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.

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.

We report on the fabrication of a photodegradable gene-delivery vector based on PEO-b-P(GMA-g-PDMAEMA) neutral–cationic brush block copolymers that possess cationic poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA) brushes for DNA compaction, poly(ethylene oxide) (PEO) as a hydrophilic block, and poly(glycidyl methacrylate) (PGMA) as the backbone. The PEO-b-P(GMA-g-PDMAEMA) copolymers were synthesized through the combination of reversible addition–fragmentation transfer (RAFT) polymerization and postmodification. A photocleavable PEO-based macroRAFT agent was first synthesized; next, the PEO-b-PGMA block copolymer was prepared by RAFT polymerization of GMA; this was followed by a click reaction to introduce the RAFT initiators on the side chains of the PGMA block; then, RAFT polymerization of DMAEMA afforded the PEO-b-P(GMA-g-PDMAEMA) copolymer. The obtained neutral–cationic brush block copolymer could effectively complex plasmid DNA (pDNA) into nanoparticles at an N/P ratio (i.e., the number of nitrogen residues per DNA phosphate) of 4. Upon UV irradiation, pDNA could be released owing to cleavage of the pDNA-binding cationic PDMAEMA side chains as well as the nitrobenzyl ester linkages at the diblock junction point. In addition, in vitro gene transfection results demonstrated that the polyplexes could be effectively internalized by cells with good transfection efficiency, and the UV irradiation protocol could considerably enhance the efficiency of gene transfection.

The fabrication of block copolymer (BCP) vesicles (polymersomes) exhibiting synchronized covalent crosslinking and bilayer permeabilization remains a considerable challenge as crosslinking typically leads to compromised membrane permeability. Herein it is demonstrated how to solve this dilemma by employing a stimuli-triggered crosslinking strategy with amphiphilic BCPs containing photolabile carbamate-caged primary amines. Upon self-assembling into polymersomes, light-triggered self-immolative decaging reactions release primary amine moieties and extensive amidation reactions then occur due to suppressed amine pK_a within hydrophobic milieu. This leads to serendipitous vesicle crosslinking and the process is associated with bilayer hydrophobicity-to-hydrophilicity transition and membrane permeabilization.

The fabrication of block copolymer (BCP) vesicles (polymersomes) exhibiting synchronized covalent crosslinking and bilayer permeabilization remains a considerable challenge as crosslinking typically leads to compromised membrane permeability. Herein it is demonstrated how to solve this dilemma by employing a stimuli-triggered crosslinking strategy with amphiphilic BCPs containing photolabile carbamate-caged primary amines. Upon self-assembling into polymersomes, light-triggered self-immolative decaging reactions release primary amine moieties and extensive amidation reactions then occur due to suppressed amine pK_a within hydrophobic milieu. This leads to serendipitous vesicle crosslinking and the process is associated with bilayer hydrophobicity-to-hydrophilicity transition and membrane permeabilization.

The fabrication of photo-degradable, protein–polyelectrolyte complex (PPC)-coated, mesoporous silica nanoparticles (MSNs) and their controlled co-release of protein and model drugs is reported. Random copolymers composed of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA), and a photolabile o-nitrobenzyl-containing monomer, 5-(2′-(dimethylamino)ethoxy)-2-nitrobenzyl methacrylate (DENBMA), are first anchored onto the MSNs and then quaternary aminated, to obtain positively charged P(OEGMA-co-TENBMA) which exhibits photo-induced charge conversion characteristics. PPCs consisting of P(OEGMA-co-TENBMA) and the protein bovine serum albumin (BSA) are utilized as capping agents for the nanopores of the MSNs. Upon UV irradiation, charge conversion of P(OEGMA-co-TENBMA) can lead to the disruption of PPCs on MSNs and co-release of BSA and rhodamine B by electrostatic repulsion.

The fabrication of a novel type of positively charged acid-disintegrable microgel loaded with insulin by electrostatic interactions and covalently immobilized with glucose oxidase (GOx) and catalase by inverse emulsion polymerization is reported, aiming for glucose-regulated insulin release by utilizing GOx/catalase cascade enzymatic reactions to trigger local pH decrease and acid-cleavage of crosslinking moieties. At the same time, a local pH decrease within the microgels also leads to the diminishment of net surface negative charges of encapsulated insulin. The above two factors both synergistically contribute to the prominently enhanced insulin release at high glucose levels (∼10–20 mM) compared to that in the absence of glucose.

