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The CD spectrum of various copolymers in aqueous solution (0.01 mg/mL). Abbreviations: CD, circular dichroism; PEG, poly(ethylene glycol); PLL, poly(levo-leucine); PRL, poly(racemic-leucine).
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In this work, racemic hybrid polypeptides poly(ethylene glycol) (PEG)-b-poly(racemic-leucine) (PRL) copolymers with different leucine residues have been synthesized and characterized. Using docetaxel as a model molecule, the high drug-loaded spherical micelles based on PEG-PRL were prepared successfully using dialysis, with a tunable particle size...
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... It is because the free drug is readily available to the system to exert its effects during a short incubation time. In contrast, the encapsulated drug molecules are released slowly into the system and require more time to show their full efficacy (Gu et al., 2012). Moreover, 5-FU@bi-MIL-88B-FC showed very low toxicity towards the FR-negative cell lines (HEK-293), demonstrating the potential of the synthesized DDS to be effectively applied for targeted drug delivery against FR-positive cancer cell lines ( Figure 7D). ...
Cancer has remained one of the leading causes of death worldwide, with a lack of effective treatment. The intrinsic shortcomings of conventional therapeutics regarding tumor specificity and non-specific toxicity prompt us to look for alternative therapeutics to mitigate these limitations. In this regard, we developed multifunctional bimetallic (FeCo) bi-MIL-88B-FC MOFs modified with folic acid—conjugated chitosan (FC) as drug delivery systems (DDS) for targeted delivery of 5-Fluorouracil (5-FU). The bi-MIL-88B nanocarriers were characterized through various techniques, including powder X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray, thermogravimetric analysis, and Fourier transform infrared spectroscopy. Interestingly, 5-FU@bi-MIL-88B-FC showed slower release of 5-FU due to a gated effect phenomenon endowed by FC surface coating compared to un-modified 5-FU@bi-MIL-88B. The pH-responsive drug release was observed, with 58% of the loaded 5-FU released in cancer cells mimicking pH (5.2) compared to only 24.9% released under physiological pH (5.4). The in vitro cytotoxicity and cellular internalization experiments revealed the superiority of 5-FU@bi-MIL-88B-FC as a highly potent targeted DDS against folate receptor (FR) positive SW480 cancer cells. Moreover, due to the presence of Fe and Co in the structure, bi-MIL-88B exhibited peroxidase-like activity for chemodynamic therapy. Based on the results, 5-FU@bi-MIL-88B-FC could serve as promising candidate for smart DDS by sustained drug release and selective targeting.
... However, this technique is highly time-consuming and expensive [59]. SEM is also used for the analysis of morphological characters [60]. ...
Polymeric micelles (PMs) have made significant progress in drug delivery applications. A robust core–shell structure, kinetic stability and the inherent ability to solubilize hydrophobic drugs are the highlights of PMs. This review presents the recent advances and understandings of PMs with a focus on the latest drug delivery applications. The types, methods of preparation and characterization of PMs are described along with their applications in oral, parenteral, transdermal, intranasal and other drug delivery systems. The applications of PMs for tumor-targeted delivery have been provided special attention. The safety, quality and stability of PMs in relation to drug delivery are also provided. In addition, advanced polymeric systems and special PMs are also reviewed. The in vitro and in vivo stability assessment of PMs and recent understandings in this area are provided. The patented PMs and clinical trials on PMs for drug delivery applications are considered indicators of their tremendous future applications. Overall, PMs can help overcome many unresolved issues in drug delivery.
... Alternatively, β2AR agonists can be conjugated with amino or carboxylic acid functional groups of copolymer [102]. The β2AR agonist loaded micelles can be prepared by the dialysis method (Fig 7) [103,104]. Briefly, β2AR ...
