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Alkaline phosphatase-triggered assembly of etoposide enhances its anticancer effect
Abstract
Etoposide is a cancer-targeting drug but an overdose of etoposide leads to immunosuppression of a patient. Therefore, development of new strategy to enhance its anticancer effect while in the meantime alleviate its adverse effect is important but challenging. In this work, with the assistance of a hydrogelator precursor Nap-Phe-Phe-Tyr(H2PO3)-OH (1P), etoposide phosphate (EP) was subjected to alkaline phosphatase (ALP)-triggered assembly which obviously enhanced its anticancer efficacy in vitro and in vivo. In vitro tests indicated that assembly of EP with 1P resulted in slow release of etoposide and long-term inhibitory effect on HeLa cells. In vivo experiments indicated that, compared with those of EP-treated mice, the tumor growth of the EP + 1P-treated mice was further inhibited while their body weight loss was alleviated. We envision that our hydrogelator-assisted assembly strategy could be applied to enhance the therapeutic effects of more drugs while in the meantime alleviate their adverse effects in the future.
... Target specific delivery 8 or site-specific delivery can be alternative to avoid the toxicity of the drug. Consequently, the site specific delivery of MP is the key factor for its effective clinical use 6 In recent decades the supramolecular hydrogels have been in practice due to their wide spread biomedical applications such as drug delivery, [9][10][11] wound healing, 12 cell fate control, 13 metal ion absorption, 14 tissue engineering, 15 biomarker sensing, 16 functional materials design, 17 etc. The supramolecular hydrogel obtained by enzyme-instructed self-assembly (EISA) are biocompatible hence, it is an ideal candidate for drug delivery. ...
... 23 Hydrogels are consisted of hydrophilic 3D networks which are comprised of peptides or polymers assembled together through ionic bond, covalent bond, or hydrogen bonding. 11,24 The physical entrapment of MP in hydrogels could sustain the drug release and thus could reduce the toxicity associated with its high dose. 1P was successfully synthesized which could dephosphorylate in presence of ALP and converts to 1. 1P + MP were developed for the site-specific delivery in SCI which has the ability to sustain the drug release. ...
... After in-vivo administration of 1P + MP solution in a SCI rat model, the MP + 1P changes to the gel due to dephosphorylation of the MP + 1P in presence of ALP present in the cells. 11 The gel then slowly releases the drug at the site, consequently a significant reduction in the proinflammatory cytokines (TNF-α and IL-1β) level was observed as comparison to the other groups including the free MP and control group rats. These results could be clearly attributed to the availability of MP at the specific site. ...
Methylprednisolone sodium phosphate (MP) is an anti-inflammatory corticosteroid which is used in the treatment of spinal cord injury (SCI), however the overdose of MP has toxic effects Therefore it is prerequisite to develop novel approaches to overcome the side effects of MP and enhance its efficacy. In the present work, we have developed alkaline phosphatase (ALP) trigger self-assembly system of oligopeptides to physically entrap and locally deliver MP. The synthesis of Nap-Phe-Phe-Tyr(H2PO3)-OH (1P) was achieved using solid phase peptide synthesis and was characterized using mass spectroscopy. The 1P is a hydrogelator, which in presence of ALP self-assembles to form the hydrogel. During the self-assembly of 1P, MP was physically entrapped without losing the physical strength of hydrogel as revealed in the rheology study. The consistency of this hydrogel and the structure was characterized using circular dichroism. The MP was released from the hydrogel in a sustain manner and 80% of the drug release was observed at 120 h. The MP + 1P were non-toxic to the cells at lower concentration however toxicity increases with the increase in concentration of MP. Further, the in-vivo administration of MP + 1P significantly reduces the pro-inflammatory cytokines and the histological analysis revealed improvement in the SCI. In conclusion, it could be stated that the synthesis of 1P for the delivery of MP provides the novel opportunity in for the treatment of SCI.
... Hydrogels are cross-linked polymeric networks that contain high water content. They can be natural or synthetic in origin and have been used in numerous applications including tissue engineering, immune protection, and drug and cell delivery [82]. The mechanical and structural properties of native tissues can be mimicked by hydrogels [83,84]. ...
Volumetric muscle loss (VML) is defined as a condition in which a large volume of skeletal muscle is lost due to physical insult. VML often results in a heightened immune response, resulting in significant long-term functional impairment. Estimates indicate that ~250,000 fractures occur in the US alone that involve VML. Currently, there is no active treatment to fully recover or repair muscle loss in VML patients. The health economics burden due to VML is rapidly increasing around the world. Immunologists, developmental biologists, and muscle pathophysiologists are exploring both immune responses and biomaterials to meet this challenging situation. The inflammatory response in muscle injury involves a non-specific inflammatory response at the injured site that is coordination between the immune system, especially macrophages and muscle. The potential role of biomaterials in the regenerative process of skeletal muscle injury is currently an important topic. To this end, cell therapy holds great promise for the regeneration of damaged muscle following VML. However, the delivery of cells into the injured muscle site poses a major challenge as it might cause an adverse immune response or inflammation. To overcome this obstacle, in recent years various biomaterials with diverse physical and chemical nature have been developed and verified for the treatment of various muscle injuries. These biomaterials, with desired tunable physicochemical properties, can be used in combination with stem cells and growth factors to repair VML. In the current review, we focus on how various immune cells, in conjunction with biomaterials, can be used to promote muscle regeneration and, most importantly, suppress VML pathology.
... Podophyllotoxin (Figure 2c) is an anticancer drug employed as a precursor in the biosynthesis of cytotoxic bioactive compounds including etopophose phosphate, teniposide, and etoposide (Ardalani et al. 2017). Teniposide and etoposide are being utilised in various cancer such as lung cancer, testicular cancer, and other types of leukaemia's and solid tumours (Gupta RS et al. 1987;Kiran et al. 2018). Podophyllotoxin is broadly distributed among plant genera including Podophyllum, Dysosma, Diphylleia, and Juniperus (Li J et al. 2013). ...
Endophytes are a potent source of bioactive compounds that mimic plant-based metabolites. The relationship of host plant and endophyte is significantly associated with alteration in fungal colonisation and the extraction of endophyte-derived bioactive compounds. Screening of fungal endophytes and their relationship with host plants is essential for the isolation of bioactive compounds. Numerous bioactive compounds with antioxidant, antimicrobial, anticancer, and immunomodulatory properties are known to be derived from fungal endophytes. Bioinformatics tools along with the latest techniques such as metabolomics, next-generation sequencing, and metagenomics multilocus sequence typing can potentially fill the gaps in fungal endophyte research. The current review article focuses on bioactive compounds derived from plant-associated fungal endophytes and their pharmacological importance. We conclude with the challenges and opportunities in the research area of fungal endophytes.
... Intracellular ALP-responsive co-assembly of dexamethasone (Dex) phosphate and a hydrogelator precursor Nap-Phe-Phe-Tyr(H2PO3)-OH boosts the anti-inflammation efficacy of Dex, as shown by Tang et al. (2017). They also reported similar efficacy enhancement when Dex is covalently conjugated to a homotypic precursor (Tang et al., 2018), or replaced by other drugs like etoposide (Kiran et al., 2018). ...