We report on the fabrication of well-defined polymer–protein bioconjugates with varying chain architectures, including star polymers, star block copolymers, and heteroarm star copolymers through the specific noncovalent interaction between avidin and biotinylated synthetic polymer precursors. Homopolymer and diblock precursors site-specifically labeled with a single biotin moiety at the chain terminal, chain middle, or diblock junction point were synthesized by a combination of atom-transfer radical polymerization (ATRP) and click reactions. By taking advantage of molecular recognition between avidin and biotin moieties, supramolecular star polymers, star block copolymers, and heteroarm star copolymers were successfully fabricated. This specific binding process was also assessed by using the diffraction optic technology (DOT) technique. We further investigated the effects of polymer molecular weights, location of biotin functionality within the polymer chain, and polymer chain conformations, that is, steric hindrance effects, on the binding numbers of biotinylated polymer chains per avidin within the polymer–protein bioconjugates, which were determined by the standard avidin/2-(4-hydroxyazobenzene)benzoic acid (HABA) assay. The binding numbers vary in the range of 1.9–3.3, depending on the molecular weights, locations of biotin functionality within synthetic polymer precursors, and polymer chain conformations.

The syntheses of well-defined 7-arm and 21-arm poly(N-isopropylacrylamide) (PNIPAM) star polymers possessing β-cyclodextrin (β-CD) cores were achieved via the combination of atom transfer radical polymerization (ATRP) and click reactions. Heptakis(6-deoxy-6-azido)-β-cyclodextrin and heptakis[2,3,6-tri-O-(2-azidopropionyl)]-β-cyclodextrin, β-CD-(N₃)₇ and β-CD-(N₃)₂₁, precursors were prepared and thoroughly characterized by nuclear magnetic resonance and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. A series of alkynyl terminally functionalized PNIPAM (alkyne-PNIPAM) linear precursors with varying degrees of polymerization (DP) were synthesized via atom transfer radical polymerization (ATRP) of N-isopropylacrylamide using propargyl 2-chloropropionate as the initiator. The subsequent click reactions of alkyne-PNIPAM with β-CD-(N₃)₇ and β-CD-(N₃)₂₁ led to the facile preparation of well-defined 7-arm and 21-arm star polymers, namely β-CD-(PNIPAM)₇ and β-CD-(PNIPAM)₂₁. The thermal phase transition behavior of 7-arm and 21-arm star polymers with varying molecular weights were examined by temperature-dependent turbidity and micro-differential scanning calorimetry, and the results were compared to those of linear PNIPAM precursors. The anchoring of PNIPAM chain terminal to β-CD cores and high local chain density for star polymers contributed to their considerably lower critical phase separation temperatures (T_c) and enthalpy changes during phase transition as compared with that of linear precursors. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 404–419, 2009

Amphiphilic ABC miktoarm star terpolymers consisting of polystyrene, poly(ε-caprolactone), and poly(N-isopropylacrylamide) arms, PS(-b-PNIPAM)-b-PCL, were synthesized via a combination of atom transfer radical polymerization, ring-opening polymerization (ROP), and click chemistry. Difunctional PS bearing an alkynyl and a primary hydroxyl moiety at the chain end, PS-alknyl-OH, was prepared by reacting azido-terminated PS with an excess of 3,5-bis(propargyloxy)benzyl alcohol (BPBA) under click conditions. The subsequent ROP of ε-caprolactone using PS-alknyl-OH macroinitiator afforded PS(-alkynyl)-b-PCL copolymer bearing an alkynyl moiety at the diblock junction point. Target PS(-b-PNIPAM)-b-PCL amphiphilic ABC miktoarm star terpolymers were then prepared via click reaction between PS(-alkynyl)-b-PCL and an excess of azido-terminated PNIPAM (PNIPAM-N₃). The removal of excess PNIPAM-N₃ was accomplished by “clicking” onto alkynyl-functionalized Wang resin. All the intermediate and final products were characterized by gel permeation chromatography, ¹H NMR, and FTIR. In aqueous solution, the obtained amphiphilic ABC miktoarm star terpolymer self-assembles into micelles possessing mixed PS/PCL cores and thermoresponsive shells, which were further characterized by dynamic laser light scattering and transmission electron microscopy. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 1636–1650, 2009

