tumor-targeted drug delivery systems in mice. The multivalency of polymers allows the attachment of different functional agents to a polymeric backbone, including chemotherapeutic and antiangiogenic drugs, as well as targeting moieties, such as the bone-targeting agent alendronate (ALN). We previously reported the conjugation of ALN and the chemotherapeutic drug paclitaxel (PTX) with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. The in vitro physicochemical properties, cancer cytotoxicity and antiangiogenic activity of HPMA copolymer-PTX-ALN conjugate were extensively characterized. The reported results warranted in vivo evaluations of the conjugate. In this manuscript, we evaluated the in vivo anticancer and antiangiogenic activity of HPMA copolymer-PTX-ALN conjugate. The conjugate exhibited an antiangiogenic effect by decreasing microvessel density (MVD), and inducing apoptotic circulating endothelial cells (CEC) following treatment of the mice. Using intravital imaging system and mCherry-labeled breast cancer cell lines, we were able to monitor noninvasively the progression of orthotopic metastatic tumors injected into the tibia of the mice. HPMA copolymer-PTX-ALN conjugate showed the greatest antitumor efficacy on mCherry-labeled 4T1 mammary adenocarcinoma inoculated into the tibia, as compared with PTX alone or in combination with ALN. Treatment with the bone-targeted polymeric conjugate demonstrated improved efficacy, was better tolerated, and was more easily administered intravenously than the clinically used PTX formulated in Cremophor/ethanol.
The past couple of years have witnessed a tremendous progress in the development of glutathione-responsive nano-vehicles for targeted intracellular drug and gene delivery, as driven by the facts that (i) many therapeutics (e.g. anti-cancer drugs, photosensitizers, and anti-oxidants) and biotherapeutics (e.g. peptide and protein drugs, and siRNA) exert therapeutical effects only inside cells like the cytosol and cell nucleus, and (ii) several intracellular compartments such as cytosol, mitochondria, and cell nucleus contain a high concentration of glutathione (GSH) tripeptides (about 2-10 mM), which is 100 to 1000 times higher than that in the extracellular fluids and circulation (about 2-20 μM). Glutathione has been recognized as an ideal and ubiquitous internal stimulus for rapid destabilization of nano-carriers inside cells to accomplish efficient intracellular drug release. In this paper, we will review recent results on GSH-responsive nano-vehicles in particular micelles, nanoparticles, capsules, polymersomes, nanogels, dendritic and macromolecular drug conjugates, and nano-sized nucleic acid complexes for controlled delivery of anti-cancer drugs (e.g. doxorubicin and paclitaxel), photosensitizers, anti-oxidants, peptides, protein drugs, and nucleic acids (e.g. DNA, siRNA, and antisense oligodeoxynucleotide). The unique disulfide chemistry has enabled novel and versatile designs of multifunctional delivery systems addressing both intracellular and extracellular barriers. We are convinced that GSH-responsive nano-carrier systems have enormous potential in targeted cancer therapy.
Gene and nucleic acid therapy are expected to play a major role in the next generation of medicine. We recently developed a multifunctional envelope-type nano device (MEND) for use as a novel non-viral gene delivery system. Poly(ethylene glycol) (PEG)ylation is a useful method for achieving a longer circulation time for delivery of the MEND to a tumour via the enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits cellular uptake and endosomal escape, which results in significant loss of activity for the delivery system. For successful gene delivery for cancer treatment, the crucial issue associated with the use of PEG, the 'PEG dilemma' must be addressed. In this review, we describe the development and applications of MEND, and discuss strategies for overcoming the PEG dilemma, based on the manipulation of intracellular trafficking of cellular uptake and endosomal release using functional devices such as specific ligands, cleavable PEG systems and endosomal fusogenic/disruptic peptides.
