Fast Cyclization of a Proline-Derived Self-Immolative Spacer Improves the Efficacy of Carbamate Prodrugs

Self-immolative (SI) spacers are sophisticated chemical constructs designed for molecular delivery or material degradation. We describe herein a (S)-2-(aminomethyl)pyrrolidine SI spacer that is able to release different types of anticancer drugs (possessing either a phenolic or secondary and tertiary hydroxyl groups) through a fast cyclization mechanism involving carbamate cleavage. The high efficiency of drug release obtained with this spacer was found to be beneficial for the in vitro cytotoxic activity of protease-sensitive prodrugs, compared with a commonly used spacer of the same class. These findings expand the repertoire of degradation machineries and are instrumental for the future development of highly efficient delivery platforms.     

Phosphate-Based Self-Immolative Linkers for Tuneable Double Cargo Release

Phosphorus-based self-immolative (SI) linkers offer a wide range of applications, such as smart materials and drug-delivery systems. Phosphorus SI linkers are ideal candidates for double-cargo delivery platforms because they have a higher valency than carbon. A series of substituted phosphate linkers was designed for releasing two phenolic cargos through SI followed by chemical hydrolysis. Suitable modifications of the lactate spacer increased the cargo release rate significantly, from 1 day to 2 hours or 5 minutes, as shown for linkers containing p-fluoro phenol. In turn, double cargo linkers bearing p-methyl phenol released their cargo more slowly (4 days, 4 hours, and 15 minutes) than their p-fluoro analogues. The α-hydroxyisobutyrate linker released both cargos in 25 minutes. Our study expands the current portfolio of SI constructs by providing a double cargo delivery option, which is crucial to develop universal SI platforms.     

Morphology engineering of a novel poly(L‐lactide)/poly(1,5‐dioxepan‐2‐one) microsphere system for controlled drug delivery

Morphology is presented as a powerful tool to control the in vitro degradation and drug release characteristics of novel drug delivery microspheres prepared from homopolymer blends of 1,5‐dioxepan‐2‐one, DXO, and L ‐lactide, L‐LA. Their performance in this respect was compared to analogous P(L‐LA‐co‐DXO) microspheres. Blends formed denser and less porous microspheres with a higher degree of matrix crystallinity than copolymers of corresponding L‐LA:DXO composition. The morphology differences of blends and copolymers, further adjustable by means of component ratio, are shown to have a vital impact on the in vitro performance. Sustained drug delivery was obtained from both copolymers and blends. Molecular weight loss was retarded and diffusion‐mediated release was inhibited in the latter case, further delaying the release process. The effects of storage on the physicochemical properties of these systems were evaluated under desiccated and moist conditions for 5 months. Storage‐induced physicochemical changes, such as matrix crystallization and molecular weight decrease, were accelerated at higher relative humidities. P(L‐LA‐co‐DXO) demonstrated higher moisture sensitivity than a PLLA‐PDXO blend of corresponding composition. The more crystalline and dense morphology of blend microspheres may thus be considered an improvement of the storage stability. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 786–796, 2000     

Simple Radical Polymerization of Poly(Alginate‐Graft‐N‐Isopropylacrylamide) Injectable Thermoresponsive Hydrogel with the Potential for Localized and Sustained Delivery of Stem Cells and Bioactive Molecules

In this study, thermoresponsive copolymers that are fully injectable, biocompatible, and biodegradable and are synthesized via graft copolymerization of poly(N‐isopropylacrylamide) onto alginate using a free‐radical reaction are presented. This new synthesis method does not involve multisteps or associated toxicity issues, and has the potential to reduce scale‐up difficulties. Chemical and physical analyses verify the resultant graft copolymer structure. The lower critical solution temperature, which is a characteristic of sol–gel transition, is observed at 32 °C. The degradation properties indicate suitable degradation kinetics for drug delivery and bone tissue engineering applications. The synthesized P(Alg‐g‐NIPAAm) hydrogel is noncytotoxic with both human osteosarcoma (MG63) cells and porcine bone marrow derived mesenchymal stem cells (pBMSCs). pBMSCs encapsulated in the P(Alg‐g‐NIPAAm) hydrogel remain viable, show uniform distribution within the injected hydrogel, and undergo osteogenic and chondrogenic differentiation under appropriate culture conditions. Furthermore, for the first time, this work will explore the influence of alginate viscosity on the viscoelastic properties of the resulting copolymer hydrogels, which influences the rate of medical device formation and subsequent drug release. Together the results of this study indicate that the newly synthesized P(Alg‐g‐NIPAAm) hydrogel has potential to serve as a versatile and improved injectable platform for drug delivery and bone tissue engineering applications.     