Unlike conventional materials that covalent bonds connecting atoms as the major force to hold the materials together , supramolecular biomaterials rely on noncovalent intermolecular interactions to assemble. The reversibility and biocompatibility of supramolecular biomaterials render them with diverse range of functions and lead to rapid development in the past two decades. This review focuses on the noncovalent and enzymatic control of supramo-lecular biomaterials, with the introduction to various triggering mechanism to initiate self-assembly. Representative applications of supramolecular biomaterials are highlighted in four categories: tissue engineering, cancer therapy , drug delivery, and molecular imaging. By introducing various applications, we intend to show enzymatic control and noncovalent interactions as a powerful tool for achieving spatiotemporal control of biomaterials both in vitro and in vivo for biomedicine.
... 17 Moreover, EISA has demonstrated the unique advantage of overcoming drug-resistance issues, 18 which makes it an emerging anticancer strategy. 14,19 Nevertheless, thus far, most of the established EISA approaches share a common strategy in which the enzyme converts hydrophilic precursors to hydrophobic assembly building blocks (e.g., phosphatases catalyzed dephosphorylation) 13,20 and initiates the subsequent self-assembly in situ. As the inverse process of dephosphorylation, the phosphorylation that is naturally mediated by kinase usually induces the disassembly process. ...
Protein kinases, the main regulators of a vast map of cellular processes, are the most attractive targets in drug discovery. Despite a few successful examples of protein kinase inhibitors, the drug discovery strategy of downregulating protein kinase activity has been quite limited and often fail even on animal models. Here, we utilize protein kinase A (PKA) activity to design PKA-triggered supramolecular assemblies with anticancer activities. Grafting a suitable peptide to PNIPAM raises the critical temperature of the LCST polymer above body temperature. Interestingly, the corresponding phosphorylated polymer has a critical temperature below body temperature, making this peptide-appended PNIPAM a suitable polymer for the PKA-triggered supramolecular assembly process. PKA-triggered assembly occurs selectively in PKA-upregulated MCF-7 cells, which disturbs the cytoskeleton and sensitize cancer cells against doxorubicin. The chemosensitization is also observed in vivo to identify effective tumor inhibitors with satisfactory biocompatibility. Overall, this phosphorylation-induced (in principle, PKA-catalyzed) supramolecular assembly opens up a promising chemotherapy strategy for combating kinase-upregulated cancer.
... The successful examples that have been reported now primarily rely on using a single trigger to control the formation of the nanomaterials in situ. For example, nanofibers have been selectively formed in different kinds of cancer cells by the overexpression of enzymes, including alkaline phosphatase (ALP), matrix metalloproteinase (MMP), transglutaminase, and cathepsin B [21][22][23][24][25][26][27][28][29][30][31][32]. The combination of two or more triggers to form nanomaterials in situ may provide for more sophisticated means of control and manipulation, but this strategy has been reported only rarely [13,33]. ...
The selective formation of nanomaterials in cancer cells and tumors holds great promise for cancer diagnostics and therapy. Until now, most strategies rely on a single trigger to control the formation of nanomaterials in situ . The combination of two or more triggers may provide for more sophisticated means of manipulation. In this study, we rationally designed a molecule ( Comp. 1 ) capable of responding to two enzymes, alkaline phosphatase (ALP), and reductase. Since the A549 lung cancer cell line showed elevated levels of extracellular ALP and intracellular reductase, we demonstrated that Comp. 1 responded in a stepwise fashion to those two enzymes and displayed a tandem molecular self-assembly behavior. The selective formation of nanofibers in the mitochondria of the lung cancer cells led to the disruption of the mitochondrial membrane, resulting in an increased level of reactive oxygen species (ROS) and the release of cytochrome C (Cyt C). ROS can react with proteins, resulting in endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). This severe ER stress led to disruption of the ER, formation of vacuoles, and ultimately, apoptosis of the A549 cells. Therefore, Comp. 1 could selectively inhibit lung cancer cells in vitro and A549 xenograft tumors in vivo . Our study provides a novel strategy for the selective formation of nanomaterials in lung cancer cells, which is powerful and promising for the diagnosis and treatment of lung cancer.
... The slow release of etoposide from the coassembled hydrogelator resulted in enhanced antitumor effects without any observable adverse effects. 130 ALP triggered the coassembly structural conversion from micelles to NFs of ICG and NapFFKYp paved the way to enrich the application of ICG for fluorescence/photoacoustic imaging and PTT, confirming the possibility of achieving personalized medicine by endogenous stimuli-instructed construction of nanostructures. 131 In fact, peptide-based coassembly drug delivery strategy also showed considerable promise in delivering vaccines, proteins, antibodies, and other biological macromolecular drugs. ...
Self-assembling peptide-based nanodrug delivery systems (NDDs), consisting of naturally occurring amino acids, not only share the advantages by traditional nanomedicine, but also possess the unique properties of excellent biocompatibility, biodegradability, flexible responsiveness, specific biological function and synthetic feasibility. Physical methods, enzyme reaction, chemical reaction and biosurface-induction are able to obtain versatile peptide-based NDDs, which mainly benefits by the flexible responsiveness. Different functional peptides and abundant covalent modifications endowed this system with precise controllability and multi-functionality. Inspired by above merits, researchers have taken advantage of self-assembling peptide-based NDDs and achieved accurate delivery of drugs to the lesion site. The present review outlines the methods designing self-assembling peptide-based NDDs for small molecule drugs, with an emphasis on the different drug delivery strategies and their applications in using peptides and peptide conjugates.
Alkaline Phosphatase (ALP) is known as one of the most crucial members of phosphatase family and encompasses the enormous ability to hydrolyze the phosphate group in various biomolecules, by this,...
Tumours, with increasing mortality around the world, have bothered human beings for decades. Enhancing the targeting of antitumor drugs to tumour tissues is the key to enhancing their antitumor effects. The tumour microenvironment is characterised by a relatively low pH, overexpression of certain enzymes, redox imbalance, etc. Therefore, smart drug delivery systems that respond to the tumour microenvironment have been proposed to selectively release antitumor drugs. Among them, peptide hydrogels as a local drug delivery system have received much attention due to advantages such as high biocompatibility, degradability and high water-absorbing capacity. The combination of peptide segments with different physiological functions allows for tumour targeting, self-aggregation, responsiveness, etc. Morphological and microstructural changes in peptide hydrogels can occur when utilising the inherent pathological microenvironment of tumours to trigger drug release, which endows such systems with limited adverse effects and improved therapeutic efficiency. Herein, this review outlined the driving forces, impact factors, and sequence design in peptide hydrogels. We also discussed the triggers to induce the transformation of peptide-based hydrogels in the tumour microenvironment and described the advancements of peptide-based hydrogels for local drug delivery in tumour treatment. Finally, we gave a brief perspective on the prospects and challenges in this field.
Radiotherapy (RT) can produce a vaccine effect and remodel a tumor microenvironment (TME) by inducing immunogenic cell death (ICD) and inflammation in tumors. However, RT alone is insufficient to elicit a systemic antitumor immune response owing to limited antigen presentation, immunosuppressive microenvironment, and chronic inflammation within the tumor. Here, a novel strategy is reported for the generation of in situ peptide‐based nanovaccines via enzyme‐induced self‐assembly (EISA) in tandem with ICD. As ICD progresses, the peptide Fbp‐GDFDFDpY (Fbp‐pY), dephosphorylated by alkaline phosphatase (ALP) forms a fibrous nanostructure around the tumor cells, resulting in the capture and encapsulation of the autologous antigens produced by radiation. Utilizing the adjuvant and controlled‐release advantages of self‐assembling peptides, this nanofiber vaccine effectively increases antigen accumulation in the lymph nodes and cross‐presentation by antigen‐presenting cells (APCs). In addition, the inhibition of cyclooxygenase 2 (COX–2) expression by the nanofibers promotes the repolarization of M2‐macrophages into M1 and reduces the number of regulatory T cells (Tregs) and myeloid‐derived suppressor cells (MDSCs) required for TME remodeling. As a result, the combination of nanovaccines and RT significantly enhances the therapeutic effect on 4T1 tumors compared with RT alone, suggesting a promising treatment strategy for tumor radioimmunotherapy.