N-Acetyl-L-cysteine (NAC) is an antioxidant and anti-inflammatory agent with significant potential in clinical applications including stroke and neuroinflammation. The drug shows high plasma binding upon IV administration, requiring high doses and associated side effects. Through the use of an appropriate delivery vehicle, the stability and efficacy of NAC can be significantly improved. Dendrimers are an emerging class of nanoscale drug delivery vehicles, which enable high drug payloads and intracellular delivery. Poly(amidoamine) (PAMAM) dendrimer-NAC conjugates having cleavable disulfide linkages are designed for intracellular delivery based on glutathione levels. We have successfully synthesized two conjugates with a cationic G4-NH(2) and an anionic G3.5-COOH PAMAM dendrimer with NAC payloads of 16 and 18 per dendrimer, respectively, as confirmed by (1)H NMR and MALDI-TOF analysis. NAC release from the conjugates at intracellular and extracellular glutathione (GSH) concentrations were evaluated by reverse phase HPLC (RP-HPLC) analysis, and approximately 70% of NAC payload was released within one hour at intracellular GSH concentrations (approximately 10 mM), whereas negligible NAC release was observed at extracellular GSH levels (2 microM). FITC-labeled conjugates showed that they enter cells rapidly and localize in the cytoplasm of lipopolysaccharide (LPS)-activated microglial cells (the target cells in vivo). The significantly improved efficacies of dendrimer-NAC conjugates in activated microglial cells was confirmed by measuring the nitrite inhibition in the cell culture medium, which is an indication of the antioxidative property of the drug. Both G4-NH(2) and G3.5-COOH conjugates showed significantly better nitrite inhibition both at 24 and 72 h compared to free NAC, by as much as a factor of 16. The results indicate that PAMAM dendrimer conjugates produce higher local NAC concentration inside the cells, with GSH-sensitive disulfide linker enabling efficient and rapid cellular release of the drug.
The data show that a reasonable argument can be made for the conclusion that in the rapidly-metabolised species of HES, mono-substituted glucose residues are present in larger proportions, allowing catabolism mediated by alpha-amylase to be more predictable.
Although paclitaxel (TAXOL) appears to be one of the most promising antineoplastic agents of the last decade, with demonstrated activity in advanced and refractory ovarian, breast, lung, and head and neck cancers, most clinical oncologists have had little experience with the agent. This is largely the result of the initially limited supply of paclitaxel and other obstacles encountered during early clinical development that restricted the drug's availability to a few investigational centers. Although a high incidence of major hypersensitivity reactions due to the Cremophor EL vehicle used in formulation disrupted and almost terminated the clinical development of paclitaxel, hypersensitivity reactions are no longer a serious problem consequent to the advent of effective premedication regimens and longer administration schemes. Instead, neutropenia is the principal toxicity of paclitaxel. At clinically relevant doses, absolute neutrophil count nadirs are severely depressed in most patients. The duration of severe neutropenia, however, is usually brief; treatment delays for unresolved hematologic toxicity are rare, and absolute neutrophil count nadirs are constant with repetitive dosing, suggesting that neutropenia is not cumulative. Asymptomatic sinus bradycardia has occurred in up to 29% of patients in phase II trials, and other cardiac disturbances, including atrioventricular conduction and bundle branch blocks, ventricular tachycardia, and possible ischemic manifestations, have been reported in approximately 3% of patients. Cardiac disturbances have primarily been noted in studies that used cardiac monitoring to more effectively detect and manage major hypersensitivity reactions. Although sinus bradycardia and conduction blocks appear to represent true toxicities, ventricular tachycardia and ischemic manifestations, which have largely been observed in patients with preexisting cardiac disease, may not be due to paclitaxel. In view of the lack of clinical significance of the cardiac effects and their infrequent occurrence, cardiac monitoring during paclitaxel is not recommended for patients without cardiac risk factors. However, until precise risk factors can be defined, patients with a significant antecedent cardiac history are generally not considered to be good candidates for paclitaxel therapy. Neurotoxicity, characterized principally by peripheral neurosensory manifestations, has generally been of mild to moderate severity, even in heavily pretreated patients at paclitaxel doses < or = 200 mg/m2. However, some patients have developed a severe sensory-motor polyneuropathy at higher doses of paclitaxel (given as a single agent or in combination with cisplatin). Patients with an antecedent peripheral neuropathy or coexisting medical illnesses associated with peripheral neuropathy (such as diabetes mellitus and substantial prior alcohol use) appear to be especially prone to developing peripheral neuropathy.(ABSTRACT TRUNCATED AT 400 WORDS)
The plasma clearance of hydroxyethyl starch (HES) depends on the initial molecular weight and the degree of substitution. So far, little attention has been paid to the clinical relevance of the C2/C6 substitution ratio of hydroxyethyl starch.
