Synthesis and biological evaluation of disulfide-linked HPMA copolymer-mesochlorin e6 conjugates

Novel polymeric delivery systems for the photosensitizer mesochlorin e6 (Mce6) were synthesized to overcome problems of systemic toxicity. A disulfide bond was included to allow for quick release of Mce6 from the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer backbone once internalized in tumor tissue. The synthesized conjugates demonstrated a time-dependent reductive cleavage with an accompanying increase in the quantum yield of singlet oxygen generation on exposure to DTT. Quicker release kinetics and a higher cytotoxicity in SKOV-3 human ovarian carcinoma cells were obtained as compared to polymer conjugate with a proteolytically cleavable GFLG spacer. These novel conjugates hold promise as clinically relevant drug delivery systems for photodynamic therapy of cancer.     

Biocompatible stimuli‐responsive nanogels for controlled antitumor drug delivery

Herein, the synthesis and potential application as cargo delivery systems of thermo‐responsive poly(N‐vinylcaprolactam) (PVCL)‐based, pH‐responsive poly(2‐(diethylamino)ethyl) methacrylate (PDEAEMA)‐based, and thermo‐, and pH‐responsive PDEAEMA/PVCL‐based core–shell nanogels are reported. All the nanogels have been synthesized using different dextran‐methacrylates (Dex‐MAs) as macro‐cross‐linkers. Doxorubicin hydrochloride (DOXO), an anticancer drug, has been effectively loaded into nanogels via hydrogen‐bonding interactions between ? OH groups of DOXO and ? OH groups of Dex‐MA chains. Drug‐release profiles at various pHs, and the cytocompatibility of the DOXO‐loaded nanogels have been assessed in vitro using cervical cancer HeLa and breast cancer MDA‐MB‐231 cell lines. In all the cases, the DOXO release is controlled by Fickian diffusion and case‐II transport, being the diffusional process dominant. In addition, DOXO‐loaded nanogels are efficiently internalized by HeLa and MDA‐MB‐231 cells and DOXO is progressively released in time. Therefore, nanogels synthesized could be suitable and potentially useful as nanocarriers for antitumor drug delivery. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1694–1705     

Synthesis of narrow‐polydispersity degradable dendronized aliphatic polyesters

The divergent dendronization of an ?‐caprolactone‐based polymer has been performed to provide access to dendronized polymers with sufficient biocompatibility and degradability for use as drug‐delivery scaffolds. The synthesis was performed through the tin(II) 2‐ethylhexanoate‐catalyzed polymerization of a γ‐functionalized ?‐caprolactone monomer, followed by the divergent growth of pendant polyester dendrons at each repeat unit. The resulting dendronized polymers were obtained up to the fourth generation with molecular weights as high as 80,000 Da and with polydispersities between 1.11 and 1.22. The fourth‐generation hydroxyl‐terminated dendronized polymer was degradable under a variety of aqueous conditions. A comparison of the dendronization approach with a procedure involving the ring‐opening polymerization of a second‐generation dendritic macromonomer reveals that the former procedure is best suited for the preparation of this family of dendronized polyesters because it requires shorter reaction times and affords materials with higher degrees of polymerization. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 3563–3578, 2004     

Synthesis of biocompatible and thermally sensitive poly(N‐vinylcaprolactam) nanogels via inverse miniemulsion polymerization: Effect of the surfactant concentration

The goal of this study was to develop a new route to prepare thermally responsive polymer nanogels. Poly(N‐vinylcaprolactam) nanogels were prepared via inverse miniemulsion polymerization (W/O) at 70 °C using n‐hexadecane as a nonpolar continuous phase, potassium persulfate as an initiator, and N,N′‐methylenebisacrylamide as a crosslinker. Sorbitan monooleate (Span 80) was used as surfactant and its influence on the polymerization kinetics and on the colloidal characteristics of the nanogels were principally investigated. It was observed that the addition of a strong “lipophobe” is required to stabilize the resulting miniemulsion. The nanogels were characterized in terms of morphology, size, zeta potential, and thermoproperties using transmission electron microscopy and dynamic light scattering. It was observed that all the nanogels obtained collapsed when the lower critical solution temperature (LCST) was raised. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 3932–3941, 2010     

Immobilization of aminothiols on poly(oxyethylene H‐phosphonate)s and poly(oxyethylene phosphate)s—An approach to polymeric protective agents for radiotherapy of cancer