The manipulation of the flexibility/rigidity of polymeric chains to control their function is commonly observed in natural macromolecules but largely unexplored in synthetic systems. Herein, we construct a series of protein-mimetic nano-switches consisting of a gold nanoparticle (GNP) core, a synthetic polypeptide linker, and an optically functional molecule (OFM), whose biological function can be dynamically regulated by the flexibility of the polypeptide linker. At the dormant state, the polypeptide adopts a flexible, random-coiled conformation, bringing GNP and OFM in close proximity that leads to the "turn-off" of the OFM. Once treated with alkaline phosphatase (ALP), the nano-switches are activated due to the increased separation distance between GNP and OFM driven by the coil-to-helix and flexible-to-rigid transition of the polypeptide linker. The nano-switches therefore enable selective fluorescence imaging or photodynamic therapy in response to ALP overproduced by tumor cells. The control over polymer flexibility represents an effective strategy to manipulate the optical activity of nano-switches, which mimics the delicate structure-property relationship of natural proteins.
Highly water-soluble small molecule-based prodrugs (5-FUPD and SAHAPD) are formulated. They comprise a phosphate group to lock the active drug payload (5-fluorouracil and SAHA) along with a turn-on fluorophore consisting of a glutathione (GSH) depletory feature. Installation of the phosphate group along with purification of final product has been accomplished in an operationally facile manner. Activation of the prodrugs is facilitated by alkaline phosphatase (ALP)-mediated hydrolysis of the phosphate group followed by 1,8-elimination. The prodrugs were found to be highly effective against ALP flared human cervical cancer (HeLa) and liver cancer (HepG2) cell lines. Most notably, they were found to be innocuous to normal liver cells (WRL-68).
Cancer is the second leading cause of death all around the world. The natural compounds derived from the endophytic flora of fungi are possible solutions to cancer treatment because they are safe for health, cost-effective, biocompatible and have fewer toxicity issues. The active ingredients in endophytic fungi that are responsible for anti-cancer activities are alkaloids, terpenoids, glycosides, saponin, peptides, steroids, phenols, quinones, and flavonoids. This review highlights the anti-cancer activities of entophytic fungus against human papillary thyroid carcinoma (IHH4), human pancreatic (PANC-1), ovarian (OVCAR-3), hepatic (HepG2), lung (A-549), human lymphoma (U937), human skin carcinoma (A431), breast (MCF-7), and Kaposi's sarcoma. The emerging evidence suggested that bioactive compounds isolated from endophytic fungi showed their anti-cancer activities by revealing the disturbance of the microtubule network caused by increased levels of Bax and Bcl-2 proteins that triggers cell cycle arrest at the G2-M phase, by inhibiting the DNA replication via binding with topoisomerase II, by regulating the activity of extracellular signal-regulated kinase and NF-kB, by evaluating the levels of p21, p27, and cyclins B/D1/E that led to cell death by apoptosis and cell cycle arrest. This review will assist readers in better comprehending bioactive chemicals and the beneficial interaction between the fungal endophytes and medicinal plants.
Epigallocatechin-3-gallate (EGCG) has been found to be an excellent natural product that is beneficial to wound healing, but the easy oxidation of EGCG limited its wide application. Herein, we employed the supramolecular hydrogel Nap-Phe-Phe-Tyr (NapFFY) to encapsulate EGCG for their sustained release in wound areas to promote healing activity in rats modal. The EGCG-hydrogel can prolong the action time of EGCG on the wound surface. In vitro experiments indicated that co-assembly of EGCG with NapFFY enables a sustained release of EGCG for more than 48 hours. In vivo experiments supported that sustained release of EGCG from EGCG-NapFFY (1:2) could effectively improve wound healing effect compared with pure EGCG. We anticipate that the combination of polyphenols and supramolecular hydrogel can be potentially exploited to craft strategies for the acceleration of wound healing and skin regeneration.
Since the 1960s the membrane‐bound enzyme alkaline phosphatase (ALP) has been utilized in drug delivery. As it cleaves phosphate substructures from drugs, auxiliary agents, and even from the surface of nanocarriers, this enzyme enables the design of drug delivery systems that can alter their properties in the body on demand. Anionic nanocarriers exhibiting bioinert properties can alter their surface to interactive once having reached the target site as due to an ALP‐triggered cleavage of anionic phosphate groups from their surface charge converts to cationic improving for instance cellular uptake. Moreover, features such as the accumulation of nanocarriers at the target site or a targeted drug release triggered by ALP can be introduced. In addition, ALP is utilized to improve the potential of numerous diagnostic systems. Within this review, one provides an overview about the activity, selectivity, and distribution of this enzyme, as well as the great variety of applications in drug delivery and diagnostics making use of it.
Hydrogels are prevalent scaffolds for tissue regeneration because of their hierarchical architectures along with outstanding biocompatibility and unique rheological and mechanical properties. For decades, researchers have found that many materials (natural, synthetic, or hybrid) can form hydrogels using different cross-linking strategies. Traditional strategies for fabricating hydrogels include physical, chemical, and enzymatical cross-linking methods. However, due to the diverse characteristics of different tissues/organs to be regenerated, tissue-customized hydrogels need to be developed through precisely controlled processes, making the manufacture of hydrogels reliant on novel cross-linking strategies. Thus, hybrid cross-linkable materials are proposed to tackle this challenge through hybrid cross-linking strategies. Here, different cross-linkable materials and their associated cross-linking strategies are summarized. From the perspective of the major characteristics of the target tissues/organs, we critically analyze how different cross-linking strategies are tailored to fit the regeneration of such tissues and organs. To further advance this field, more appropriate cross-linkable materials and cross-linking strategies should be investigated. In addition, some innovative technologies, such as 3D bioprinting, the internet of medical things (IoMT), and artificial intelligence (AI), are also proposed to improve the development of hydrogels for more efficient tissue regeneration.
Cyclative cleavage of an amine-carbamate self-immolative spacer to deliver a hydroxyl cargo was inhibited by the spacer derivatisation with a phosphate monoester handle. This trifunctional spacer was installed in a...
The need for long-term treatments of chronic diseases has motivated the widespread development of long-acting parenteral formulations (LAPFs) with the aim of improving drug pharmacokinetics and therapeutic efficacy. LAPFs have been proven to extend the half-life of therapeutics, as well as to improve patient adherence; consequently, this enhances the outcome of therapy positively. Over past decades, considerable progress has been made in designing effective LAPFs in both preclinical and clinical settings. Here we review the latest advances of LAPFs in preclinical and clinical stages, focusing on the strategies and underlying mechanisms for achieving long acting. Existing strategies are classified into manipulation of in vivo clearance and manipulation of drug release from delivery systems, respectively. And the current challenges and prospects of each strategy are discussed. In addition, we also briefly discuss the design principles of LAPFs and provide future perspectives of the rational design of more effective LAPFs for their further clinical translation.