Fabrication of novel core–shell PLGA and alginate fiber for dual‐drug delivery system

Biodegradable fibers for the controlled delivery of anti‐inflammatory agent dexamethasone were developed and studied. Mono and core–shell structure fiber are prepared by wet‐spinning solutions of hydrophobic poly (lactide‐co‐glycolide) and hydrophilic alginic acid shell. The two model drugs, dexamethasone and dexamethasone‐21‐phosphate, were entrapped in core and shell, respectively. These fibers were characterized in terms of morphology, diameters, mechanical properties, in vitro degradation, and drug release. The optical microscopy and scanning electron microscopy photos revealed directly that fibers possessed core–shell structure. The release of dexamethasone and dexamethasone‐21‐phosphate was investigated, and the results showed that alginate shell retarded dexamethasone release significantly in both early and late stages. The core–shell structure fiber release shows a two stage release of dexamethasone and dexamethasone‐21‐phosphate with distinctly different release rates, and minimal initial burst release is observed. The results indicated that the prepared fibers are efficient carrier for both types of dexamethasone. Copyright © 2016 John Wiley & Sons, Ltd.     

Biodegradable thermo‐ and pH‐responsive hydrogels for oral drug delivery

In this article, novel smart hydrogels based on biodegradable pH sensitive poly(L ‐glutamic acid‐g‐2‐hydroxylethyl methacrylate) (PGH) chains and temperature‐sensitive hydroxypropylcellulose‐g‐acrylic acid (HPC‐g‐AA) segments were designed and synthesized. The influence of pH and temperature on the equilibrium swelling ratios of the hydrogels was discussed. The optical transmittance of the hydrogels was also changed as a function of temperature, which reflecting that the HPC‐g‐AA part of the hydrogels became hydrophobic at the temperature above the lower critical solution temperature (LCST). At the same time, the LCST of the hydrogels had a visible pH‐dependent behavior. Scanning electron microscopic analysis revealed the morphology of the hydrogels before and after enzymatic degradation. The biodegradation rate of the hydrogels was directly related to the PGH content and the pH value. The in vitro release of bovine serum albumin from the hydrogels were investigated. The release profiles indicated that both the HPC‐g‐AA and PGH contents played important roles in the drug release behaviors. These results show that the smart hydrogels seem to be of great promise in pH–temperature oral drug delivery systems. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Controlled ring‐opening polymerization of lactones and lactides

1,5‐dioxepan‐2‐one (DXO) is presented as a versatile component in biodegradable polymers for biomedical applications. Copolymerization of DXO and L‐lactide yielded a semi‐crystalline, yet flexible, material where the extent of crystallinity and erosion characteristics were controlled by an appropriate choice of copolymer composition. Crosslinked PDXO was polymerized as a novel biodegradable elastomer. The degradation behavior of these materials were explored in vitro. Microspheres from poly(DXO‐co‐L‐LA) were prepared and shown to be promising candidates for controlled release. The polymer composition and drug solubility provided effective means of controlling the drug delivery pattern.     