This study describes the synthesis and characterization of polymer complexes constructed from the radioprotective agent S‐2(3‐aminopropylamino) ethylphosphorothioic acid dihydrate (amifostine or WR‐2721), applied in the radiation cancer treatment, and biodegradable poly(oxyethylene H‐phosphonate), poly(hydroxyoxyethylene phosphate), or poly(methyloxyethylene phosphate). The immobilization of another radioprotector, used in cancer radiotherapy, 1‐(3‐aminopropyl)aminoethanethiol (WR‐1065) on the same polymers is also achieved through a covalent bond (Atherton‐Todd reaction coupling), ionic bond, and physical complexation, respectively. The structure of the complexes formed is elucidated by ¹H‐ ¹³C‐, ³¹P NMR and FTIR spectroscopy. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 1349–1363, 2007     

Poly(amidoamine) Conjugates Containing Doxorubicin Bound via an Acid‐Sensitive Linker

Poly(amidoamine)s with amino pendant groups were prepared by hydrogen‐transfer polyaddition of primary and secondary amines to bis‐acrylamines. Dansyl cadaverine (DC) doxorubicin (Dox) were bound to the polymers via a cis‐aconityl spacer to give conjugates containing 3 µg of DC per mg of polymer and 28 to 35 µg of Dox per mg of polymer. Release of DC and Dox at physiological and acidic pH varied from 0 to 35% over 48 h and was pH dependent. Although the ISA1Dox conjugate (IC₅₀ = 6 µg Dox · mL^?1) presented similar toxicity as the parent polymer without Dox, ISA23Dox showed increased toxicity (IC₅₀ = 10 µg Dox · mL^?1). These results suggest that ISA23Dox is able to release biologically active Dox in vitro and that this conjugate might be suitable for further development.

     

Advanced design of t and pH dual‐responsive PDEAEMA–PVCL core–shell nanogels for siRNA delivery

The synthesis, characterization, and potential application as gene delivery systems of biodegradable dual‐responsive core–shell nanogels based on poly(2‐diethylaminoethyl) methacrylate (PDEAEMA) and poly(N‐vinylcaprolactam) (PVCL) are reported. These core–shell nanogels, having a PDEAEMA‐based core and a PVCL‐based shell, were synthesized by batch seeded emulsion polymerization. An indepth study of their swelling behavior was carried out, which presented a dual‐dependent thermo‐ and pH sensitivity. Core–shell nanogels synthesized formed complexes spontaneously through electrostatic interactions when mixing with small interfering RNA (siRNA) molecules. Moreover, the core–shell nanogel/siRNA complexes showed higher polyanion exchange resistance compared to that of the PDEAEMA‐based nanogel/siRNA complexes, indicating that the PVCL‐based shell enhanced the stability of the complexes. In vitro siRNA release profiles showed that siRNA release was controlled by the pH of the medium as well as by the crosslinking density of the PVCL‐based shell. These results indicate that dual‐responsive core–shell nanogels synthesized could be potentially useful as gene delivery systems. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3203–3217     

Self‐Assembled Supramolecular Nanogels as a Safe and Effective Drug Delivery Vector for Cancer Therapy

Simple construction and manipulation of low‐molecular‐weight supramolecular nanogels, based on the introduction of multiple hydrogen bonding interactions, with the desired physical properties to achieve effective and safe delivery of drugs for cancer therapy remain highly challenging. Herein, a novel supramolecular oligomer cytosine (Cy)‐polypropylene glycol containing self‐complementary multiple hydrogen‐bonded Cy moieties is developed, which undergoes spontaneous self‐assembly to form nanosized particles in an aqueous environment. Phase transitions and scattering studies confirm that the supramolecular nanogels can be readily tailored to obtain the desired phase‐transition temperature and temperature‐induced release of the anticancer drug doxorubicin (DOX). The resulting nanogels exhibit an extremely high load carrying capacity (up to 24.8%) and drug‐entrapment stability, making the loading processes highly efficient. Importantly, in vitro cytotoxicity assays indicate that DOX‐loaded nanogels possess excellent biosafety for drug delivery applications under physiological conditions. When the environmental temperature is increased to 40 °C, DOX‐loaded nanogels trigger rapid DOX release and exert cytotoxic effects, significantly reducing the dose required compared to free DOX. Given its simplicity, low cost, high reliability, and efficiency, this newly developed temperature‐responsive nanocarrier has highly promising potential for controlled release drug delivery systems.

