Synthesis and characterization of double thermo‐responsive block copolymer consisting N‐isopropylacrylamide by atom transfer radical polymerization

In this thesis, we studied the convenient synthesis and characterizations of thermo‐responsive materials with double response. To achieve these, AB‐type diblock copolymers comprising of poly(N‐isopropylacrylamide) (NIPAAm) segment and poly(NIPAAm‐co‐(N‐(hydroxymethyl)acrylamide) (HMAAm)) one were designed. That was synthesized in one‐pot using an atom transfer radical polymerization (ATRP) technique. Poly(NIPAAm‐co‐HMAAm)s synthesized separately showed sensitive thermo‐response and the cloud point was completely tunable by the composition of HMAAm. As expected, the block copolymers exhibited double thermo‐responsive profiles in aqueous solution. The responsive behavior was discussed by precise trace by ¹H NMR and turbidity measurements. From these results, we could confirm almost independent dehydration of each segment. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 6142–6150, 2008     

Facile synthesis of triple‐stimuli (photo/pH/thermo) responsive copolymers of 2‐diazo‐1,2‐naphthoquinone‐mediated poly(N‐isopropylacrylamide‐co‐N‐hydroxymethylacrylamide)

A series of poly(N‐isopropylacrylamide‐co‐N‐hydroxymethylacrylamide) P(NIPAM‐co‐NHMA) copolymers were firstly synthesized via free radical polymerization. Then, the hydrophobic, photosensitive 2‐diazo‐1,2‐naphthoquinone (DNQ) molecules were partially and randomly grafted onto P(NIPAM‐co‐NHMA) backbone through esterification to obtain a triple‐stimuli (photo/pH/thermo) responsive copolymers of P(NIPAM‐co‐NHMA‐co‐DNQMA). UV‐vis spectra showed that the lower critical solution temperature (LCST) of P(NIPAM‐co‐NHMA) ascended with increasing hydrophilic comonomer NHMA molar fraction and can be tailored by pH variation as well. The LCST of the P(NIPAM‐co‐NHMA) went down firstly after DNQ modification and subsequently shifted to higher value after UV irradiation. Meanwhile, the phase transition profile of P(NIPAM‐co‐NHMA‐co‐DNQMA) could be triggered by pH and UV light as expected. Thus, a triple‐stimuli responsive copolymer whose solution properties could be, respectively, modulated by temperature, light, and pH, has been achieved. These stimuli‐responsive properties should be very important for controlled release delivery system. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2763–2773, 2009     

New Linear and Star‐Shaped Thermogelling Poly([R]‐3‐hydroxybutyrate) Copolymers

The synthesis of multi‐arm poly([R]‐3‐hydroxybutyrate) (PHB)‐based triblock copolymers (poly([R]‐3‐hydroxybutyrate)‐b‐poly(N‐isopropylacrylamide)‐b‐[[poly(methyl ether methacrylate)‐g‐poly(ethylene glycol)]‐co‐[poly(methacrylate)‐g‐poly(propylene glycol)]], PHB‐b‐PNIPAAM‐b‐(PPEGMEMA‐co‐PPPGMA), and their subsequent self‐assembly into thermo‐responsive hydrogels is described. Atom transfer radical polymerization (ATRP) of N‐isopropylacrylamide (NIPAAM) followed by poly(ethylene glycol) methyl ether methacrylate (PEGMEMA) and poly(propylene glycol) methacrylate (PPGMA) was achieved from bromoesterified multi‐arm PHB macroinitiators. The composition of the resulting copolymers was investigated by ¹H and ¹³C J‐MOD NMR spectroscopy as well as size‐exclusion chromatography (SEC), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). The copolymers featuring different architectures and distinct hydrophilic/hydrophobic contents were found to self‐assemble into thermo‐responsive gels in aqueous solution. Rheological studies indicated that the linear one‐arm PHB‐based copolymer tend to form a micellar solution, whereas the two‐ and four‐arm PHB‐based copolymers afforded gels with enhanced mechanical properties and solid‐like behavior. These investigations are the first to correlate the gelation properties to the arm number of a PHB‐based copolymer. All copolymers revealed a double thermo‐responsive behavior due to the NIPAAM and PPGMA blocks, thus allowing first the copolymer self‐assembly at room temperature, and then the delivery of a drug at body temperature (37 °C). The non‐significant toxic response of the gels, as assessed by the cell viability of the CCD‐112CoN human fibroblast cell line with different concentrations of the triblock copolymers ranging from 0.03 to 1 mg mL^?1, suggest that these PHB‐based thermo‐responsive gels are promising candidate biomaterials for drug‐delivery applications.     