Introduction
α-synuclein (SNCA), a major component of Lewy body is a pathological hallmark of Parkinson’s disease (PD). Mutations in the SNCA gene cause misfolding and aggregation of SNCA protein, which results in neurodegeneration. Several studies have established the neuroprotective benefits of β2-adrenoreceptor (β2AR) agonists in PD However, β2AR agonists are associated with peripheral side effects- tachycardia, palpitation, pulmonary edema, myocardial ischemia, and cardiac arrhythmia due to βARactivation in peripheral tissues. PD therapy with β2AR agonists, therefore, warrants a brain-specific delivery.
Area covered
This review highlights the SNCA mediated neurodegenerative pathways in PD and also various treatment strategies under investigation to lower SNCA gene expression, primarily focusing on β2AR mediated pathway. The review also discusses the beneficial and side effects of β2AR agonists in PD treatment by reviewing clinical trials, epidemiological studies, and meta-analysis data. Here we depict the need to develop a novel drug delivery system to achieve brain-specific delivery of β2AR agonists to overcome peripheral side effects and also propose various nano delivery strategies to achieve the same.
Expert opinion
Brain targeted delivery of β2AR agonists via various nano delivery systems will help in the downregulation of SNCA gene expression in PD and also to overcome peripheral off-target side effects of β2AR agonists.
... The polymer syntheses were adapted from literature. 32,33 Details of the synthesis can be found in the supporting information. ...
We studied the assembly of nanoparticles with oppositely charged linear and periodic copolymers (CPs), alternating ionic and polar sequences, in the dilute range of polymer concentration. For the first time, we considered CPs displaying a contour length much higher than the AuNP perimeter. We assumed that such CPs will enable to collect a finite number of NPs into linear nanostructures with a gain of colloidal stability and a better structural control compared to electrostatic complexes obtained with homo polyelectrolytes. As a case study, we synthesized anionic gold nanoparticles (AuNPs) and CPs consisting of alternated cationic poly-L-lysine (PLL) blocks and polar sequences of poly(ethyleneglycol) (PEG). We showed that complexation of AuNPs with CPs is quite similar to that observed with homo PLL. In that respect, finite size nanometric clusters, of less than 30 NPs, outside the electro neutrality domain and a fast phase separation occurs at the electro neutrality. Nevertheless, the presence of PEG blocks allowed us to highlight some specific effects. First, the global charge of the positively charged clusters was found to be always lower for CP based clusters than for homo PLL with a dependence of the charge with the number and the mass of the PEG blocks. Second, in spite of this effect which should have promoted the formation of dense structure, the fractal dimension characterizing the structure of the clusters in bulk was found to be always below 1.8. Finally, we showed that PEG blocks influence the interparticle distance by disfavoring plasmon delocalization when the clusters are dispersed in water and collapse around the nanoparticles when the clusters are deposited on substrate.
... DTX has some limitations including insignificant oral delivery (< 5% in mice), low permeability, poor water-solublity (4.93 μg mL −1 ), undergoing hepatic first pass effect and P-glycoprotein (P-gp) efflux [29,30]. Recently, a commercial injection form (Tax-otere®) in which the drug is dissolved in a Tween 80/ethanol mixture, and nanocarriers including nanoparticles of poly(methyl methacrylate) core-thiolated chitosan shell [31], polymeric micelles of poly(ethylene glycol)-block-poly(amino acids) hybrid poly(peptides) [32], nanoparticles of H40-poly(lactide)-block-d-α-tocopheryl poly(ethylene glycol) 1000 succinate [33] and hyaluronic acid-coated cholesteryl hemisuccinate vesicles [34] have been reported for DTX. However, some of these formulations can lead to several adverse effects due to the drug itself or their solvent systems [35]. ...