     

Synthesis of poly(ester‐amide) dendrimers based on 2,2‐Bis(hydroxymethyl) propanoic acid and glycine

Water‐soluble, biodegradable, and biocompatible poly(ester‐amide) dendrimers with hydroxyl functional groups are synthesized from previously prepared AB₂ adduct of 2,2‐bis(hydroxymethyl) propanoic acid (bis‐MPA) and glycine as a repeating unit. Two esterification procedures using different coupling reagent/catalyst systems (DCC/DPTS or EDC/DMAP) are studied with respect to efficiency, ease of products purification, and quality of the final products. Both procedures have their own benefits and drawbacks, depending on dendrimer generation. The synthesized poly(ester‐amide) dendrimers as well as commercially available bis‐MPA dendrimers, poly(ester‐amide) hyperbranched polymer, and poly(vinyl alcohol) are used for preparation of solid dispersions of sulfonylurea antidiabetic drug glimepiride to improve its poor water‐solubility. In vitro dissolution studies show in comparison with pure glimepiride in crystalline or amorphous form, to the same extent improved glimepiride solubility for solid dispersions based on dendritic polymers, but not for poly(vinyl alcohol). The amount of glimepiride complexed with both dendrimer types increases with dendrimer generation. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 3292–3301     

Thiol‐responsive micelles based on nonionic gemini surfactants with a cystine disulfide spacer

Thiol‐responsive micelles consisting of novel nonionic gemini surfactants with a cystine disulfide spacer are reported. The gemini surfactants, (C₁₈‐Cys‐mPEG)₂ and ((C₁₈)₂‐Lys‐Cys‐mPEG)₂, were synthesized from polyethylene glycol, cysteine, and stearic acid, and their structures were confirmed by ¹H NMR and gel permeation chromatography. (C₁₈‐Cys‐mPEG)₂ and ((C₁₈)₂‐Lys‐Cys‐mPEG)₂ formed micelles with average diameters of 13 and 22 nm above the critical micelle concentration of 6.5 and 4.7 µg mL^?1, respectively. The micelles of ((C₁₈)₂‐Lys‐Cys‐mPEG)₂ containing more stearoyl groups showed encapsulated more hydrophobic indomethacin (IMC) with higher entrapment efficiencies than those of (C₁₈‐Cys‐mPEG)₂. The gemini surfactant micelles exhibited an accelerated release of encapsulated IMC with the concentration of the reducing agent, glutathione (GSH), whereas they were unaffected by the presence of reduced GSH (GSSG). The 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)?2‐(4‐sulfophenyl)?2H‐tetrazolium studies revealed the noncytotoxic nature of the gemini surfactant micelles. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 582–589     

Approach to peptide decorated micelles via RAFT polymerization

Pyridyldisulfide (PDS) functionalized telechelic polymers of oligo(ethyleneglycol) acrylate (PEG‐A) and their amphiphilic triblock copolymers with styrene (St) were synthesized directly by reversible addition‐fragmentation chain transfer (RAFT) polymerization using a new bifunctional RAFT agent, S,S‐bis[α,α′‐dimethyl‐α″‐(2‐pyridyl disulfide) ethyl acetate] trithiocarbonate (BDPET). The homopolymerization of PEG‐A was found to be well controlled using BDPET (PDI < 1.2). The ABA triblock copolymers poly(PEG‐A)‐b‐poly(St)‐b‐poly(PEG‐A) with narrow molecular weight distribution (PDI < 1.25) were synthesized using poly(PEG‐A) as a macro‐RAFT agent. UV‐vis spectroscopic analysis revealed that 85 mol % of poly(PEG‐A) and 78 mol % of poly(PEG‐A)‐b‐poly(St)‐b‐poly(PEG‐A) retained PDS end group functionality. Micelles were observed to form from poly(PEG‐A)‐b‐poly(St)‐b‐poly(PEG‐A). The presence of PDS groups within the micelle corona was evidenced by UV‐vis spectroscopy and fluorescence spectroscopy. The PDS groups within the corona were then used to functionalize the micelles with a thiol group bearing model peptide, reduced glutathione, and a thiol modified fluorophore, rhodamine B, under mild reaction conditions. UV‐vis and fluorescence spectrocopies revealed that approximately 80% PDS groups from the amphiphilic copolymer were tethered within the micelle coronas and accessible to glutathione and fluorophore attachment. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 899–912, 2009     