Self‐assembly of thermo‐ and pH‐responsive poly(acrylic acid)‐b‐poly(N‐isopropylacrylamide) micelles for drug delivery

Self‐assembled thermo‐ and pH‐responsive poly(acrylic acid)‐b‐poly(N‐isopropylacrylamide) (PAA‐b‐PNIPAM) micelles for entrapment and release of doxorubicin (DOX) was described. Block copolymer PAA‐b‐PNIPAM associated into core‐shell micelles in aqueous solution with collapsed PNIPAM block or protonated PAA block as the core on changing temperature or pH. Complexation of DOX with PAA‐b‐PNIPAM triggered by the electrostatic interaction and release of DOX from the complexes due to the changing of pH or temperature were studied. Complex micelles incorporated with DOX exhibited pH‐responsive and thermoresponsive drug release profile. The release of DOX from micelles was suppressed at pH 7.2 and accelerated at pH 4.0 due to the protonation of carboxyl groups. Furthermore, the cumulative release of DOX from complex micelles was enhanced around LCST ascribed to the structure deformation of the micelles. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 5028–5035, 2008     

Atypical transition temperature dependence of poly(N‐isopropylacrylamide) and poly(N‐isopropylacrylamide‐co‐acrylamide) nanocomposites on the content of exfoliated montmorillonites

Exfoliated montmorillonite (MMT)/poly(N‐isopropylacrylamide) (PNIPAAm) and MMT/poly(N‐isopropylacrylamide‐co‐acrylamide) [P(NIPAAm‐co‐AAm)] nanocomposites were fabricated by soap‐free emulsion polymerization. Interestingly, as the content of MMT was increased from 0 to 10 wt %, the glass transition temperature of MMT/PNIPAAm was decreased from 145 to 122 °C, whereas that of the MMT/P(NIPAAm‐co‐AAm) increased from 95 to 153 °C. Although the lower critical solution temperature (LCST) of 32 °C for the MMT/PNIPAAm nanocomposites in aqueous solutions was slightly increased with the content of MMT, that of the MMT/P(NIPAAm‐co‐AAm) was decreased from 70 to 65 °C. A mechanism that the hydrogen bonds between the amide groups of PNIPAAm were interfered by the exfoliated MMT nano‐platelets for the MMT/PNIPAAm nanocomposites and the preferred absorption of acrylamide units to the MMT nanoplatelets rather than N‐isopropylacrylamide in the MMT/P(NIPAAm‐co‐AAm) nanocomposites was suggested to interpret these unusual transition behavior. © 2009 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 47: 524–530, 2009     

Dual thermo‐ and pH‐sensitive network‐grafted hydrogels formed by macrocrosslinker as drug delivery system

Dual thermo‐ and pH‐sensitive network‐grafted hydrogels made of poly(N,N‐dimethylaminoethyl methacrylate) (PDMAEMA) network and poly(N‐isopropylacrylamide) (PNIPAM) grafting chains were successfully synthesized by the combination of atom transfer radical polymerization (ATRP), reversible addition‐fragmentation chain transfer (RAFT) polymerization, and click chemistry. PNIPAM having two azide groups at one chain end [PNIPAM‐(N₃)₂] was prepared with an azide‐capped ATRP initiator of N,N‐di(β‐azidoethyl) 2‐chloropropionylamide. Alkyne‐pending poly(N,N‐dimethylaminoethyl methacrylate‐co‐propargyl acrylate) [P(DMAEMA‐co‐ProA)] was obtained through RAFT copolymerization using dibenzyltrithiocarbonate as chain transfer agent. The subsequent click reaction led to the formation of the network‐grafted hydrogels. The influences of the chemical composition of P(DMAEMA‐co‐ProA) on the properties of the hydrogels were investigated in terms of morphology and swelling/deswelling kinetics. The dual stimulus‐sensitive hydrogels exhibited fast response, high swelling ratio, and reproducible swelling/deswelling cycles under different temperatures and pH values. The uptake and release of ceftriaxone sodium by these hydrogels showed both thermal and pH dependence, suggesting the feasibility of these hydrogels as thermo‐ and pH‐dependent drug release devices. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Novel temperature‐ and pH‐responsive graft copolymers composed of poly(L‐glutamic acid) and poly(N‐isopropylacrylamide)