Redox‐Responsive Resilin‐Like Hydrogels for Tissue Engineering and Drug Delivery Applications

Resilin, a protein found in insect cuticles, is renowned for its outstanding elastomeric properties. The authors' laboratory previously developed a recombinant protein, which consisted of consensus resilin‐like repeats from Anopheles gambiae, and demonstrated its potential in cartilage and vascular engineering. To broaden the versatility of the resilin‐like protein, this study utilizes a cleavable crosslinker, which contains a disulfide bond, to develop smart resilin‐like hydrogels that are redox‐responsive. The hydrogels exhibit a porous structure and a stable storage modulus (G′) of ≈3 kPa. NIH/3T3 fibroblasts cultured on hydrogels for 24 h have a high viability (>95%). In addition, the redox‐responsive hydrogels show significant degradation in a reducing environment (10 mm glutathione (GSH)). The release profiles of fluorescently labeled dextrans encapsulated within the hydrogels are assessed in vitro. For dextran that is estimated to be larger than the mesh size of the gel, faster release is observed in the presence of reducing agents due to degradation of the hydrogel networks. These studies thus demonstrate the potential of using these smart hydrogels in a variety of applications ranging from scaffolds for tissue engineering to drug delivery systems that target the intracellular reductive environments of tumors.     

Relationship among drug delivery behavior,degradation behavior and morphology of copolylactones derived from glycolide,l‐lactide and ε‐caprolactone

A series of copolylactones was synthesized by ring‐opening copolymerization of glycolide, L ‐lactide and ?‐caprolactone, using stannous octoate as catalyst. The in vitro degradation behaviors of them were studied and data demonstrated different degradation rates which mainly depended on the compositions. Investigation of the 5‐fluorouracil (5‐Fu) release from these copolylactones revealed that the composition, degradation rate and the morphology of the polymeric matrix played an important role on the drug release kinetics. A sustained 5‐Fu release without initial time lag was obtained from random poly(lactide‐co‐glycolide‐co‐caprolactone) (r‐PGLC) drug carrier, and it differed from the cases of polylactide (PLA) or random poly(lactide‐co‐glycolide) (PLGA), which usually showed an initial time lag or biphasic drug release behavior. It was due to the low glass transition temperature (T _g) of the r‐PGLC and the drug would diffuse faster in rubbery state under the experimental temperature. Furthermore, a significant change in the drug release behavior of r‐PGLC was observed when the temperatures were changed around the T _g of the drug carrier, which implied that the drug release behavior could be regulated by adjusting the morphology of the drug carrier. Copyright © 2002 John Wiley & Sons, Ltd.     

pH‐ and β‐cyclodextrin‐responsive micelles based on polyaspartamide derivatives as drug carrier

A novel kind of graft polymer poly(aspartic acid)‐ethanediamine‐g‐adamantane/methyloxy polyethylene glycol (Pasp‐EDA‐g‐Ad/mPEG) was designed and synthesized for drug delivery in this study. The chemical structure of the prepared polymer was confirmed by proton NMR. The obtained polymer can self‐assemble into micelles which were stable under a physiological environment and displayed pH‐ and β‐cyclodextrin (β‐CD)‐responsive behaviors because of the acid‐labile benzoic imine linkage and hydrophobic adamantine groups in the side chains of the polymer. The doxorubicin (Dox)‐loaded micelles showed a slow release under physiological conditions and a rapid release after exposure to weakly acidic or β‐CD environment. The in vitro cytotoxicity results suggested that the polymer was good at biocompatibility and could remain Dox biologically active. Hence, the Pasp‐EDA‐g‐Ad/mPEG micelles may be applied as promising controlled drug delivery system for hydrophobic antitumor drugs. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1387–1395     

Enzyme‐Responsive Polymeric Vesicles for Bacterial‐Strain‐Selective Delivery of Antimicrobial Agents

Antimicrobial resistance poses serious public health concerns and antibiotic misuse/abuse further complicates the situation; thus, it remains a considerable challenge to optimize/improve the usage of currently available drugs. We report a general strategy to construct a bacterial strain‐selective delivery system for antibiotics based on responsive polymeric vesicles. In response to enzymes including penicillin G amidase (PGA) and β‐lactamase (Bla), which are closely associated with drug‐resistant bacterial strains, antibiotic‐loaded polymeric vesicles undergo self‐immolative structural rearrangement and morphological transitions, leading to sustained release of antibiotics. Enhanced stability, reduced side effects, and bacterial strain‐selective drug release were achieved. Considering that Bla is the main cause of bacterial resistance to β‐lactam antibiotic drugs, as a further validation, we demonstrate methicillin‐resistant S. aureus (MRSA)‐triggered release of antibiotics from Bla‐degradable polymeric vesicles, in vitro inhibition of MRSA growth, and enhanced wound healing in an in vivo murine model.     