Interpolymer Complexes of Water‐Soluble Nonionic Polysaccharides with Polycarboxylic Acids and Their Applications

Literature data as well as our own experimental results devoted to the complexation of polycarboxylic acids with various water‐soluble polysaccharides (methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, starch, and dextran) by means of hydrogen bonding are systematized and analyzed. The specific peculiarities of interpolymer complexes based on polysaccharides‐polycarboxylic acids are demonstrated. The perspectives for the application of these interpolymer complexes are considered. It was shown that these materials possess good biocompatibility and adhesive properties. The promising directions for further study of interpolymer complexes between polycarboxylic acids and nonionic polysaccharides as well as existing gaps in the knowledge in this field are pointed out.

Formation of compact IPCs and hydrophilic interpolymer associates.     

Synthesis and characterization of star oligo/poly(2,2‐dimethyltrimethylene carbonate)s containing cholic acid moieties

Star oligo/poly(2,2‐dimethyltrimethylene carbonate)s containing cholic acid moieties were synthesized through the ring‐opening polymerization of 2,2‐dimethyltrimethylene carbonate (DTC) initiated by cholic acid with hydroxyl groups. Through the control of the feed ratio of the initiator cholic acid to the monomer DTC, a series of star oligomers/polymers with different molecular weights were obtained. The star oligomers/polymers were characterized with Fourier transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, combined size exclusion chromatography/multi‐angle laser light scattering analysis, wide‐angle X‐ray scattering, polarizing light microscopy, and differential scanning calorimetry. Compared with linear poly(2,2‐dimethyltrimethylene carbonate), these star oligo/poly(2,2‐dimethyltrimethylene carbonate)s had much faster hydrolytic degradation rates. With one of the star oligomers/polymers, a microsphere drug‐delivery system of a submicrometer size was fabricated with a very convenient ultrasonic dispersion method that did not involve toxic organic solvents. The in vitro drug release was studied. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 6688‐6696, 2006     

Control of thermal properties and hydrolytic degradation in poly(lactic acid) polymer stars through control of isospecificity of polymer arms

The synthesis of a family of polymer stars with arms of varied tacticities is discussed. The effect of polymer tacticity on the physical properties of these polymer stars is dramatic. Dipentaerythritol cores support six poly(lactic acid) arms. Lewis acidic tin and/or aluminum catalysts control the polymerization to afford polymer stars of variable tacticity. Analysis of these polymers by ¹H NMR spectroscopy, thermogravimetric analysis, powder X‐ray diffraction, and differential scanning calorimetry reveals the effects of tacticity control on the physical properties of the polymer stars. Hydrolytic decomposition studies suggest that the degradation profile of a polymer star may also be tuned by stereochemical control. Differences between isotactic samples derived from rac‐lactide and L ‐lactide are heightened by longer arms of 50 and 100 monomer units. Control of polymer isospecificity shows that a ～70% isotacticity bias is necessary to induce crystallinity and alter the thermal and degradation properties of the material. Above 70% isotacticity, the degradation properties and thermal transitions can be further tuned across a relatively wide range. This technique allows for significant tunability to the physical properties of aliphatic polyester polymer stars. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Well‐defined drug‐conjugated biodegradable nanoparticles by azide–alkyne click crosslinking in miniemulsion

A new type of biodegradable polymer–drug nanoconjugate was fabricated via the combination of oil‐in‐water miniemulsion and Huisgen azide–alkyne click chemistry. Diazide‐functionalized paclitaxel (PTXL) were prepared through functional group transformation on the C‐2′ and C‐7 positions of PTXL and served as both drug carrier and crosslinker. Acetylene‐functionalized polylactide (PLA) was used as the base polymer. Oil‐in‐water miniemulsion technique was used to create nanodroplets with diameters of round 50 nm, which were used as nanoreactors to control the size and morphology of the drug conjugates. Using sodium ascorbate/CuSO₄·5H₂O as catalysts, click reaction was performed within the nanodroplets between the azide functionalities of the PTXL‐based crosslinker and the pendant acetylene groups of the functional PLA. High extent of reaction was confirmed by FTIR analysis and the resulting drug‐conjugated nanoparticles were characterized by dynamic light scattering, transmission electron microscopy, and atomic force microscopy measurements. These NPs exhibited considerable degradation in proteinase K solution within 1 week. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Facile Fabrication of Thermo‐Responsive and Reduction‐Sensitive Polymeric Micelles for Anticancer Drug Delivery