Short peptides can self-assemble into supramolecular materials and be used for promising biomedical applications. This area of research has seen tremendous development in recent years. However, the preparation of nanofibers with a predefined secondary structure through rational design remains a challenge. Herein, a peptide-based building block, Fmoc-KKYpYp-COOH (P1), was rationally designed for dual-triggered self-assembly by pH and enzyme for the first time. By delicately modulating the surface charges of the peptides using different triggers, i.e. pH or enzyme, we have designed peptides that are capable of self-assembling into nanoscale structures with distinct secondary structures. Upon ALP treatment, precursor P1 was efficiently transformed into a hydrogelator, Fmoc-KKYY-COOH (P2), and self-assembled to nanofibers with a partial α-helix structure. In contrast, P1 displays a typical fibrous network structure with a predominant β-sheet arrangement upon pH stimulus. Furthermore, P1 was successfully used to co-assemble with a prodrug under ALP catalysis without compromising the anti-cancer activity of the drug. The combination index (CI) values indicated a synergistic effect between P1 and Ep. We envision that this study will provide a powerful approach for rationally designing peptide nanofibers with a predefined secondary structure in the future.
Controlled intracellular chemical reactions to regulate cellular functions remain a challenge in biology mimetic systems. Herein, we developed an intra-mitochondrial bio-orthogonal reaction to induce aggregation induced emission. In situ carbonyl ligation inside mitochondria drives the molecules to form nano-aggregates with green fluorescence, which leads to depolarization of the mitochondrial membrane, generation of ROS, and subsequently mitochondrial dysfunction. This intra-mitochondrial carbonyl ligation shows great potential for anticancer treatment in various cancer cell lines.
Premature ovarian failure (POF) is the most frequently occurred disease in ovary. Direct inhibition of mammalian target of rapamycin (mTOR) activity can treat woman POF but brings adverse effects to women. Herein, by rational design of a hydrogelator Nap-Phe-Phe-Asp-Arg-Leu-Tyr-OH (Y) and co-assembling Y with an inhibitor of receptor tyrosine kinase (RTK, an upstream kinase of mTOR), Ala-Glu-Ala-Ala-Leu-Tyr-Lys-Asn-Leu-Leu-His-Ser-OH (Inh), to form hydrogel Gel Y + Inh, we develop a “smart” strategy of RTK-responsive disassembly of the hydrogel to release Inh. Release of Inh moderately inhibits the activity of mTOR and therefore delays ovarian aging. Oocyte and zygote experiments show that Gel Y + Inh improves both meiotic maturation of the oocytes and early embryonic development of the zygotes. In vivo animal experiments indicate that Gel Y + Inh effectively delays ovarian aging in aged mice by down regulation of mTOR activity, stimulation of ovaries to secrete estrogen and progesterone, and development of more antral follicles for reproduction. We expect that our new hydrogel Gel Y + Inh could be applied to treat woman POF, as well as delay ovarian aging, in clinic in the near future.
Nap-GFFpYK-etoposide1/2 (NFE1/2) increase the water solubility of etoposide, speed up its cellular uptake and protect the etoposide from MDR-mediated efflux, thus significantly improving the anticancer efficacy.
Enzymatic reactions and noncovalent (i.e., supramolecular) interactions are two fundamental nongenetic attributes of life. Enzymatic noncovalent synthesis (ENS) refers to a process where enzymatic reactions control intermolecular noncovalent interactions for spatial organization of higher-order molecular assemblies that exhibit emergent properties and functions. Like enzymatic covalent synthesis (ECS), in which an enzyme catalyzes the formation of covalent bonds to generate individual molecules, ENS is a unifying theme for understanding the functions, morphologies, and locations of molecular ensembles in cellular environments. This review intends to provide a summary of the works of ENS within the past decade and emphasize ENS for functions. After comparing ECS and ENS, we describe a few representative examples where nature uses ENS, as a rule of life, to create the ensembles of biomacromolecules for emergent properties/functions in a myriad of cellular processes. Then, we focus on ENS of man-made (synthetic) molecules in cell-free conditions, classified by the types of enzymes. After that, we introduce the exploration of ENS of man-made molecules in the context of cells by discussing intercellular, peri/intracellular, and subcellular ENS for cell morphogenesis, molecular imaging, cancer therapy, and other applications. Finally, we provide a perspective on the promises of ENS for developing molecular assemblies/processes for functions. This review aims to be an updated introduction for researchers who are interested in exploring noncovalent synthesis for developing molecular science and technologies to address societal needs.
We develop a coassembly nanosystem based on fenofibrate and ketoprofen by tactfully utilizing their coincidental benzophenone interaction, which greatly enhances bioavailability of fenofibrate and plays a role of dual-targeted treatment...
In recent years, research on supramolecular hydrogels for biomedical applications developed rapidly by covalently conjugating their hydrogelators with functional moieties including therapeutic agents and imaging probes. Such conjugation can not only endow hydrogels with specific functions but also enhance the performance of the functional moieties. Therefore, these evolutionary conjugates may create a great leap for the application of supramolecular hydrogels in clinical scenarios, especially in a bio-imaging or a sustained drug release system. In order to draw inspiration from the rapid advancement in this field and establish cornerstones for innovative exploration in the follow-up research, herein, we review the recent advances of the covalently conjugated hydrogelators and their biomedical applications in imaging and therapies. Besides, we provide our views on the remaining challenges and a perspective on future trends of conjugated hydrogelators.
Targeted delivery of chemotherapies to the tumor cells is one of the biggest challenges in cancer treatment. Herein, we synthesized smart dipeptide nanoparticles for cancer-specific targeting and intracellular pH-sensitive release of chemotherapies. Diphenylalanine peptide was synthesized and further developed as nanoparticles (NPs) which were functionalized with folic acid utilizing carbodiimide reaction. Doxorubicin (Dox) was loaded to self-assembling non-functionalized (FF-Dox) and folate functionalized peptides NPs (FA-FF-Dox). Moreover, the experiments revealed the pH-sensitive release of Dox for both FA-FF-Dox and FF-Dox due to the protonation of Schiff base and amines present in peptides at low pH, enhancing intracellular release subsequent to receptor-mediated endocytosis. Further, biodistribution and pharmacokinetics study revealed enhanced targeting efficiency of FA-FF-Dox with high accumulation in tumor.
Intact and stable bone reconstruction is ideal for the treatment of periodontal bone destructions but remains challenging. In research, biomaterials are used to encapsulate stem cell or bioactive factor for periodontal bone regeneration but, to the best of our knowledge, using supramolecular hydrogel to encapsulate bioactive factors for their sustained release in bone defect area to promote periodontal bone regeneration has not been reported. Herein, we used a well studied hydrogelator NapFFY to coassemble with SDF-1 and BMP-2 to prepare a new supramolecular hydrogel SDF-1/BMP-2/NapFFY. In vitro and in vivo results indicated that these two bioactive factors were ideally, synchronously, sustained released from the hydrogel to effectively promote the regeneration and reconstruction of periodontal bone tissues. Specifically, after the bone defect areas were treated with our SDF-1/BMP-2/NapFFY hydrogel for 8 weeks using maxillary critical-sized periodontal bone defect model rats, a superior bone regeneration rate of 56.7% bone volume (BV) fraction was achieved in these rats. We anticipate that our SDF-1/BMP-2/NapFFY hydrogel could replace bone transplantation in clinic for the repair of periodontal bone defect and periodontally accelerated osteogenic orthodontics (PAOO) in near future.