A series of novel temperature‐ and pH‐responsive graft copolymers, poly(L ‐glutamic acid)‐g‐poly(N‐isopropylacrylamide), were synthesized by coupling amino‐semitelechelic poly(N‐isopropylacrylamide) with N‐hydroxysuccinimide‐activated poly(L ‐glutamic acid). The graft copolymers and their precursors were characterized, by ESI‐FTICR Mass Spectrum, intrinsic viscosity measurements and proton nuclear magnetic resonance (¹H NMR). The phase‐transition and aggregation behaviors of the graft copolymers in aqueous solutions were investigated by the turbidity measurements and dynamic laser scattering. The solution behavior of the copolymers showed dependence on both temperature and pH. The cloud point (CP) of the copolymer solution at pH 5.0–7.4 was slightly higher than that of the solution of the PNIPAM homopolymer because of the hydrophilic nature of the poly(glutamic acid) (PGA) backbone. The CP markedly decreased when the pH was lowered from 5 to 4.2, caused by the decrease in hydrophilicity of the PGA backbone. At a temperature above the lower critical solution temperature of the PNIPAM chain, the copolymers formed amphiphilic core‐shell aggregates at pH 4.5–7.4 and the particle size was reduced with decreasing pH. In contrast, larger hydrophobic aggregates were formed at pH 4.2. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 4140–4150, 2008     

Synthesis and characterization of pH‐sensitive and thermosensitive double hydrophilic graft copolymers

A series of poly(N‐isopropylacrylamide)‐co‐poly(N^ε‐benzyloxycarbonyl‐L ‐lysine) graft copolymers (PNIPAm‐co‐PZLLys) with different side chains (degree of polymerization, DP = 5～40) and unit ratios (from 30 to 70 mol %) were prepared via free radical polymerization, followed by cleaving benzyloxycarbonyl groups (Z groups) to obtain the double hydrophilic graft copolymer, poly(N‐isopropylacrylamide)‐co‐poly(L ‐lysine) (PNIPAm‐co‐PLLys). The pH‐ and temperature‐response properties of the graft copolymers in aqueous solution were studied. The experimental results indicate L15‐N30 and L15N‐70, that is, the PNIPAm‐co‐PLLys having the poly(L ‐lysine) of DP = 15 as side chains as well as 30 and 70 mol %, respectively, of PNIPAm as backbone, have coil‐to‐helix transitions from pH 6 to pH 12 at room temperature and form uniform nanoscale micelle‐like dispersions in aqueous solution at pH 12. The graft copolymers also could form uniform and nanoscale micelle‐like structures at 50 °C in pH 6 buffer solution due to slightly polymer aggregation. With temperature and pH increased, both the deprotonated PLLys side chains and PNIPAm backbone become hydrophobic, leading to polymer precipitation. These results illustrate that a double tunable hydrophilic graft copolymer had been successfully synthesized via a simple radical polymerization, and could form micelles without serious polymer aggregation at a lower pH and a higher temperature. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Synthesis and self‐assembling of poly(N‐isopropylacrylamide‐block‐poly(L‐lactide)‐block‐poly(N‐isopropylacrylamide) triblock copolymers prepared by combination of ring‐opening polymerization and atom transfer radical polymerization

