Yan Xiao

Fine tuning micellar core-forming block of poly(ethylene glycol)-block-poly(ε-caprolactone) amphiphilic copolymers based on chemical modification for the solubilization and delivery of doxorubicin.

This study aimed to optimize poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL)-based amphiphilic block copolymers for achieving a better micellar drug delivery system (DDS) with improved solubilization and delivery of doxorubicin (DOX). First, the Flory-Huggins interaction parameters between DOX and the core-forming segments [i.e., poly(ε-caprolactone) (PCL) and poly[(ε-caprolactone-co-γ-(carbamic acid benzyl ester)-ε-caprolactone] (P(CL-co-CABCL))] was calculated to assess the drug-polymer compatibility. The results indicated a better compatibility between DOX and P(CL-co-CABCL) than that between DOX and PCL, motivating the synthesis of monomethoxy-poly(ethylene glycol)-b-poly[(ε-caprolactone-co-γ-(carbamic acid benzyl ester)-ε-caprolactone] (mPEG-b-P(CL-co-CABCL)) block copolymer. Second, two novel block copolymers of mPEG-b-P(CL-co-CABCL) with different compositions were prepared via ring-opening polymerization of CL and CABCL using mPEG as a macroinitiator and characterized by (1)H NMR, FT-IR, GPC, WAXD, and DSC techniques. It was found that the introduction of CABCL decreased the crystallinity of mPEG-b-PCL copolymer. Micellar formation of the copolymers in aqueous solution was investigated with fluorescence spectroscopy, DLS and TEM. mPEG-b-P(CL-co-CABCL) copolymers had a lower critical micelle concentration (CMC) than mPEG-b-PCL and subsequently led to an improved stability of prepared micelles. Furthermore, both higher loading capacity and slower in vitro release of DOX were observed for micelles of copolymers with increased content of CABCL, attributed to both improved drug-core compatibility and favorable amorphous core structure. Meanwhile, DOX-loaded micelles facilitated better uptake of DOX by HepG2 cells and were mainly retained in the cytosol, whereas free DOX accumulated more in the nuclei. However, possibly because of the slower intracellular release of DOX, DOX-loaded micelles were less potent in inhibiting cell proliferation than free DOX in vitro. Taken together, the introduction of CABCL in the core-forming block of mPEG-b-PCL resulted in micelles with superior properties, which hold great promise for drug delivery applications.

Self-assembly of pH-sensitive mixed micelles based on linear and star copolymers for drug delivery.

Comicellization of a star block copolymer poly(ε-caprolactone)-block-poly(diethylamino)ethyl methacrylate (S(PCL-b-PDEAEMA)) and a linear block copolymer methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) (mPEG-b-PCL) was developed to enhance the stability and lower the cytotoxicity of the micelles. The two copolymers self-assembled into the mixed micelles with a common PCL core surrounded by a mixed PDEAEMA/mPEG shell in aqueous solution. This core-shell structure was transformed to the core-shell-corona structure at high pH due to the collapse of the PDEAEMA segment. The properties of the polymeric micelles were greatly dependent on the weight ratio of the two copolymers and the external pH. As increasing the mPEG-b-PCL content, the size and the zeta potential of the mixed micelles were lowered while the pH-dependent stability and the biocompatibility were improved. Moreover, an increase in pH accelerated the release of indomethacin (IND) from the mixed micelles in vitro. These results augured that the mixed micelles could be applied as a stable pH-sensitive release system.

Synthesis, characterization, fluorescence labeling and cellular internalization of novel amine -functionalized poly(ethylene glycol)- block -poly(ε-caprolactone) amphiphilic block copolymers