Nanoprobes are advantageous over small molecular probes in sensitivity but most luminescence molecules used to construct the nanoprobes often suffer from an aggregation-caused quenching effect. Herein, we rationally designed a small molecular probe Cys(StBu)-Lys(Ru(bpy)3²⁺)-CBT (1) which “smartly” self-assembled into nanoparticles 1-NPs inside cells with non-quenched, persistent phosphorescence. Employing this property, we successfully applied 1 for long time sensing biothiol activity in living HepG2 cells and tumors. We envision that, by modifying the amino group with an enzyme substrate, our probe 1 could be further developed for sensing intracellular enzyme activity with non-quenched, persistent phosphorescence.
A high concentration of paclitaxel (PTX) is used as an anti-tumor chemotherapy but is toxic to immune cells. At lower concentrations, PTX was found able to stimulate the anti-tumor potentials of immune cells. Thus, decreasing the cytotoxicity of PTX at high concentration while maintaining its anti-tumor stimulation to immune cells remains challenging. Herein, by employing a click condensation reaction, we rationally designed a PTX derivative, Cys(StBu)-Arg-Arg-Arg-Lys(PTX)-CBT (1), for the facile preparation of its nanoparticle 1-NP. In vitro assays indicated that, at high PTX concentrations, 1-NP showed significantly lower cytotoxicity to macrophages than did PTX, and could be efficiently phagocytosed by macrophages and consequently polarize the cells into an anti-tumor state in a dose-dependent manner. In vivo experiments further confirmed that 1-NP had a higher anti-tumor efficacy than did free PTX but lower cytotoxicity to immune cells in both immune organs and tumor sites. Our results suggest that, by using different doses of 1-NP, patients can precisely regulate the activation of the immune system for an effective anti-tumor and balanced autoimmune responses. We also envision that our strategy could lead to a combined use of immunotherapy and chemotherapy for a more efficient anti-tumor treatment in the future.
Targeting organelles by modulating the redox potential of mitochondria is a promising approach to kill cancer cells that minimizes acquired drug resistance. It, however, lacks selectivity because mitochondria performs essential functions for (almost) all cells. We show that enzyme-instructed self-assembly (EISA), a bioinspired molecular process, selectively generates the assemblies of redox modulators (e.g., triphenyl phosphinium (TPP)) in the pericellular space of cancer cells for uptake, which allows selectively targeting the mitochondria of cancer cells. The attachment of TPP to a pair of enantiomeric, phosphorylated tetrapeptidic produces the precursors (L-1P or D-1P) that form oligomers. Upon dephosphorylation catalyzed by ectophosphatases (e.g., alkaline phosphatase (ALP)) overexpressed on cancer cells (e.g., Saos2), the oligomers self-assemble to form nanoscale assemblies only on the surface of the cancer cells. The cancer cells thus uptake these assemblies of TPP via endocytosis, mainly via caveolae/raft dependent pathway. Inside the cells, the assemblies of TPP-peptide conjugates escape from lysosome, induce dysfunction of mitochondria to release cyto-chrome c, and result in cell death, while the controls (i.e., omitting TPP motif, inhibiting ALP, or removing phosphate trigger) hardly kill the Saos2 cells. Most importantly, the repeated stimulation of the cancers by the precursors, unex-pectedly, sensitizes the cancer cells to the precursors. As the first example of the integration of subcellular targeting with cell targeting, this study validates the spatial control of the assemblies of non-specific cytotoxic agents by EISA as a promising molecular process for selectively killing cancer cells without inducing acquired drug resistance.
Anticancer chemotherapy drugs challenge hematopoietic tissues to regenerate but commonly produce long-term sequelae. Chemotherapy-induced deficits in hematopoietic stem or stromal cell function have been described, but the mechanisms mediating hematopoietic dysfunction remain unclear. Administration of multiple cycles of cisplatin chemotherapy causes substantial sensory neuropathy. Here we demonstrate that chemotherapy-induced nerve injury in the bone marrow of mice is a crucial lesion impairing hematopoietic regeneration. Using pharmacological and genetic models, we show that the selective loss of adrenergic innervation in the bone marrow alters its regeneration after genotoxic insult. Sympathetic nerves in the marrow promote the survival of constituents of the stem cell niche that initiate recovery. Neuroprotection by deletion of Trp53 in sympathetic neurons or neuroregeneration by administration of 4-methylcatechol or glial-derived neurotrophic factor (GDNF) promotes hematopoietic recovery. These results demonstrate the potential benefit of adrenergic nerve protection for shielding hematopoietic niches from injury.
Although cancer cell secretome profiling is a promising strategy used to identify potential body fluid-accessible cancer biomarkers, questions remain regarding the depth to which the cancer cell secretome can be mined and the efficiency with which researchers can select useful candidates from the growing list of identified proteins. Therefore, we analyzed the secretomes of 23 human cancer cell lines derived from 11 cancer types using one-dimensional SDS-PAGE and nano-LC-MS/MS performed on an LTQ-Orbitrap mass spectrometer to generate a more comprehensive cancer cell secretome. A total of 31,180 proteins was detected, accounting for 4,584 non-redundant proteins, with an average of 1,300 proteins identified per cell line. Using protein secretion-predictive algorithms, 55.8% of the proteins appeared to be released or shed from cells. The identified proteins were selected as potential marker candidates according to three strategies: (i) proteins apparently secreted by one cancer type but not by others (cancer type-specific marker candidates), (ii) proteins released by most cancer cell lines (pan-cancer marker candidates), and (iii) proteins putatively linked to cancer-relevant pathways. We then examined protein expression profiles in the Human Protein Atlas to identify biomarker candidates that were simultaneously detected in the secretomes and highly expressed in cancer tissues. This analysis yielded 6-137 marker candidates selective for each tumor type and 94 potential pan-cancer markers. Among these, we selectively validated monocyte differentiation antigen CD14 (for liver cancer), stromal cell-derived factor 1 (for lung cancer), and cathepsin L1 and interferon-induced 17-kDa protein (for nasopharyngeal carcinoma) as potential serological cancer markers. In summary, the proteins identified from the secretomes of 23 cancer cell lines and the Human Protein Atlas represent a focused reservoir of potential cancer biomarkers.
Alkaline phosphatase (AP) was covalently linked to the two antitumor monoclonal antibodies, L6 (anticarcinoma) and 1F5 (anti-B lymphoma), forming conjugates that could bind to antigen-positive tumor cells. The conjugates were able to convert the prodrugs, mitomycin phosphate (MOP) and etoposide phosphate (EP), into an active mitomycin C derivative, mitomycin alcohol, and etoposide, respectively. MOP and EP were less toxic to cultured cells from the H2981 lung adenocarcinoma than their respective hydrolysis products, mitomycin alcohol and etoposide, by a factor greater than 100, and they were also less toxic in mice. Pretreatment of H2981 cells with L6-AP greatly enhanced the cytotoxic effects of MOP and EP, while 1F5-AP caused no such enhancement. A strong antitumor response was observed in H2981-bearing mice that were treated with L6-AP followed 24 h later by either MOP or a combination of MOP and EP. This response was superior to that of MOP or combinations of MOP and EP given alone.