Novel thermo‐responsive poly(N‐isopropylacrylamide)‐block‐poly(l ‐lactide)‐block‐poly(N‐isopropylacylamide) (PNIPAAm‐b‐PLLA‐b‐PNIPAAm) triblock copolymers were successfully prepared by atom transfer radical polymerization of NIPAAm with Br‐PLLA‐Br macroinitiator, using a CuCl/tris(2‐dimethylaminoethyl) amine (Me₆TREN) complex as catalyst at 25 °C in a N,N‐dimethylformamide/water mixture. The molecular weight of the copolymers ranges from 18,000 to 38,000 g mol^?1, and the dispersity from 1.10 to 1.28. Micelles are formed by self‐assembly of copolymers in aqueous medium at room temperature, as evidenced by ¹H NMR, dynamic light scattering (DLS) and transmission electron microscopy (TEM). The critical micelle concentration determined by fluorescence spectroscopy ranges from 0.0077 to 0.016 mg mL^?1. ¹H NMR analysis in selective solvents confirmed the core‐shell structure of micelles. The copolymers exhibit a lower critical solution temperature (LCST) between 32.1 and 32.8 °C. The micelles are spherical in shape with a mean diameter between 31.4 and 83.3 nm, as determined by TEM and DLS. When the temperature is raised above the LCST, micelle size increases at high copolymer concentrations due to aggregation. In contrast, at low copolymer concentrations, decrease of micelle size is observed due to collapse of PNIPAAm chains. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3274–3283     

Synthesis and characteristics of poly(methacrylic acid‐co‐N‐isopropylacrylamide) thermosensitive composite hollow latex particles and their application as drug carriers

In this work, the poly(methacrylic acid‐co‐N‐isopropylacrylamide) thermosensitive composite hollow latex particles was synthesized by a three‐step reaction. The first step was to synthesize the poly(methyl methacrylate‐co‐methacrylic acid) (poly(MMA‐MAA)) copolymer latex particles by the method of soapless emulsion polymerization. The second step was to polymerize methacrylic acid (MAA), N‐isopropylacrylamide (NIPAAm), and N,N′‐methylenebisacrylamide in the presence of poly(MMA‐MAA) latex particles to form the linear poly(methyl methacrylate‐co‐methacrylic acid)/crosslinking poly(methacrylic acid‐co‐N‐isopropylacrylamide) (poly(MMA‐MAA)/poly(MAA‐NIPAAm)) core–shell latex particles. In the third step, the core–shell latex particles were heated in the presence of ammonia solution to form the crosslinking poly(MAA‐NIPAAm) thermosensitive hollow latex particles. The morphologies of poly(MMA‐MAA)/poly(MAA‐NIPAAm) core–shell latex particles and poly(MAA‐NIPAAm) hollow latex particles were observed. The influences of crosslinking agent and shell composition on the lower critical solution temperature of poly(MMA‐MAA)/poly(MAA‐NIPAAm) core–shell latex particles and poly(MAA‐NIPAAm) hollow latex particles were, respectively, studied. Besides, the poly(MAA‐NIPAAm) thermosensitive hollow latex particles were used as carriers to load with the model drug, caffeine. The effect of various variables on the amount of caffeine loading and the efficiency of caffeine release was investigated. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 5203–5214     

Synthesis of chitosan‐based thermo‐ and pH‐responsive porous nanoparticles by temperature‐dependent self‐assembly method and their application in drug release

In this research, thermo‐ and pH‐responsive chitosan‐based porous nanoparticles were prepared by the temperature‐dependent self assembly method. The chitosan‐graft‐poly(N‐isopropylacrylamide) (CS‐g‐PNIPAAm) copolymer solution was prepared through polymerization of N‐isopropylacrylamide (NIPAAm) monomer in the presence of chitosan (CS) solution using cerium ammounium nitrate as the initiator. Then, CS‐g‐PNIPAAm solution was diluted by deionized water and heated to 40 °C for CS‐g‐PNIPAAm self‐assembly. After that, CS‐g‐PNIPAAm assembled to form micelles in which shell layer was CS. Crosslinking agent was used to reinforce the micelle structure to form nanoparticle. The molar ratio of CS/NIPAAm in the feed mixture was changed to investigate its effect on structure, morphology, thermal‐ and pH‐responsive properties of the nanoparticles. TEM images showed that a porous structure of nanoparticles was developed. The synthesized nanoparticles carried positive charges on the surface and exhibited stimuli‐responsive properties, and their mean diameter thus could be manipulated by changing pH value and temperature of the environment. The nanoparticles showed a continuous release of the encapsulated doxycycline hyclate up to 10 days during an in‐vitro release experiment. These porous particles with environmentally sensitive properties are expected to be utilized in hydrophilic drug delivery system. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 5126–5136, 2009     