A self-nanoemulsifying drug delivery system (SNEDDS) was developed as a novel route to enhance the efficacy of docetaxel lipophilic drug. SNEDDS comprised ethyl oleate, Tween 80 and poly(ethylene glycol) 600, as oil, surfactant and co-surfactant, and formed stabilized monodispersed oil nanodroplets upon dilution in water. SNEDDS represented encapsulation efficiency and loading capacity of 21.4 and 52.7%, respectively. The docetaxel release profile from the drug-loaded SNEDDS was recorded, its effectiveness against MCF-7 cell line was investigated, and an IC50 value of 0.98 ± 0.05 μg mL⁻¹ was attained. The drug-loaded SNEDDS was administrated in rats, and the pharmacokinetic parameters of maximum concentration of 22.2 ± 0.8 μg mL⁻¹, time to attain this maximum concentration of 230 min, and area under the curve of 1.71 ± 0.18 μg min mL⁻¹ were obtained. The developed SNEDDS formulation can be represented as an alternative to docetaxel administration.
... Moreover, we can also hypothesize that H-bonding between exposed amide groups of the disordered polypeptide chains and drug molecules in the core of PEG-P(D,L-Leu) micelles would favor micellar drug solubilization in addition to other interaction forces. Our observations are in accordance with the behavior of micellar carriers with conformationally rigid hydrophobic P(L-Leu) segments in the cores where decreased cargo loading was observed [2,19,50]. Drug release data from PEG-P(D,L-Leu)/m showed that the individual drug release rates practically did not change for binary drug formulations compared to the single drug-loaded micelles: over 90% of drugs were released within 24 h at physiological pH, both in the presence as well as absence of FBS (Fig. S5). We next utilized an indirect approach to determine whether encapsulation of drug combination into the micelles decreases premature release of loaded drugs in whole blood by the erythrocyte vs. buffer or plasma partitioning method [26]. ...
... When BT-474 cells were treated with drug combination at a 17-AAG/PTX ratio of 4:1 in vitro, it was found that there was only 10-fold reduction in the IC 50 of PTX in combination as opposed to the 1000-fold reduction seen when the cells were treated with drugs at a 2:1 ratio and this was also reflected in less pronounced synergistic activity of drug combination (the CI value at IC 50 increased from 0.09 to 0.5, Table 5 and Table S5). This further reinforces the importance of spatial-temporal Table 5 Comparison of IC 50 synchronization of delivery of the drugs at a defined ratio to retain synergy of action, as was reported in our previous work [53] Animals treated with (17-AAG + PTX)/m had the longest survival times, with only 2 out of 7 animals reaching the point of termination in the span of 85 days (Fig. 2C). On the other hand, median survival for animals treated with the 17-AAG/m + PTX/m cocktail (48 days) was only slightly better than free PTX group (42 days) or the untreated control (40 days). ...
... IC50 values were calculated with respect to 17-AAG and represent mean ± SD of at least three independent experiments. Combination of 17-AAG and PTX was examined at a 2:1 w/w ratio. ...
... Regardless of their size, the loaded micelles exhibited similar release behavior, with a sustained drug release over up to 72 h, and were more active than the free drug toward MCF-7 human breast cancer cells. 428 Polymeric micellar particles loaded with PTX were formed in an aqueous medium by facilitating the self-association of amphiphilic block copolymers having hydrophilic PEG segments and modified polyaspartate hydrophobic segments in which one-half of the carboxylic groups were esterified with 4phenyl-1-butanol. PTX was incorporated into the inner core of the micelle system by physical entrapment through hydrophobic interactions between the drug and the specially designed hydrophobic block. ...