Paclitaxel (PTX) is one of the most successful drugs ever used in cancer chemotherapy, acting against a variety of cancer types. Formulating PTX with Cremophor EL and ethanol (Taxol®) realized its clinical potential, but the formulation falls short of expectations due to side effects such as peripheral neuropathy, hypotension, and hypersensitivity. Abraxane®, the albumin bound PTX, represents a superior replacement of Taxol® that mitigates the side effects associated with Cremophor EL. While Abraxane® is now considered a gold standard in chemotherapy, its 21% response rate leaves much room for further improvement. The quest for safer and more effective cancer treatments has led to the development of a plethora of innovative PTX formulations, many of which are currently undergoing clinical trials. In this context, we review recent development of PTX drug delivery systems and analyze the design principles underpinning each delivery strategy. We chose several representative examples to highlight the opportunities and challenges of polymeric systems, lipid-based formulations, as well as prodrug strategies.
The ability to tune the inter-subunit interaction within the virus capsid may be critical to assembly and biological function. This process was extended here with peptide/DNA co-assembled viral mimics. The resulting co-assemblies, formed and stabilized by both peptide nanofibril–DNA and peptide nanofibril–nanofibril interactions, were tuned through hydrophobic packing interactions of the peptide sequences. By strengthening peptide side-chain complementarity and/or elongating the peptide chain (from 4 to 8 residues), we report strengthening the inter-nanofibril interaction to create stable nanococoons that give high gene-transfection efficacy.
Immunogenicity depends on two key factors: antigenicity and adjuvanticity. The presence of exogenous or mutated antigens explains why infected cells and malignant cells can initiate an adaptive immune response provided that the cells also emit adjuvant signals as a consequence of cellular stress and death. Several infectious pathogens have devised strategies to control cell death and limit the emission of danger signals from dying cells, thereby avoiding immune recognition. Similarly, cancer cells often escape immunosurveillance owing to defects in the molecular machinery that underlies the release of endogenous adjuvants. Here, we review current knowledge on the mechanisms that underlie the activation of immune responses against dying cells and their pathophysiological relevance.
‘Smart’ bioresponsive materials that are sensitive to biological signals or to pathological abnormalities, and interact with or are actuated by them, are appealing therapeutic platforms for the development of next-generation precision medications. Armed with a better understanding of various biologically responsive mechanisms, researchers have made innovations in the areas of materials chemistry, biomolecular engineering, pharmaceutical science, and micro- and nanofabrication to develop bioresponsive materials for a range of applications, including controlled drug delivery, diagnostics, tissue engineering and biomedical devices. This Review highlights recent advances in the design of smart materials capable of responding to the physiological environment, to biomarkers and to biological particulates. Key design principles, challenges and future directions, including clinical translation, of bioresponsive materials are also discussed.
Immunogenicity depends on two key factors: antigenicity and adjuvanticity. The presence of exogenous or mutated antigens explains why infected cells and malignant cells can initiate an adaptive immune response provided that the cells also emit adjuvant signals as a consequence of cellular stress and death. Several infectious pathogens have devised strategies to control cell death and limit the emission of danger signals from dying cells, thereby avoiding immune recognition. Similarly, cancer cells often escape immunosurveillance owing to defects in the molecular machinery that underlies the release of endogenous adjuvants. Here, we review current knowledge on the mechanisms that underlie the activation of immune responses against dying cells and their pathophysiological relevance.
Employing cellular environment for the self-assembly of supramolecular nanofibers for biological applications has been widely explored. But using one precursor to differentiate the extra- and intracellular environments to self-assemble into two different nanofibers remains challenging. With the knowledge that the extracellualr environment of some cancer cells contains large amount of alkaline phosphatase (ALP) while their intracellular environment is glutathione (GSH)-abundant in mind, we rationally designed a precursor Cys(SEt)-Glu-Tyr(H2PO3)-Phe-Phe-Gly-CBT (1) which can efficiently yield amphiphilic 2 and 2-D to self-assemble into two different nanofibers in hydrogels under the sequential treatment of ALP and GSH. We envision that, by employing a click condensation reaction, this work offers a platform for facilely post modulation of supramolecular nanofibers, and the versatile precursor 1 could be used to kill two birds with one stone.
Direct delivery of cytokines using nanocarriers holds great promise for cancer therapy. However, the nanometric scale of the vehicles made them susceptible to size-dependent endocytosis, reducing the plasma membrane-associated apoptosis signaling. Herein, we report a tumor microenvironment-responsive and transformable nanocarrier for cell membrane targeted delivery of cytokine. This formulation is comprised of a phospholipase A2 (PLA2) degradable liposome as a shell, and complementary DNA nanostructures (designated as nanoclews) decorated with cytokines as the cores. Utilizing the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a model cytokine, we demonstrate that the TRAIL loaded DNA nanoclews are capable of transforming into nanofibers after PLA2 activation. The nanofibers with micro-scaled lengths efficiently present the loaded TRAIL to death receptors on the cancer cell membrane and amplified the apoptotic signaling with reduced TRAIL internalization.
Besides tight and specific ligand-receptor interactions, the rate regulation of the formation of molecular assemblies is one of fundamental features of cells. But the latter receives little exploration for developing anticancer therapeutics. Here we show that a simple molecular design of the substrates of phosphatases-tailoring the number of phosphates on peptidic substrates-is able to regulate the rate of molecular self-assembly of the enzyme reaction product. Such a rate regulation allows selective inhibition of osteosarcoma cells over hepatocytes, which promises to target cancer cells in a specific organ. Moreover, our result reveals that the direct measurement of the rate of the self-assembly in a cell-based assay provides precise assessment of the cell targeting capability of self-assembly. This work, as the first report establishing rate regulation of a multiple-step process to inhibit cells selectively, illustrates a fundamentally new approach for controlling the fate of cells.
Podophyllin-containing materials have been used as folk medicines for centuries. In the 1950s, scientists began a search to identify a more effective podophyllotoxin derivative. These efforts eventually resulted in the development of a new class of antineoplastic agents which target the DNA unwinding enzyme, topoisomerase II. The history of the development of one of the first identified topoisomerase II inhibitors, etoposide, is reviewed in this paper. Critical developments in etoposide's mechanism of action, pharmacology and administration schedule are summarised. The clinical benefits of the recently marketed etoposide prodrug, etoposide phosphate (Etopophos) are also detailed. The current status of other clinically approved anticancer agents which target topoisomerase II is briefly reviewed.
Polymers, ceramics and metals have historically dominated the application of materials in medicine. Yet rationally designed materials that exploit specific, directional, tunable and reversible non-covalent interactions offer unprecedented advantages: they enable modular and generalizable platforms with tunable mechanical, chemical and biological properties. Indeed, the reversible nature of supramolecular interactions gives rise to biomaterials that can sense and respond to physiological cues, or that mimic the structural and functional aspects of biological signalling. In this Review, we discuss the properties of several supramolecular biomaterials, as well as their applications in drug delivery, tissue engineering, regenerative medicine and immunology. We envision that supramolecular biomaterials will contribute to the development of new therapies that combine highly functional materials with unmatched patient- and application-specific tailoring of both material and biological properties.