Synthesis and characterization of PNIPAM‐b‐(PEA‐g‐PDEA) double hydrophilic graft copolymer

A series of well‐defined double hydrophilic graft copolymers, consisting of poly(N‐isopropylacrylamide)‐b‐poly(ethyl acrylate) (PNIPAM‐b‐PEA) backbone and poly(2‐(diethylamino)ethyl methacrylate) (PDEA) side chains, were synthesized by successive atom transfer radical polymerization (ATRP). The backbone was firstly prepared by sequential ATRP of N‐isopropylacrylamide and 2‐hydroxyethyl acrylate at 25 °C using CuCl/tris(2‐(dimethylamino)ethyl)amine as catalytic system. The obtained diblock copolymer was transformed into macroinitiator by reacting with 2‐chloropropionyl chloride. Next, grafting‐from strategy was employed for the synthesis of poly(N‐isopropylacrylamide)‐b‐[poly(ethyl acrylate)‐g‐poly(2‐(diethylamino)ethyl methacrylate)] (PNIPAM‐b‐(PEA‐g‐PDEA)) double hydrophilic graft copolymer. ATRP of 2‐(diethylamino)ethyl methacrylate was initiated by the macroinitiator at 40 °C using CuCl/hexamethyldiethylenetriamine as catalytic system. The molecular weight distributions of double hydrophilic graft copolymers kept narrow. Thermo‐ and pH‐responsive micellization behaviors were investigated by fluorescence spectroscopy, ¹H NMR, dynamic light scattering, and transmission electron microscopy. Unimolecular micelles with PNIPAM‐core formed in acidic environment (pH = 2) with elevated temperature (≥32 °C); whereas, the aggregates turned into vesicles in basic surroundings (pH ≥ 7.2) at room temperature. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 5638–5651, 2008     

Lactic acid‐ and carbonate‐based crosslinked polymeric micelles for drug delivery

Our objective was to synthesize and evaluate lactic acid‐ and carbonate‐based biodegradable core‐ and core‐corona crosslinkable copolymers for anticancer drug delivery. Methoxy poly(ethylene glycol)‐b‐poly(carbonate‐co‐lactide‐co‐5‐methyl‐5‐allyloxycarbonyl‐1,3‐dioxane‐2‐one) [mPEG‐b‐P(CB‐co‐LA‐co‐MAC)] and methoxy poly(ethylene glycol)‐b‐poly(acryloyl carbonate)‐b‐poly(carbonate‐co‐lactide) [mPEG‐b‐PMAC‐b‐P(CB‐co‐LA)] copolymers were synthesized by ring‐opening polymerization of LA, CB, and MAC using mPEG as an macroinitiator and 1,8‐diazabicycloundec‐7‐ene as a catalyst. These amphiphilic copolymers which exhibited low polydispersity and critical micelle concentration values (0.8–1 mg/L) were used to prepare micelles with or without drug and stabilized by crosslinking via radical polymerization of double bonds introduced in the core and interface to improve stability. mPEG₁₁₄‐b‐P(CB₈‐co‐LA₃₅‐co‐MAC_2.5) had a higher drug encapsulation efficiency (78.72% ± 0.15%) compared to mPEG₁₁₄‐b‐PMAC_2.5‐b‐P(CB₉‐co‐LA₃₉) (20.29% ± 0.11%).¹H NMR and IR spectroscopy confirmed successful crosslinking (～70%) while light scattering and transmission electron microscopy were used to determine micelle size and morphology. Crosslinked micelles demonstrated enhanced stability against extensive dilution with aqueous solvents and in the presence of physiological simulating serum concentration. Furthermore, bicalutamide‐loaded crosslinked micelles were more potent compared to non‐crosslinked micelles in inhibiting LNCaP cell proliferation irrespective of polymer type. Finally, these results suggest crosslinked micelles to be promising drug delivery vehicles for chemotherapy. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