Targeted delivery combined with controlled drug release has a pivotal role in the future of personalized medicine. This review covers the principles, advantages, and drawbacks of passive and active targeting based on various polymer and magnetic iron oxide nanoparticle carriers with drug attached by both covalent and noncovalent pathways. Attention is devoted to the tailored conjugation of targeting ligands (e.g., enzymes, antibodies, peptides) to drug carrier systems. Similarly, the approaches toward controlled drug release are discussed. Various polymer-drug conjugates based, for example, on polyethylene glycol (PEG), N-(2-hydroxypropyl)methacrylamide (HPMA), polymeric micelles, and nanoparticle carriers are explored with respect to absorption, distribution, metabolism, and excretion (ADME scheme) of administrated drug. Design and structure of superparamagnetic iron oxide nanoparticles (SPION) and condensed magnetic clusters are classified according to the mechanism of noncovalent drug loading involving hydrophobic and electrostatic interactions, coordination chemistry, and encapsulation in porous materials. Principles of covalent conjugation of drugs with SPIONs including thermo- and pH-degradable bonds, amide linkage, redox-cleavable bonds, and enzymatically-cleavable bonds are also thoroughly described. Finally, results of clinical trials obtained with polymeric and magnetic carriers are analyzed highlighting the potential advantages and future directions in targeted anticancer therapy.
... The formulation containing Tween 80 exhibited one potential deficiency with respect to physical instability and toxicity of the vehicle. 16 Therefore, in the current study, the novel X-shaped reduction-sensitive block copolymer (PLGA) 2 -SS-4-arm-PEG 2000 was designed, which was expected to afford nanomicelles better micellar stability as well as possessing greater potential for improving the therapeutic efficacy of DTX. synthesis of (Plga) 2 -ss-4-arm-Peg 2000 ...
... Xiao and Wang structural difference between the synthesized polymers and the standards, they could be used to verify the absence of polymer impurity as well as to evaluate the molecular weight distribution of the polymers. 16 ...
To study the effects of X-shaped amphiphilic block copolymers on delivery of docetaxel (DTX) and the reduction-sensitive property on drug release, a novel reduction-sensitive amphiphilic copolymer, (PLGA)2-SS-4-arm-PEG2000 with a Gemini-like X-shape, was successfully synthesized. The formation of nanomicelles was proved with respect to the blue shift of the emission fluorescence as well as the fluorescent intensity increase of coumarin 6-loaded particles. The X-shaped polymers exhibited a smaller critical micelle concentration value and possessed higher micellar stability in comparison with those of linear ones. The size of X-shaped (PLGA)2-SS-4-arm-PEG2000 polymer nanomicelles (XNMs) was much smaller than that of nanomicelles prepared with linear polymers. The reduction sensitivity of polymers was confirmed by the increase of micellar sizes as well as the in vitro drug release profile of DTX-loaded XNMs (DTX/XNMs). Cytotoxicity assays in vitro revealed that the blank XNMs were nontoxic against A2780 cells up to a concentration of 50 µg/mL, displaying good biocompatibility. DTX/XNMs were more toxic against A2780 cells than other formulations in both dose- and time-dependent manners. Cellular uptake assay displayed a higher intracellular drug delivery efficiency of XNMs than that of nanomicelles prepared with linear polymers. Besides, the promotion of tubulin polymerization induced by DTX was visualized by immunofluorescence analysis, and the acceleration of apoptotic process against A2780 cells was also imaged using a fluorescent staining method. Therefore, this X-shaped reduction-sensitive (PLGA)2-SS-4-arm-PEG2000 copolymer could effectively improve the micellar stability and significantly enhance the therapeutic efficacy of DTX by increasing the cellular uptake and selectively accelerating the drug release inside cancer cells.
... Self-assembled polymeric micelles with core/shell structures enable the system to incorporate poorly water-soluble drugs in the hydrophobic core and protect them from degradation in physiological media [6]. For example, the hydrophobic core of the micelles composed of PCL-PEG offers a reservoir for the incorporation of drugs, while the pegylated shell along with its nanoscopic size guarantees the carrier remain un-recognized by the reticuloendothelial system and undergo a long-circulation period in the blood [7,8,9]. ...