Multidrug resistance (MDR) remains the biggest challenge in treating cancers. Herein we propose the intracellular self-assembly of nanodrugs as a new strategy for overcoming MDR. By employing a biocompatible condensation reaction, we rationally designed a taxol derivative Ac-Arg-Val-Arg-Arg-Cys(StBu)-Lys(taxol)-2-cyanobenzothiazole (CBT-Taxol) which could be subjected to furin-controlled condensation and self-assembly of taxol nanoparticles (Taxol-NPs). In vitro and in vivo studies indicated that, compared with taxol, CBT-Taxol showed a 4.5-fold or 1.5-fold increase in anti-MDR effects, respectively, on taxol-resistant HCT 116 cancer cells or tumors without being toxic to the cells or the mice. Our results demonstrate that structuring protease-susceptible agents and assembling them intracellularly into nanodrugs could be a new optimal strategy for overcoming MDR.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Alkaline phosphatase (ALP)-catalyzed hydrogelation has been extensively explored and found wide applications. Spectroscopic and electrochemical approaches are commonly employed for the detection of ALP activity. Herein, by rational design of a fluorescence probe Fmoc-K(FITC)FFYp (P1), we incorporated sol-gel transition with fluorescence "turn-off" and developed a new method for quantitative sensing ALP activity in vitro and in living cells. Under the catalysis of ALP, P1 was converted to hydrogelator Fmoc-K(FITC)FFY (1) which self-assembles into nanofibers to form Gel I. Accompanying this sol-gel transition, the fluorescence emission of P1 was turned off. Our assay was employed to detect ALP activity over the range of 0-2.8 U/mL with a limit of detection (LOD) of 0.06 U/mL. ALP-inhibitor-treated cell imaging indicated that P1 could be applied for sensing ALP activity in living cells. Our method provides a new option for real time and quantitative sensing ALP activity in vitro and even in living cells.
Fibrils formed by proteins are vital components for cells. However, selective formation of xenogenous nanofibrils of small molecules on mammalian cells has yet to be observed. Here we report an unexpected observation of hydrogel/nanonets of a small D-peptide derivative in pericellular space. Surface and secretory phosphatases dephosphorylate a precursor of a hydrogelator to trigger the self-assembly of the hydrogelator and to result in pericellular hydrogel/nanonets selectively around the cancer cells that overexpress phosphatases. Cell-based assays confirm that the pericellular hydrogel/nanonets block cellular mass exchange to induce apoptosis of cancer cells, including multidrug-resistance (MDR) cancer cells, MES-SA/Dx5. Pericellular hydrogel/nanonets of small molecules to exhibit distinct functions illustrates a fundamentally new way to engineer molecular assemblies spatiotemporally in cellular microenvironment for inhibiting cancer cell growth and even metastasis.
Washable wound dressing: A dissolvable dendritic thioester hydrogel for wound closure has been developed. The hydrogel sealant adheres strongly to tissues, closes an ex vivo vein puncture, and withstands high pressures placed on a wound. This material can be washed off upon exposure to thiolates because a thiol-thioester exchange takes place, and gradual wound re-exposure may be achieved during surgical care.
Abstract To improve the efficacy podophyllotoxin (PODO) and etoposide (ETOPO) were encapsulated in poly-d,l-lactide nanoparticles (PLA NPs). The size of synthesised PODO-loaded PLA NPs and ETOPO-loaded PLA NPs was 100 ± 17 nm and 163 ± 20 nm and their encapsulation efficiency was 17 and 48%, respectively. In vitro release studies showed initial burst release followed by slow and sustained release. In vitro cytotoxicity of synthesised NPs was assessed using A549 and CHO-K1 cells. Blank PLA NPs did not show any toxicity. While PODO-loaded PLA NPs showed higher in vitro cytotoxicity in comparison to ETOPO-loaded PLA NPs against both cell lines. Also, the cytotoxicity of both PODO-loaded PLA NPs and ETOPO-loaded PLA NPs was higher compared to pure drugs. Hence, this study documents the improvement in efficacy of these molecules upon encapsulation in PLA NPs and could be an important strategy for better therapeutics.
A kinetic method for the determination of alkaline phosphatase activity is described. Following the recommendations of the Enzyme Commission of the IUB, optimal conditions have been worked out. The results are given in mU/ml. In the authors' laboratory, the range of normal individuals is 61–171 mU/ml (25°). Summarizing the results of different investigators, values between 46 and 190 mU/ml (25°) should be considered normal.
Cell death by visible light: Photodynamic therapy (PDT) is a relatively underemployed method for treatment of diseases including cancer. Recent improvements in synthetic and analysis methods of metal complexes provide for red-light-activated drugs with potential application in PDT.
Gene therapy is used to induce immune responses, regulate tumor growth, or sensitize tumor cells to specific treatment. For sensitizing tumor cells to specific drug, we considered a prodrug-converting system using membrane-bound intestinal alkaline phosphatase (IAP) as the prodrug-activating genes. The IAP is capable of converting a relatively non-cytotoxic prodrug, etoposide phosphate (EP), into etoposide with a significant antitumor activity. We used the retroviral vector for transducing IAP gene into SNU638 gastric cancer cells and EP was prepared by phosphorylation of etoposide. To determine the chromosomal incorporation of membrane-bound IAP gene and AP activity in IAP gene-transduced cells (SNU638/IAP), we performed genomic PCR and AP activity analysis. In genomic DNA of SNU638/IAP cells, full cDNA fragment of a 2.5 kb IAP was detected, and AP activity was shown at most 15 approximately 18-fold increase compared with control cells. According to the in vitro cytotoxicity study, SNU638/IAP cells greatly enhanced the cytotoxic effect in proportion to the concentration of EP, while control cells didn't cause any cytotoxic effects after EPtreatment. Especially, the cell population of G2/M phase was increased in EP-treated SNU638/ IAP cells because P4 DNA unknotting activity of topoisomerase II was decreased by EP treatment such as the action mechanism of etoposide. Finally, a strong antitumor response was observed in SNU638/IAP cancer cells-bearing nude mice that were treated with EP. These results suggest that the prodrug-converting system by membrane-bound IAP gene and EP prodrug is useful as the strong strategy of gene therapy for cancer treatment.
The self-assemby of fluorenylmethoxycarbonyl(Fmoc)-dipeptides into fibrous hydrogels under physiological conditions for three-dimensiona cell culture, is demonstrated. The self-assemby of Fmoc-dipeptides is driven by hydrogen onding and φ-φ interaction, that is, the attractive interactions between φ electrons in the aromatic fluorenyl rings. Gels that were stable at physiological pH were subsequently tested for their ability to support proliferation and retention of phenotype bovine chondrocytes. The structural and physical properties of these gels were found to be dictated by the amino acid sequenceof the peptide building blocks.
Hydrogels are polymeric materials distinguished by high water content and diverse physical properties. They can be engineered
to resemble the extracellular environment of the body’s tissues in ways that enable their use in medical implants, biosensors,
and drug-delivery devices. Cell-compatible hydrogels are designed by using a strategy of coordinated control over physical
properties and bioactivity to influence specific interactions with cellular systems, including spatial and temporal patterns
of biochemical and biomechanical cues known to modulate cell behavior. Important new discoveries in stem cell research, cancer
biology, and cellular morphogenesis have been realized with model hydrogel systems premised on these designs. Basic and clinical
applications for hydrogels in cell therapy, tissue engineering, and biomedical research continue to drive design improvements
using performance-based materials engineering paradigms.