Stimuli‐Responsive Theragrippers for Chemomechanical Controlled Release

We report on a therapeutic approach using thermo‐responsive multi‐fingered drug eluting devices. These therapeutic grippers referred to as theragrippers are shaped using photolithographic patterning and are composed of rigid poly(propylene fumarate) segments and stimuli‐responsive poly(N‐isopropylacrylamide‐co‐acrylic acid) hinges. They close above 32 °C allowing them to spontaneously grip onto tissue when introduced from a cold state into the body. Due to porosity in the grippers, theragrippers could also be loaded with fluorescent dyes and commercial drugs such as mesalamine and doxorubicin, which eluted from the grippers for up to seven days with first order release kinetics. In an in vitro model, theragrippers enhanced delivery of doxorubicin as compared to a control patch. We also released theragrippers into a live pig and visualized release of dye in the stomach. The design of such tissue gripping drug delivery devices offers an effective strategy for sustained release of drugs with immediate applicability in the gastrointestinal tract.     

Amphiphilic Polymethacrylate‐ and Polystyrene‐Based Chemical Delivery Systems for Damascones

Amphiphilic polystyrene‐ and polymethacrylate‐based β‐acyloxy ketones were investigated as potential delivery systems for the controlled release of damascones by retro‐1,4‐addition in applications of functional perfumery. A series of random copolymers being composed of the hydrophobic damascone‐release unit and a second hydrophilic monomer were obtained by radical polymerization in organic solution by using 2,2′‐azobis[2‐methylpropanenitrile] (AIBN) as the radical source (Schemes 2 and 3). A first evaluation of the polymer conjugates in acidic or alkaline buffered aqueous solution, and in the presence of a surfactant, showed that polymethacrylates and polystyrenes having a carboxylic acid function as hydrophilic group are particularly interesting for the targeted applications (Table 2). The release of δ‐damascone ( 1 ) from polymers with poly(methacrylic acid) and poly(vinylbenzoic acid) comonomers in different stoichiometric ratios was thus followed over several days at pH 4, 7, and 9 by comparison of fluorescence probing, solvent extraction, and particle‐size measurements (Tables 3 and 4). In acidic media, the polymers were found to be stable, and almost no δ‐damascone ( 1 ) was released. In neutral or alkaline solution, where the carboxylic acid functions are deprotonated, the concentration of 1 increased over time. In the case of the polymethacrylates, the fluorescence probing experiments showed an increasing hydrophilicity of the polymer backbone with increasing fragrance release, whereas in the case of the polystyrene support, the hydrophilicity of the environment remained constant. These results suggest that the nature of the polymer backbone may have a stronger influence on the fragrance release than the ratio of hydrophilic and hydrophobic monomers in the polymer chain.     

Dendritic Polyglycerol‐Derived Nano‐Architectures as Delivery Platforms of Gemcitabine for Pancreatic Cancer

Dendritic polyglycerol‐co‐polycaprolactone (PG‐co‐PCL)‐derived block copolymers are synthesized and explored as nanoscale drug delivery platforms for a chemotherapeutic agent, gemcitabine (GEM), which is the cornerstone of therapy for pancreatic ductal adenocarcinoma (PDAC). Current treatment strategies with GEM result in suboptimal therapeutic outcome owing to microenvironmental resistance and rapid metabolic degradation of GEM. To address these challenges, physicochemical and cell‐biological properties of both covalently conjugated and non‐covalently stabilized variants of GEM‐containing PG‐co‐PCL architectures have been evaluated. Self‐assembly behavior, drug loading and release capacity, cytotoxicity, and cellular uptake properties of these constructs in monolayer and in spheroid cultures of PDAC cells are investigated. To realize the covalently conjugated carrier systems, GEM, in conjunction with a tertiary amine, is attached to the polycarbonate block grafted from the PG‐co‐PCL core. It is observed that pH‐dependent ionization properties of these amine side‐chains direct the formation of self‐assembly of block copolymers in the form of nanoparticles. For non‐covalent encapsulation, a facile “solvent‐shifting” technique is adopted. Fabrication techniques are found to control colloidal and cellular properties of GEM‐loaded nanoconstructs. The feasibility and potential of these newly developed architectures for designing carrier systems for GEM to achieve augmented prognosis for pancreatic cancer are reported.     