The development of thermo‐responsive and reduction‐sensitive polymeric micelles based on an amphiphilic block copolymer poly[(PEG‐MEMA)‐co‐(Boc‐Cyst‐MMAm)]‐block‐PEG (denoted PEG‐P‐SS‐HP) for the intracellular delivery of anticancer drugs is reported. PTX, as model drug, was loaded into the PEG‐P‐SS‐HP micelles with an encapsulation efficiency >90%, resulting in a high drug loading content (up to 35 wt%). The PTX‐loaded PEG‐P‐SS‐HP micelles show slow drug release in PBS and rapid release after incubation with DTT. The PTX‐loaded micelles display a better cytotoxic effect than the free drug, whereas empty micelles are found to be non‐toxic. The thermo‐responsive and reduction‐sensitive polymeric micelles described may serve as promising carriers for cytostatic drugs.

     

Synthesis of Degradable Poly[(Ethylene Glycol)‐co‐(Glycolic Acid)] via the Post‐Polymerization Oxyfunctionalization of Poly(Ethylene Glycol)

To enhance the limited degradability of poly(ethylene glycol) (PEG), a straightforward method of synthesizing poly[(ethylene glycol)‐co‐(glycolic acid)] (P(EG‐co‐GA)) via a ruthenium‐catalyzed, post‐polymerization oxyfunctionalization of various PEGs is developed. Using this method, a set of copolymers with GA compositions of up to 8 mol% are prepared with minimal reduction in molecular weight (<10%) when compared to their commercially available starting materials. The P(EG‐co‐GA) copolymers are shown to undergo hydrolysis under mild conditions.

     

Amphiphilic comb-like polymers based on poly(oxyethylene)s as drug-delivery carriers

Comb-like polymers with biocompatible oxyethylene backbones and amphiphilic side groups were synthesized via polymer-analogous reactions. Using these polymers, indomethacin-loaded polymeric micelles were fabricated with various drug-to-polymer weight ratios using the oil-in-water emulsion technique. In addition, the size, size distribution, CMC, drug-loading content, and entrapment efficiency of the polymeric micelles were analyzed. The volume-weighted diameters of polymeric micelles ranged from 10 to 140 nm and were narrowly distributed for passive targeting drug delivery. The CMCs were lower (approximately 10(-8) M) than for conventional surfactants and block copolymers.     

Bioreducible and core‐crosslinked hybrid micelles from trimethoxysilyl‐ended poly(ε‐caprolactone)‐S‐S‐poly(ethylene oxide) block copolymers: Thiol‐ene click synthesis and properties

Bioreducible and core‐crosslinked hybrid micelles were for the first time fabricated from biodegradable and biocompatible trimethoxysilyl‐terminated and disulfide‐bond‐linked block copolymers poly(ε‐caprolactone)‐S‐S‐poly(ethylene oxide), which were prepared by combining thiol‐ene coupling reaction and ring‐opening polymerization. The molecular structures, physicochemical, self‐assembly, and bioreducible properties of these copolymers were thoroughly characterized by means of FTIR, ¹H NMR, gel permeation chromatography, differential scanning calorimetry, wide‐angle X‐ray diffraction, dynamic light scattering (DLS), and transmission electron microscopy. The core‐crosslinking sol‐gel reaction was confirmed by ¹H NMR, and the core‐crosslinked hybrid micelles contained about 3 wt % of silica. The bioreducible property of both uncrosslinked and core‐crosslinked micelles in 10 mM 1,4‐dithiothreitol (DTT) solution was monitored by DLS, which demonstrated that the PEO corona gradually shedded from the PCL core. The anticancer doxorubicin drug‐loaded micelles showed nearly spherical morphology compared with blank micelles, presenting a DTT reduction‐triggered drug‐release profile at 37 °C. Notably, the core‐crosslinked hybrid micelles showed about twofold drug loading capacities and a half drug‐release rate compared with the uncross‐liked counterparts. This work provides a useful platform for the fabrication of bioreducible and core‐crosslinked hybrid micelles potential for anticancer drug delivery system. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012