We report on the one-pot synthesis of well-defined ABC miktoarm star terpolymers consisting of poly(2-(dimethylamino)ethyl methacrylate), poly(ε-caprolactone), and polystyrene or poly(ethylene oxide) arms, PS(-b-PCL)-b-PDMA and PEO (-b-PCL)-b-PDMA, taking advantage of the compatibility and mutual tolerability of reaction conditions (catalysts and monomers) employed for atom transfer radical polymerization (ATRP), ring-opening polymerization (ROP), and click reactions. At first, a novel trifunctional core molecule bearing alkynyl, hydroxyl group, and bromine moieties, alkynyl(OH)Br, was synthesized via the esterification reaction of 5-ethyl-5-hydroxymethyl-2,2-dimethyl-1,3-dioxane with 4-oxo-4-(prop-2-ynyloxy)butanoic acid, followed by deprotection and monoesterification of alkynyl(OH)₂ with 2-bromoisobutyryl bromide. In the presence of trifunctional core molecule, alkynyl(OH)Br, and CuBr/PMDETA/Sn(Oct)₂ catalytic mixtures, target ABC miktoarm star terpolymers, PS(-b-PCL)-b-PDMA and PEO(-b-PCL)-b-PDMA, were successfully synthesized in a one-pot manner by simultaneously conducting the ATRP of 2-(dimethylamino)ethyl methacrylate (DMA), ROP of ε-caprolactone (ε-CL), and the click reaction with azido-terminated PS (PS-N₃) or azido-terminated PEO (PEO-N₃). Considering the excellent tolerability of ATRP to a variety of monomers and the fast expansion of click chemistry in the design and synthesis of polymeric and biorelated materials, it is quite anticipated that the one-pot concept can be applied to the preparation of well-defined polymeric materials with more complex chain architectures. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3066–3077, 2009

Well-defined amphiphilic and thermoresponsive ABC miktoarm star terpolymer consisting of poly(ethylene glycol), poly(tert-butyl methacrylate), and poly(N-isopropylacrylamide) arms, PEG(-b-PtBMA)-b-PNIPAM, was synthesized via a combination of consecutive click reactions and atom transfer radical polymerization (ATRP). Click reaction of monoalkynyl-terminated PEG with a trifunctional core molecule bis(2-azidoethyl)amine, (N₃)₂NH, afforded difunctional PEG possessing an azido and a secondary amine moiety at the chain end, PEG-NHN₃. Next, the amidation of PEG-NHN₃ with 2-chloropropionyl chloride led to PEG-based ATRP macroinitiator, PEG(N₃)Cl. The subsequent ATRP of N-isopropylacrylamide (NIPAM) using PEG(N₃)Cl as the macroinitiator led to PEG(N₃)-b-PNIPAM bearing an azido moiety at the diblock junction point. Finally, well-defined ABC miktoarm star terpolymer, PEG(-b-PtBMA)-b-PNIPAM, was prepared via the click reaction of PEG(N₃)-b-PNIPAM with monoalkynyl-terminated PtBMA. In aqueous solution, the obtained ABC miktoarm star terpolymer self-assembles into micelles consisting of PtBMA cores and hybrid PEG/PNIPAM coronas, which are characterized by dynamic and static laser light scattering, and transmission electron microscopy. On heating above the phase transition temperature of PNIPAM in the hybrid corona, micelles initially formed at lower temperatures undergo further structural rearrangement and fuse into much larger aggregates solely stabilized by PEG coronas. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 4001–4013, 2009

We report on the synthesis of well-defined amphiphilic copolymer brushes possessing alternating poly(methyl methacrylate) and poly(N-isopropylacrylamide) grafts, poly(PMMA-alt-PNIPAM), via a combination of atom transfer radical polymerization (ATRP) and click reaction (Scheme 1). Firstly, the alternating copolymerization of N-[2-(2-bromoisobutyryloxy)ethyl]maleimide (BIBEMI) with 4-vinylbenzyl azide (VBA) affords poly(BIBEMI-alt-VBA). Bearing bromine and azide moieties arranged in an alternating manner, multifunctional poly(BIBEMI-alt-VBA) is capable of initiating ATRP and participating in click reaction. The subsequent ATRP of methyl methacrylate (MMA) using poly(BIBEMI-alt-VBA) as the macroinitiator leads to poly(PMMA-alt-VBA) copolymer brush. Finally, amphiphilic poly(PMMA-alt-PNIPAM) copolymer brush bearing alternating PMMA and PNIPAM grafts is synthesized via the click reaction of poly(PMMA-alt-VBA) with an excess of alkynyl-terminated PNIPAM (alkynyl-PNIPAM). The click coupling efficiency of PNIPAM grafts is determined to be ∼80%. Differential scanning calorimetry (DSC) analysis of poly(PMMA-alt-PNIPAM) reveals two glass transition temperatures (T_g). In aqueous solution, poly(PMMA-alt-PNIPAM) supramolecularly self-assembles into spherical micelles consisting of PMMA cores and thermoresponsive PNIPAM coronas, which were characterized via a combination of temperature-dependent optical transmittance, micro-differential scanning calorimetry (micro-DSC), dynamic and static laser light scattering (LLS), and transmission electron microscopy (TEM). © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2608–2619, 2009