We report in this paper a facile way to prepare novel amine-functionalized monomethoxy-poly(ethylene glycol)-b-poly(e-caprolactone) (mPEG-b-PCL) amphiphilic block copolymers, which are subsequently fluorescently labeled. In our synthetic route, monomethoxy-poly(ethylene glycol)-b-poly[e-caprolactone-co-γ-(carbamic acid benzyl ester)-e-caprolactone] [mPEG-b-P(CL-co-CABCL)] copolymers were synthesized viaring-opening polymerization (ROP) of e-caprolactone (CL) and a newly developed monomer, γ-(carbamic acid benzyl ester)-e-caprolactone (CABCL) at varied ratios using mPEG as macroinitiator and Sn(Oct)2 as catalyst. Subsequent deprotection upon removal of carbobenzoxy (Cbz) group yielded monomethoxy-poly(ethylene glycol)-b-poly(e-caprolactone-co-γ-amino-e-caprolactone) [mPEG-b-P(CL-co-ACL)] copolymers bearing primary amine functional groups on the PCL block. The structures of polymers were characterized with NMR, FT-IR and GPC techniques. These amphiphilic block copolymers self-assembled into micelles in aqueous solution and the critical micelle concentration (CMC) was dependent on the compositions of the copolymers. In addition, the particle size and morphology of micelles were studied with DLS and TEM, respectively. In vitro study demonstrated that the micelles were nontoxic to human fibroblasts based on MTT and live/dead assays. Furthermore, a proof-of-concept usage of amino groups for bioconjugation was illustrated by tagging the copolymer with a fluorophore, fluorescein isothiocyanate (FITC). Internalization of FITC-labeled micelles by fibroblast cells was observed under fluorescence microscopy. Through facile conjugation of chemical moieties such as drugs, peptides, proteins or fluorophores, micelles prepared with these amine-functionalized mPEG-b-PCL copolymers hold great promise in biomedical applications.

Functional poly(ε-caprolactone) based materials: preparation, self-assembly and application in drug delivery.

Recent advances in synthesis of functional poly-ε-caprolactone (PCL) and its self-assembly behavior, as well as application in drug delivery have been reviewed. Three strategies including end group functionalization, postpolymerization modification and new monomer preparation have been summarized to show possibilities for PCL derivatives. Complex architectures like cyclic and multi-arm PCL have been emphasized. Both chemical composition and topology have coordinately affected the property of PCL-based materials on the molecular level. A large variety of PCLs with sophisticated topology like block, graft, cyclic, and star have displayed versatile morphologies in solutions. These selfassembly aggregates have been applied as nano-scaled drug carries either to physically encapsulate or covalently conjugate drugs for controlled release. In particular, PCL with pendant groups has been extensively studied to illustrate the noncovalent interaction with drugs and the influence on the release profile. In general, functional PCL has shown great potential in construct of complicated supramolecular structures, and thus as ideal drug carriers for sustainable and targeted delivery.

Synthesis of biodegradable chiral polyesters by asymmetric enzymatic polymerization and their formulation into microspheres

Materials with selective bio-responsiveness could have potential in medical applications. Here we report the synthesis of chiral microspheres obtained from non-crystalline aliphatic polyesters, with the aim to use chirality to program polymer microsphere degradation. By enzymatic enantioselective kinetic resolution polymerization from racemic monomers, hydroxyl-terminated (R)-, (S)- and racemic poly-(4-methylcaprolatone) (PMCL) were successfully synthesized. Preliminary degradation experiments with Candida Antarctica Lipase B show that the degradation rate can be tuned by the polymer chirality. Chiral microspheres around 40 microns were obtained after acrylation of the polymers and subsequent in situ cross-linking in an oil-in-water (O-W) emulsion evaporation approach.

Preparation of poly(methyl methacrylate) grafted hydroxyapatite nanoparticles via reverse ATRP

Surface-initiated reverse atom transfer radical polymerization (reverse ATRP) technical was successfully employed to modify hydroxyapatite (HAP) nanoparticles with poly(methyl methacrylate) (PMMA). The peroxide initiator moiety for reverse ATRP was covalently attached to the HAP surface through the surface hydroxyl groups. Reverse ATRP of methyl methacrylate (MMA) from the initiator-functionalized HAP was carried out, and the end bromide groups of grafted PMMA initiated ATRP of MMA subsequently. Fourier transformation infrared (FTIR) spectroscopy, thermal gravimetric analysis (TGA) and transmission electron microscopy (TEM) were employed to confirm the grafting and to characterize the nanoparticle structure. The grafted PMMA gave HAP nanoparticles excellent dispersibility in MMA monomer. As the amount of grafted PMMA increased, the dispersibility of surface-grafted HAP and the compressive strength of HAP/PMMA composites were improved.