Because of the particular characteristics of the tumor microenvironment and tumor angiogenesis, it is possible to design drug delivery systems that specifically target anti-cancer drugs to tumors. Most of the conventional chemotherapeutic agents have poor pharmacokinetics profiles and are distributed non-specifically in the body leading to systemic toxicity associated with serious side effects. Therefore, the development of drug delivery systems able to target the tumor site is becoming a real challenge that is currently addressed. Nanomedicine can reach tumor passively through the leaky vasculature surrounding the tumors by the Enhanced Permeability and Retention effect whereas ligands grafted at the surface of nanocarriers allow active targeting by binding to the receptors overexpressed by cancer cells or angiogenic endothelial cells. This review is divided into two parts: the first one describes the tumor microenvironment and the second one focuses on the exploitation and the understanding of these characteristics to design new drug delivery systems targeting the tumor. Delivery of conventional chemotherapeutic anti-cancer drugs is mainly discussed.
A supramolecular hydrogel based on D-amino acids, which resists hydrolysis catalyzed by proteinase K and offers long-term biostability, exhibits controlled release in vivo, as proved by the pharmacokinetics of encapsulated 125I tracers and the SPECT imaging of the hydrogel-encapsulated 131I tracers. As the first in vivo imaging investigation of the drug release properties of the supramolecular hydrogel, isotope encapsulation serves as a valid, useful assay for characterizing the controlled release properties of supramolecular hydrogels in vivo. Our results indicate that supramolecular hydrogels promise new biomaterials for controlled drug release.
Aptamer advantages: Cell-specific delivery of the anticancer drug cisplatin through a nucleolinaptamer- conjugated, cisplatin-encapsulating liposome delivery system is described. Calcein was incorporated into the target MCF-7 cells (see top image) but not into LNCaP cells (see bottom image). More importantly, the extent of delivery can be controlled by using a complementary DNA of the aptamer as an antidote.
Paclitaxel (Taxol), a diterpene plant product that promotes tubulin polymerization, has documented activity against a number of solid tumors, including ovarian cancer and breast cancer.
Our purpose was to conduct a phase II clinical trial investigating the response of patients with advanced recurrent ovarian carcinoma to high-dose paclitaxel combined with granulocyte colony-stimulating factor (G-CSF).
A prospective phase II clinical trial of patients with advanced-stage, recurrent ovarian cancer was undertaken. Patients received 250 mg/m2 paclitaxel every 21 days; cycles were given on a rigid schedule; delays were permitted only for extreme circumstances. G-CSF at a dose of 10 micrograms/kg per day was given to ameliorate myelo-suppression. If a patient showed fever and neutropenia, G-CSF dosage was increased to 20 micrograms/kg per day so that paclitaxel dose intensity could be maintained. Patients were assessed for response every two cycles, and those with complete radiographic resolution of disease underwent peritoneoscopy.
Forty-four patients were assessable for response. Twenty-one had a reduction in tumor volume greater than 50%, yielding an objective response rate of 48% (21 of 44 patients; 95% confidence interval, 32%-63%). Six (14%) of the 44 patients had complete radiographic resolution of disease; two of the six also had negative biopsy specimens and washings at peritoneoscopy. Age, number of prior regimens, and clinical platinum resistance did not influence response rate or ability to maintain dose intensity. Dose intensity was maintained at the targeted level for up to 14 consecutive cycles of therapy.
We observed a 48% response rate with dose-intense paclitaxel for patients with advanced-stage, platinum-resistant, recurrent ovarian cancer. The response rate is higher than previously reported for paclitaxel at a lower dose in similar cohorts of patients treated without G-CSF. Comparison of phase II studies of paclitaxel suggests a dose-response relationship. Therapy with dose-intense paclitaxel and G-CSF should be considered for patients with advanced, platinum-refractory ovarian cancer.
To assess the pharmacokinetics and bioequivalence of etoposide following intravenous (i.v.) administration of etoposide phosphate (Etopophos; Bristol-Myers Squibb, Princeton, NJ), a prodrug of etoposide, and VePesid (Bristol-Myers Squibb).
Forty-nine solid tumor patients were randomized to receive Etopophos or VePesid on day 1 of a day-1,3,5 schedule of treatment. The alternate drug was given on day 3 and repeated on day 5. The dose, 150 mg/m2 of etoposide equivalent, was administered by constant rate infusion over 3.5 hours. The plasma concentrations of etoposide phosphate and etoposide were determined using validated high-performance liquid chromatography (HPLC) assays. Pharmacokinetic parameters were calculated by a noncompartmental method. Etopophos was considered to be bioequivalent to VePesid if the 90% confidence limits for the differences in mean maximum concentration (Cmax) and AUCinf of etoposide were contained within 80% to 125% for the long-transformed data.
Forty-one patients were assessable for pharmacokinetics and bioequivalence assessment. Following i.v. administration, etoposide phosphate was rapidly and extensively converted to etoposide in systemic circulation, resulting in insufficient data to estimate its pharmacokinetics. The mean bioavailability of etoposide from Etopophos, relative to VePesid, was 103% (90% confidence interval, 99% to 106%) based on Cmax, and 107% (90 confidence interval, 105% to 110%) based on area under the concentration versus time curve from zero to infinity (AUCinf) values. Mean terminal elimination half-life (t1/2), steady-state volume of distribution (Vss), and total systemic clearance (CL) values of etoposide were approximately 7 hours, 7 L/m2, and 17 mL/min/m2 after Etopophos and VePesid treatments, respectively. The main toxicity observed was myelosuppression, characterized by leukopenia and neutropenia.
With respect to plasma levels of etoposide, i.v. Etopophos is bioequivalent to i.v. VePesid.
DNA topoisomerases are the magicians of the DNA world by allowing DNA strands or double helices to pass through each other, they can solve all of the topological problems of DNA in replication, transcription and other cellular transactions. Extensive biochemical and structural studies over the past three decades have provided molecular models of how the various subfamilies of DNA topoisomerase manipulate DNA. In this review, the cellular roles of these enzymes are examined from a molecular point of view.
In materials science, a dynamic property sensitive to an environmental change (heat, light, electric current, pH, and other chemical or physical changes) is indispensable for intelligent materials. Such organic materials, however, are very limited even in conventional polymers. This paper clearly demonstrates that, regardless of the low molecular weight, a glycosylated amino acid derivative newly screened by a combinatorial method forms a macroscopic supramolecular hydrogel that reversibly swells or shrinks in response to the external temperature. Using the unique thermal response of the present hydrogel, we carried out the controlled release of DNA and the perfect removal of bisphenol A from the polluted water. Recently, advanced supramolecular polymers, in which monomers are noncovalently connected, are expected to be highly advantageous over traditional polymers because of their tunable and recyclable characteristics. The present result newly confers a dynamic feature on the supramolecular polymers, which is desirable for the sophisticated application in many fields.
Partial protein sequence data obtained on intestinal alkaline phosphatase indicated a high degree of homology with the reported sequence of the placental isoenzyme. Accordingly, placental alkaline phosphatase cDNA was cloned and used as a probe to clone intestinal alkaline phosphatase cDNA. The latter is somewhat larger (3.1 kilobases) than the cDNA for the placental isozyme (2.8 kilobases). Although the 3' untranslated regions are quite different, there is almost 90% homology in the translated regions of the two isozymes. There are, however, significant differences at their amino and carboxyl termini and a substitution of an alanine in intestinal alkaline phosphatase for a glycine in the active site of the placental isozyme.
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