In this content, a small molecular ligand of prostate specific membrane antigen (SMLP) conjugated poly (caprolactone) (PCL)-b-poly (ethylene glycol) (PEG) copolymers with different block lengths were synthesized to construct a satisfactory drug delivery system. Four different docetaxel-loaded polymeric micelles (DTX-PMs) were prepared by dialysis with particle sizes less than 60 nm as characterized by dynamic light scattering (DLS) and transmission electron microscope (TEM). Optimization of the prepared micelles was conducted based on short-term stability and drug-loading content. The results showed that optimized systems were able to remain stable over 7 days. Compared with Taxotere, DTX-PMs with the same ratio of hydrophilic/hydrophobic chain length displayed similar sustained release behaviors. The cytotoxicity of the optimized targeted DTX-PCL12K-PEG5K-SMLP micelles (DTX-PMs2) and non-targeted DTX-PCL12K-mPEG5K micelles (DTX-PMs1) were evaluated by MTT assays using prostate specific membrane antigen (PSMA) positive prostate adenocarcinoma cells (LNCaP). The results showed that the targeted micelles had a much lower IC50 than their non-targeted counterparts (48 h: 0.87±0.27 vs 13.48±1.03 µg/ml; 72 h: 0.02±0.008 vs 1.35±0.54 µg/ml). In vitro cellular uptake of PMs2 showed 5-fold higher fluorescence intensity than that of PMs1 after 4 h incubation. According to these results, the novel nano-sized drug delivery system based on DTX-PCL-PEG-SMLP offers great promise for the treatment of prostatic cancer.
... To decrease or eliminate the serious side-effects during chemotherapy, various polymeric nanoparticles, including micelles [10] [11] [12], vesicles [13] [14] [15] [16], nanogels [17] [18] [19] and dendrimers [20] [21], amongst others, are employed for controlled delivery of SMW antitumor drugs. The polymer-based nanovehicles offer significant advantages for smart drug delivery: (i) tremendous diversity of polymer matrices, (ii) convenient surface modification, (iii) high drug-loading efficiency, (iv) excellent stability and long half-life in the circulatory system, (v) increased accumulation in the lesion location, (vi) tunable polymer degradation for temporal control over drug release, (vii) ameliorated drug bioavailability and efficacy, and so on [22] [23] [24]. ...
... These adopt the regular secondary conformations (i.e., a-helix and b-fold) that serve as an additional factor to direct and enhance the formation of nanoparticles [36]. As a necessary complement, the racemic polypeptides with equal proportions of levorotatory and dextrorotatory amino acids have also been revealed to possess many unique characteristics (e.g., improved solubility and drug-loading capacity) as a benefit of the flexible polypeptide chains [11] [37] [38]. ...
Two kinds of triblock poly(ethylene glycol)-polyleucine (PEG-PLeu) copolymers were synthesized through the ring-opening polymerization of L-Leu N-carboxyanhydride (NCA), or equivalent D-Leu NCA and L-Leu NCA with amino-terminated PEG as a macroinitiator. The amphiphilic copolymers spontaneously self-assembled into spherical micellar aggregations in aqueous environment. The micelle with racemic polypeptide core exhibited smaller critical micelle concentration and diameter compared to those with levorotatory polypeptide core. A model anthracycline antineoplastic agent, i.e., doxorubicin (DOX), was loaded into micelles through nanoprecipitation, and PEG-P(D,L-Leu) micelle exhibited higher drug loading efficacy than that with P(L-Leu) core attributed to its flexible and compact core. The sustained in vitro DOX release from micelles with both levorotatory and racemic polypeptide cores was observed, and the DOX-loaded PEG-P(D,L-Leu) micelle exhibited slower release rate. More interestingly, DOX-loaded micelles exhibited chirality-mediated antitumor efficacy in vitro and in vivo, which are all better than that of free DOX. Furthermore, both enhanced tumor inhibition and excellent security in vivo were confirmed by histopathological or in situ cell apoptosis analyses. Therefore, DOX-loaded PEG-PLeu micelles appeared to be an interesting nanoscale polymeric formulation for promising malignancy chemotherapy.