Construction of temperature responsive hybrid crosslinked self‐assemblies based on PEG‐b‐P(MMA‐co‐MPMA)‐b‐PNIPAAm triblock copolymer: ATRP synthesis and thermoinduced association behavior

A novel amphiphilic thermosensitive poly(ethylene glycol)₄₅‐b‐poly(methyl methacrylate₄₆‐co‐3‐(trimethoxysilyl)propyl methacrylate)₂‐b‐poly(N‐isopropylacrylamide)₄₂₉ (PEG₄₅‐b‐P(MMA₄₆‐co‐MPMA₂)‐b‐PNIPAAm₄₂₉) triblock copolymer was synthesized via consecutive atom transfer radical polymerization techniques. The thermoinduced association behavior of the resulting triblock copolymers in aqueous medium was further investigated in detail by ¹H NMR, transmission electron microscopy, and dynamic light scattering. The results showed that at the temperature (25 °C) below the LCST, PEG₄₅‐b‐P(MMA₄₆‐co‐MPMA₂)‐b‐PNIPAAm₄₂₉ triblock copolymers self‐assembled into the core crosslinked micelles with the hydrophobic P(MMA‐co‐MPMA) block constructing a dense core, protected by the mixed soluble PEG and PNIPAAm chains acting as a hydrophilic shell simultaneously. With an increase in temperature, the resulting core‐shell micelles converted into a new type of micelles with the hydrophilic PEG chains stretching out from the hydrophobic core through the collapsed PNIPAAm shell. On the other hand, at the temperature (40 °C) above the LCST, such triblock copolymers formed the crosslinked vesicles with the hydrophobic PNIPAAm and P(MMA‐co‐MPMA) blocks constructing a membrane core and the soluble PEG chains building the hydrophilic lumen and the shell. On further decreasing the temperature, the resulting vesicles underwent transformation from the shrunken to the expanded status, leading to the formation of swollen vesicles with enlarged size. This study is believed to present the first formation of two types of hybrid crosslinked self‐assemblies by thermoinduced regulation. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Synthesis of well‐defined PNIPAM‐b‐(PEA‐g‐P2VP) double hydrophilic graft copolymer via sequential SET‐LRP and ATRP and its “schizophrenic” Micellization behavior in aqueous media

A series of well‐defined double hydrophilic graft copolymers, consisting of poly(N‐isopropylacrylamide)‐b‐poly(ethyl acrylate) backbone and poly(2‐vinylpyridine) side chains, were synthesized by successive single‐electron‐transfer living radical polymerization (SET‐LRP) and atom transfer radical polymerization (ATRP). The backbone was prepared by sequential SET‐LRP of N‐isopropylacrylamide and 2‐hydroxyethyl acrylate at 25 °C using CuCl/tris(2‐(dimethylamino)ethyl)amine as the catalytic system. The obtained diblock copolymer was transformed into the macroinitiator by reacting with 2‐chloropropionyl chloride. Next, grafting‐from strategy was used for the synthesis of poly(N‐isopropylacrylamide)‐b‐[poly(ethyl acrylate)‐g‐poly(2‐vinylpyridine)] double hydrophilic graft copolymer. ATRP of 2‐vinylpyridine was initiated by the macroinitiator at 25 °C using CuCl/hexamethyldiethylenetriamine as the catalytic system. The synthesis of both the backbone and the side chains are controllable. Thermo‐ and pH‐responsive schizophrenic micellization behaviors were investigated by ¹H NMR, fluorescence spectroscopy, dynamic light scattering, and transmission electron microscopy. Unimolecular micelles with PNIPAM‐core formed in acidic environment (pH = 2) with elevated temperature (T ≥ 32 °C), whereas the aggregates turned into spheres with PEA‐g‐P2VP‐core accompanied with the lifting of pH values (pH ≥ 5.3) at room temperature. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 15–23, 2010     