Synthesis, self-assembly, and pH-responsive behavior of (photo-crosslinked) star amphiphilic triblock copolymer

Conventional polymeric micelles employed as drug carriers suffer from the drawback of disaggregation when diluted into body fluids, giving rise to premature release of drugs. In this work, cinnamate was chosen as a crosslinker to overcome this issue and regulate pH response. A series of photo-crosslinkable star amphiphilic triblock copolymers, star poly(ε-caprolactone)-b-poly(2-cinnamoyloxyethyl methacrylate)-b-poly(2-(dimethylamino)ethyl methacrylate) (SPCL-b-PCEMA-b-PDMAEMA), were prepared by combination of stepwise reversible addition-fragment chain transfer (RAFT) polymerization and carbodiimide-mediated coupling reaction. These star amphiphilic copolymers could self-assemble into core-shell-corona micelles. Facile photo crosslinking of the micelles was carried out via UV irradiation. The crosslinked micelles showed an improved stability determined by critical micelle concentration (CMC). The degree of photo crosslinking was easily regulated by tuning UV irradiation time, and the hydrodynamic diameters (D(h)) decreased with increasing degree of photo crosslinking. The pH responses of micelles were investigated by dynamic light scattering (DLS), indicating pH-induced swelling-shrinking behavior. For photo-crosslinked micelle, its capability of swelling-shrinking weakened with increasing crosslinking degree, suggesting that pH response was controlled by crosslinking density. This novel photo-crosslinked micelle system with adjustable pH response was expected to have potential as drug carriers for controlled release.

Enhanced infarct myocardium repair mediated by thermosensitive copolymer hydrogel-based stem cell transplantation

Mesenchymal stem cell (MSC) transplantation by intramyocardial injection has been proposed as a promising therapy strategy for cardiac repair after myocardium infarction. However, low retention and survival of grafted MSCs hinder its further application. In this study, copolymer with N-isopropylacrylamide/acrylic acid/2-hydroxylethyl methacrylate-poly(ɛ-caprolactone) ratio of 88:9.6:2.4 was bioconjugated with type I collagen to construct a novel injectable thermosensitive hydrogel. The injectable and biocompatible hydrogel-mediated MSC transplantation could enhance the grafted cell survival in the myocardium, which contributed to the increased neovascularization, decreased interstitial fibrosis, and ultimately improved heart function to a significantly greater degree than regular MSC transplantation. We suggest that this novel hydrogel has the potential for future stem cell transplantation.

Systematic Comparison of HEA and HEMA as Initiators in Enzymatic Ring-Opening Polymerizations

Two initiators containing a cleavable ester bond were compared in the lipase-catalyzed ROP of CL and PDL. The results show that transesterification reactions are present at high rates throughout the enzymatic ROP and start at low conversion. HEA and HEMA displayed similar reaction efficiencies as initiators (acyl acceptors) in the enzymatic ROP. However, transacylation reactions on the HEA-initiated polyesters were found to be 15 times faster. While in both cases the amount of HEA- and HEMA-initiated polymers could be maximized by short reaction times, a well-defined (meth)acrylation by this approach was not possible. Our results show that transesterification reactions have to be considered when performing an enzyme-catalyzed ROP.

Synthesis of star-shaped PCL-based copolymers via one-pot ATRP and their self-assembly behavior in aqueous solution

A series of star-shaped poly(ɛ-caprolactone) (PCL)-based diblock and triblock copolymers containing 2-(dimethylamino)ethyl methacrylate (DMAEMA or DMA) and oligo(ethylene glycol)monomethyl ether methacrylate (OEGMA or OEG) were synthesized by one-pot atom transfer radical polymerization (ATRP) using a sixarm PCL-based macroinitiator. The precursor and the resultant copolymers were analyzed via proton nuclear magnetic resonance spectra (1H NMR) and size exclusion chromatography (SEC). The monomer reactivity ratios for DMAEMA (r1) and OEGMA (r2) were estimated to be near unity and r1×r2=1, which indicates the random distribution of the monomers in the final copolymers. Self-assembly behavior of these copolymers was investigated by fluorimetry, 1H NMR, dynamic light scattering (DLS), transmission electronic microscopy (TEM), potentiometric titrations, and zeta potential measurements. The results suggested that the star copolymers were responsive to salinity depending on their composition and structure.