Double hydrophilic diblock copolymer, poly(N,N-dimethylacrylamide)-b-poly(N-isopropylacrylamide-co-3-azidopropylacrylamide) (PDMA-b-P(NIPAM-co-AzPAM), containing azide moieties in one of the blocks was synthesized via consecutive reversible addition-fragmentation chain transfer polymerization. The obtained diblock copolymer molecularly dissolves in aqueous solution at room temperature, and can further supramolecularly self-assemble into core-shell nanoparticles consisting of thermoresponsive P(NIPAM-co-AzPAM) cores and water-soluble PDMA coronas above the lower critical solution temperature of P(NIPAM-co-AzPAM) block. As the micelle cores contain reactive azide residues, core crosslinking can be facilely achieved upon addition of difunctional propargyl ether via click chemistry. In an alternate approach in which the PDMA-b-P(NIPAM-co-AzPAM) diblock copolymer was dissolved in a common organic solvent (DMF), the core-crosslinked (CCL) micelles can be fabricated via “click” crosslinking upon addition of propargyl ether and subsequent dialysis against water. CCL micelles prepared by the latter approach typically possess larger sizes and broader size distributions, compared with that obtained by the former one. In both cases, the obtained (CCL) micelles possess thermoresponsive cores, and the swelling/shrinking of which can be finely tuned with temperature, rendering them as excellent candidates as intelligent drug nanocarriers. Because of the high efficiency and quite mild conditions of click reactions, we expect that this strategy can be generalized for the structural fixation of other self-assembled nanostructures. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 860–871, 2008

A novel primary amine-containing monomer, 1-(3′-aminopropyl)-4-acrylamido-1,2,3-triazole hydrochloride (APAT), was prepared from N-propargylacrylamide and 3-azidopropylamine hydrochloride via copper-catalyzed Huisgen 1,3-dipolar cycloaddition (click reaction). Poly(N-isopropylacrylamide)-b-poly(1-(3′-aminopropyl)-4-acrylamido-1,2,3-triazole hydrochloride), PNIPAM-b-PAPAT, was then synthesized via consecutive reversible addition-fragmentation chain transfer polymerizations of N-isopropylacrylamide and APAT. In aqueous solution, the obtained thermoresponsive double hydrophilic block copolymer dissolves molecularly at room temperature and self-assembles into micelles with PNIPAM cores and PAPAT shells at elevated temperature. Because of the presence of highly reactive primary amine moieties in PAPAT block, two types of covalently stabilized nanoparticles namely core crosslinked and shell crosslinked micelles with ‘inverted’ core-shell nanostructures were facilely prepared upon the addition of glutaric dialdehyde at 25 and 50 °C, respectively. In addition, the obtained structure-fixed micelles were incorporated with gold nanoparticles via in situ reduction of preferentially loaded HAuCl₄. High resolution transmission electron microscopy revealed that gold nanoparticles can be selectively loaded into the crosslinked cores or shells, depending on the micelle templates employed. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 6518–6531, 2008

Poly(2-(dimethylamino)ethyl methacrylate)-b-poly(γ-methacryloxypropyl-trimethoxysilane) (PDMA-b-PMPS) was synthesized via consecutive reversible addition-fragmentation chain transfer (RAFT) polymerizations in 1,4-dioxane. Subsequent micellization of the obtained amphiphilic diblock polymer in aqueous solution led to the formation of nanoparticles consisting of hydrophobic PMPS cores and well-solvated PDMA shells. Containing tertiary amine residues, PDMA blocks in micelle coronas can spontaneously catalyze the sol–gel reactions of trimethoxysilyl groups within PMPS cores, leading to the formation of hybrid nanoparticles coated with PDMA brushes. Transmission electron microscopy (TEM) and laser light scattering (LLS) revealed the presence of monodisperse spherical hybrid nanoparticles, and the grafting density of PDMA chains at the surface of nanoparticle cores was estimated to be ∼5.8 nm²/chain. PDMA brushes exhibit dual stimuli-responsiveness, and the swelling/collapse of them can be finely tuned with solution pH and temperatures. The obtained multi-responsive hybrid nanoparticles might find potential applications in fields such as smart devices, recyclable catalysts, and intelligent nanocarriers for drug delivery or gene transfection. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 2379–2389, 2008

Controlled radical polymerizations of N-ethylmethylacrylamide (EMA) by atom transfer radical polymerization and reversible addition-fragmentation chain transfer processes were investigated in detail for the first time, employing complementary characterization techniques including gel permeation chromatography, ¹H NMR spectroscopy, and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. In both cases, relatively good control of the polymerization of EMA was achieved, as revealed by the linear evolution of molecular weights with monomer conversions and the low polydispersity of poly(N-ethylmethylacrylamide) (PEMA). The thermal phase transitions of well-defined PEMA homopolymers with polydispersities less than 1.2 and degrees of polymerization up to 320 in aqueous solution were determined by temperature-dependent turbidity measurements. The obtained cloud points (CPs) vary in the range of 58–68 °C, exhibiting inverse molecular weight and polymer concentration dependences. Moreover, the presence of a carboxyl group instead of an alkyl one at the PEMA chain end can elevate its CP by ∼3–4 °C. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 60–69, 2008