Chemo‐Enzymatic Synthesis of Degradable PTMC‐b‐PECA‐b‐PTMC Triblock Copolymers and their Micelle Formation for pH‐Dependent Controlled Release

A series of degradable triblock copolymers, poly(trimethylene carbonate)‐block‐poly[poly(ethylene glycol)‐co‐cyclic acetal]‐block‐poly(trimethylene carbonate) (PTMC‐b‐PECA‐b‐PTMC), were chemo‐enzymatically synthesized. Cyclic acetal was introduced into a poly(ethylene glycol) segment as a degradable segment to impart a pH‐dependent degradation nature and to prevent the production of acidic degradation products. Amphiphilic polymeric micelles were successfully prepared, and the properties of the micelles were significantly affected by their chemical compositions and the molecular weights. A drug release study showed that the release rate increased as the pH of the buffer decreased due to the degradation of the cyclic acetal segments, indicating its high utility for pH‐sensitive controlled release.

     

Controlled Release of a Sparingly Water‐Soluble Anticancer Drug through pH‐Responsive Functionalized Gold‐Nanoparticle‐Decorated Liposomes

The binding and detachment of carboxyl‐modified gold nanoparticles from liposomes is used for controlled drug delivery. This study reveals that the binding and detachment of nanoparticles from liposomes depends on the degree of hydration of the liposomes. Liposomes with a lower hydration level undergo stronger electrostatic interactions with negatively charged gold nanoparticles, thus leading to a slower detachment of the carboxyl‐modified gold nanoparticles under gastric conditions. Therefore, under gastric conditions, gold‐nanoparticle‐decorated dipalmitoylphosphatidylcholine (DPPC) liposomes exhibit an at least ten‐times‐slower drug release compared to gold‐nanoparticle‐decorated 1,2‐dimyristoyl‐sn‐glycero‐3‐phosphocholine (DMPC) liposomes, although both liposomes in the bare state fail to pursue controlled release. Our study also reveals that one can modulate the drug‐release rate by simply varying the concentration of nanoparticles. This study highlights a novel strategy for the controlled release of drug molecules from liposomes.     

A p‐Hydroxyphenacyl–Benzothiazole–Chlorambucil Conjugate as a Real‐Time‐Monitoring Drug‐Delivery System Assisted by Excited‐State Intramolecular Proton Transfer

Among the well‐known phototriggers, the p‐hydroxyphenacyl (pHP) group has consistently enabled the very fast, efficient, and high‐conversion release of active molecules. Despite this unique behavior, the pHP group has been ignored as a delivery agent, particularly in the area of theranostics, because of two major limitations: Its excitation wavelength is below 400 nm, and it is nonfluorescent. We have overcome these limitations by incorporating a 2‐(2′‐hydroxyphenyl)benzothiazole (HBT) appendage capable of rapid excited‐state intramolecular proton transfer (ESIPT). The ESIPT effect also provided two unique advantages: It assisted the deprotonation of the pHP group for faster release, and it was accompanied by a distinct fluorescence color change upon photorelease. In vitro studies showed that the p‐hydroxyphenacyl–benzothiazole–chlorambucil conjugate presents excellent properties, such as real‐time monitoring, photoregulated drug delivery, and biocompatibility.     