Bioengineering functional copolymers. III. Synthesis of biocompatible poly[(N‐isopropylacrylamide‐co‐maleic anhydride)‐g‐poly(ethylene oxide)]/poly(ethylene imine) macrocomplexes and their thermostabilization effect on the activity of the enzyme penicillin G acylase

Stimuli‐responsive poly[(N‐isopropylacrylamide‐co‐maleic anhydride)‐g‐poly(ethylene oxide)]/poly(ethylene imine) macrobranched macrocomplexes were synthesized by (1) the radical copolymerization of N‐isopropylacrylamide and maleic anhydride with α,α′‐azobisisobutyronitrile as an initiator in 1,4‐dioxane at 65 °C under a nitrogen atmosphere, (2) the polyesterification (grafting) of prepared poly(N‐isopropylacrylamide‐co‐maleic anhydride) containing less than 20 mol % anhydride units with α‐hydroxy‐ω‐methoxy‐poly(ethylene oxide)s having different number‐average molecular weights (M_n = 4000, 10,000, or 20,000), and (3) the incorporation of macrobranched copolymers with poly(ethylene imine) (M_n = 60,000). The composition and structure of the synthesized copolymer systems were determined by Fourier transform infrared, ¹H and ¹³C NMR spectroscopy, and chemical and elemental analyses. The important properties of the copolymer systems (e.g., the viscosity, thermal and pH sensitivities, and lower critical solution temperature behavior) changed with increases in the molecular weight, composition, and length of the macrobranched hydrophobic domains. These copolymers with reactive anhydride and carboxylic groups were used for the stabilization of penicillin G acylase (PGA). The conjugation of the enzyme with the copolymers significantly increased the thermal stability of PGA (three times at 45 °C and two times at 65 °C). © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1580–1593, 2003     

Synthesis and characteristics of poly(methyl methacrylate‐co‐methacrylic acid)/poly(methacrylic acid‐co‐N‐isopropylacrylamide) thermosensitive semi‐hollow latex particles and their application to drug carriers

In this work, the poly(methyl methacrylate‐co‐methacrylic acid)/poly(methacrylic acid‐co‐N‐isopropylacrylamide) thermosensitive composite semi‐hollow latex particles was synthesized by three processes. The first process was to synthesize the poly(methyl methacrylate‐co‐methacrylic acid) (poly (MMA‐MAA)) copolymer latex particles by the method of soapless emulsion polymerization. The second process was to polymerize methacrylic acid (MAA), N‐isopropylacrylamide (NIPAAm), and crosslinking agent, N,N′‐methylenebisacrylamide, in the presence of poly(MMA‐MAA) latex particles to form the linear poly(methyl methacrylate‐co‐methacrylic acid)/crosslinking poly(methacrylic acid‐co‐N‐isopropylacrylamide) (poly(MMA‐MAA)/poly(MAA‐NIPAAm)) core–shell latex particles with solid structure. In the third process, part of the linear poly(MMA‐MAA) core of core–shell latex particles was dissolved by ammonia to form the poly(MMA‐MAA)/poly(MAA‐NIPAAm) thermosensitive semi‐hollow latex particles. The morphologies of the semi‐hollow latex particles show that there is a hollow zone between the linear poly(MMA‐MAA) core and the crosslinked poly(MAA‐NIPAAm) shell. The crosslinking agent and shell composition significantly influenced the lower critical solution temperature of poly(MMA‐MAA)/poly(MAA‐NIPAAm) semi‐hollow latex particles. Besides, the poly(MMA‐MAA)/poly(MAA‐NIPAAm) thermosensitive semi‐hollow latex particles were used as carriers to load with the model drug, caffeine. The processes of caffeine loaded into the semi‐hollow latex particles appeared four situations, which was different from that of solid latex particles. In addition, the phenomenon of caffeine released from the semi‐hollow latex particles was obviously different from that of solid latex particles. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 3441–3451     