10 patients with cerebrovascular circulatory disturbance received hemodilution therapy for 10 days, consisting of 10% HES 200/0.5 (mean molecular weight 200 kD, degree of substitution 0.5) with a C2/C6 ratio of 13.4. A second group of 10 patients received a starch solution with identical initial molecular weight and degree of substitution but with a C2/C6 ratio of 5.7.
After the administration of a single dose, no significant differences between the two groups were observed. After repeated administration, significant differences could be detected in hemorheology, coagulation and elimination (p<0.01). The larger C2/C6 ratio led to a higher intravascular mean molecular weight (95 vs. 84 kD), which in turn led to a higher increase in serum concentration during the therapy (14.7 vs.8.6 mg/ml). Hematocrit was lowered more (-30,5 vs. -23,5%) and plasma viscosity was increased more. There was also a more pronounced increase in partial thromboplastin time (+30% vs. +13%) and a factor of 2 larger decrease of factor VIII/von Willebrand factor-complex (p <0.01), which exceeded the dilution effect.
The higher C2/C6 ratio of HES 200/0.5/13.4 slows down enzymatic degradation. After repeated administration of this starch, large molecules accumulate which are inefficiently degraded. The same effect has been observed after therapy with highly-substituted HES. This accumulation of large molecules leads to a beneficial longer lasting volume effect. The disadvantages include an increase in plasma viscosity and coagulation disturbances, which cannot be explained with the respective dilution effect alone. For these reasons, the C2/C6 ratio is of clinical relevance and should be included in the product labeling in the future.
Hydroxyethyl starch (HES) is one of the most frequently used plasma substitutes. A variety of different HES solutions exist worldwide, which differ greatly in their pharmacological properties. HES is classified according to its manufactured or in vitro molecular weight (MW) into high MW (450-480 kDa), medium MW (200 kDa), and low MW (70 kDa) starch preparations. However, this is not sufficient, because as HES is metabolized in vivo, its MW changes, and it is the in vivo MW which is responsible for the therapeutic and adverse effects of each HES. The rate of metabolization depends mainly on the degree of hydroxyethyl substitution (ranging from 0.4 to 0.7), and the C2/C6 ratio of hydroxyethylation. A high degree of substitution and a high C2/C6 ratio lead to a slow metabolization of HES, resulting in a large in vivo MW. Slowly degradable high MW HES 450/0.7 and medium MW HES 200/0.62 have a high in vivo MW and are eliminated slowly via the kidneys. As a result, these starches have a relatively long-lasting volume effect. When infusing higher volumes (>1500 ml) are infused, large molecules accumulate in the plasma. This can result in bleeding complications due to decreased factor VIII/von Willebrand factor, platelet function defects, incorporation into fibrin clots, and an unfavorable effect on rheological parameters. Rapidly degradable medium MW HES 200/0.5 or low MW HES 70/0.5 are quickly split in vivo into smaller, more favorable molecule sizes, resulting in faster renal elimination, shorter volume effect, and fewer adverse effects on coagulation and rheological parameters. For historical and marketing reasons, only slowly degradable, high MW HES (480/0.7) is available in the United States. In Europe, a large variety of HES solutions are available, dominated by medium MW, easily degradable HES (200/0.5). Because of increasing international competition and the availability of newly developed starches, it is important to be aware of the pharmacological properties of HES and the advantages and disadvantages of the individual preparations.
The taxanes are anticancer cytotoxics that stabilise cellular microtubules. Two members, paclitaxel and docetaxel have substantial activity. One or both agents are widely accepted as evidence-based components of therapy for advanced breast, lung, and ovarian carcinomas. Paclitaxel has recently been approved in the USA for the adjuvant treatment of early stage node-positive breast carcinoma.