γ‐Butyrolactone Copolymerization with the Well‐Documented Polymer Drug Carrier Poly(ethylene oxide)‐block‐poly(ε‐caprolactone) to Fine‐Tune Its Biorelevant Properties

Polymeric drug carriers exhibit excellent properties that advance drug delivery systems. In particular, carriers based on poly(ethylene oxide)‐block‐poly(ε‐caprolactone) are very useful in pharmacokinetics. In addition to their proven biocompatibility, there are several requirements for the efficacy of the polymeric drug carriers after internalization, e.g., nanoparticle behavior, cellular uptake, the rate of degradation, and cellular localization. The introduction of γ‐butyrolactone units into the hydrophobic block enables the tuning of the abovementioned properties over a wide range. In this study, a relatively high content of γ‐butyrolactone units with a reasonable yield of ≈60% is achieved by anionic ring‐opening copolymerization using 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene as a very efficient catalyst in the nonpolar environment of toluene with an incorporated γ‐butyrolactone content of ≈30%. The content of γ‐butyrolactone units can be easily modulated according to the feed ratio of the monomers. This method enables control over the rate of degradation so that when the content of γ‐butyrolactone increases, the rate of degradation increases. These findings broaden the application possibilities of polyester‐polyether‐based nanoparticles for biomedical applications, such as drug delivery systems.     

In situ forming PLGA implant for 90 days controlled release of leuprolide acetate for treatment of prostate cancer

In prostate cancer, hormone therapy via leuprolide acetate drug (LUP) is used to lower the level of testosterone down to castration level to effectively control the development of prostate cancer. The objective of this study was to evaluate the effective parameters in degradation and controlled release of an injectable in situ formed polymeric implant, loaded with leuprolide acetate, in order to achieve an optimum formulation for sustained drug release for 90 days with minimum burst release. The main problem associating with such implants is their high burst release. Designing an injectable implant with sustained and minimum burst release has thus become an attractive challenge in drug delivery field. Effects of type of poly(lactic‐co‐glycolic acid) 75:25 copolymers (RG752, RG756) and addition of nano‐hydroxyapatite (HA) particles on degradation rates of the implants and release profiles were examined in vitro and in vivo in a rabbit animal model. Results showed that implants containing polymers with higher molecular weights had significantly lower weight loss and molecular weight reduction. Adding nanoparticles of hydroxyapatite into poly(lactic‐co‐glycolic acid) implants caused further reduction in degradation rates, leading to a more sustained drug release in vivo, with reduced burst release. Different conventional kinetic models were applied to drug release and degradation data. The degradation data fit well to the first‐order degradation model. Higuchi model was the best kinetic release model fitted to the experimental in vitro release data. This study led to an optimum formulation (RG756:RG752 3:1 + 5% HA) with sustained leuprolide release and testosterone suppression over a 90‐day period with significant decrease of burst release phase (50%, p < 0.001) compared with the conventional Eligard formulation. The histopathology test showed that the formulated implant had no effects of toxicity or tissue necrosis in organs of the animal model. Copyright © 2017 John Wiley & Sons, Ltd.     

Novel Biodegradable Polymer with Redox‐Triggered Backbone Cleavage Through Sequential 1,6‐Elimination and 1,5‐Cyclization Reactions

In the past decade, the self‐immolative biodegradable polymer arose as a novel paradigm for its efficient degradation mechanism and vast potential for advanced biomedical applications. This study reports successful synthesis of a novel biodegradable polymer capable of self‐immolative backbone cleavage. The monomer is designed by covalent conjugations of both pendant redox‐trigger (p‐nitrobenzyl alcohol) and self‐immolative linker (p‐hydroxybenzyl alcohol) to the cyclization spacer (n‐2‐(hydroxyethyl)ethylene diamine), which serves as the structural backbone. The polymerization of the monomer with hexamethylene diisocyanate yields a linear redox‐sensitive polymer that can systemically degrade via sequential 1,6‐elimination and 1,5‐cyclization reactions within an effective timeframe. Ultimately, the polymer's potential for biomedical application is simulated through in vitro redox‐triggered release of paclitaxel from polymeric nanoparticles.