Finely Tuned Thermo‐Responsive Block Copolymer Micelles for Photothermal Effect‐Triggered Efficient Cellular Internalization

Although biodegradable amphiphilic block copolymer micelles have been widely applied in the clinical applications as drug delivery nanocarriers, low‐efficiency cellular internalization frequently reduces therapeutic efficacy of the loaded drugs. Here, photothermal effect‐promoted cellular internalization of finely tuned thermo‐responsive amphiphilic biodegradable block copolymer nanocarriers via noninvasive stimuli of near‐infrared (NIR) light irradiation is demonstrated. Amphiphilic block copolymers, poly(ε‐caprolactone)‐block‐poly(N‐isopropylacrylamide‐co‐N,N‐dimethylacrylamide) (PCL‐b‐P(NIPAM‐co‐DMA)), are prepared with finely tuned compositions of P(NIPAM‐co‐DMA) for desirable lower critical solution temperature of the block copolymer micelles in aqueous solution. The block copolymers are then used to co‐encapsulate doxorubicin and indocyanine green, which show high encapsulation efficiency and significant photothermal effect upon exposure to NIR light irradiation. The photothermal effect‐induced collapse and hydrophilic‐to‐hydrophobic transition of P(NIPAM‐co‐DMA) shells significantly enhance the interactions between drug‐loaded micelles and cell membranes, which dramatically promote the cellular internalization of the micelles and therapeutic efficacy of loaded anticancer drugs.

     

Thermo‐ and pH‐induced self‐assembly of P(AA‐b‐NIPAAm‐b‐AA) triblock copolymers synthesized via RAFT polymerization

A series of environmentally sensitive ABA triblock copolymers with different block lengths were prepared by reversible addition‐fragmentation chain transfer (RAFT) polymerization from acrylic acid (AA) and N‐isopropylacrylamide (NIPAAm). The GPC and ¹H NMR analyses demonstrated the narrow molecular weight distribution and precise chemical structure of the prepared P(AA‐b‐NIPAAm‐b‐AA) triblock copolymers owing to the controlled/living characteristics of RAFT polymerization. The lower critical solution temperature (LCST) of the triblock copolymers could be tailored by adjusting the length of PAA block and controlled by the pH value. Under heating, the triblock copolymers underwent self‐assemble in dilute aqueous solution and formed nanoparticles revealed via TEM images. Physically crosslinked nanogels induced by inter‐/intra‐hydrogen bonding or core‐shell micelle particles thus could be obtained by changing environmental conditions. With a well‐defined structure and stimuli‐responsive properties, the P(AA‐b‐NIPAAm‐b‐AA) copolymer is expected to be employed as a nanocarrier for biomedical applications in controlled‐drug delivery and targeting therapy. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1109–1118     

“On–off” switching of dynamically controllable self‐assembly formation of double‐responsive block copolymers with tunable LCSTs

We report here a reversible self‐assembly formation system using block copolymers with thermo‐tunable properties. A series of double‐responsive block copolymers, poly(N‐isopropylacrylamide (NIPAAm))‐block‐poly(NIPAAm‐co‐N‐(isobutoxymethyl)acrylamide (BMAAm)) with two lower critical solution temperatures were synthesized by one‐pot atom transfer radical polymerization via sequential monomer addition. When dissolved in aqueous solution at room temperature, the block copolymers remained unimeric. Upon heating above room temperature, the block copolymers self‐assembled into micellar structures. The micelle formation temperature and the resulting diameter were controlled by varying the BMAAm content. ¹H Nuclear Magnetic Resonance, dynamic light scattering, field‐emission scanning electron microscopy, and fluorescence spectra revealed the presence of a monodisperse nanoassembly, and demonstrated the assembly formation/inversion process was fully reversible. Moreover, a model hydrophobic molecule, pyrene, was successfully loaded into the micelle core by including pyrene in the original polymer solution. Further heating resulted in mesoscopic micelle aggregation and precipitation. This dual micelle and aggregation system will find utility in drug delivery applications as a thermal trigger permits both aqueous loading of hydrophobic drugs and their subsequent release. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010