Thermoresponsive self‐assembled nanovesicles based on amphiphilic triblock copolymers and their potential applications as smart drug release carriers

A series of thermoresponsive triblock copolymers, methoxy poly(ethylene oxide)‐b‐poly(ε‐caprolactone)‐b‐poly(N‐isopropylacrylamide) (mPEO‐b‐PCL‐b‐PNIPAM), with different PCL and PNIPAM block lengths, were synthesized by a combination of ring opening polymerization and reversible addition‐fragmentation chain transfer polymerization techniques. The triblock copolymers undergo self‐assembly in aqueous solutions forming stable nanovesicles of various sizes with a lipid membrane structure similar to body cells as revealed by transmission electron microscopy. The nanovesicle is thermoresponsive, that is, its size is tunable using the temperature as a switch: shrinks at a temperature above the lower critical solution temperature (LCST) and expands at a temperature below the LCST. The corresponding LCST of the triblock copolymers is adjustable by varying the PNIAM segment length as well as the PCL segment length and covers a range from 33.9 to 41.0°C in water. The diameter of nanovesicles for mPEO_3k‐b‐PCL_5k‐b‐PNIPAM_13.2k is about 177.7 nm below the LCST and 138.9 nm above the LCST, as determined by dynamic light scattering. It was demonstrated using indomethacin, a popular anti‐inflammation medicine, that the triblock copolymers can effectively act as a drug release carrier under the right human physiological conditions, that is, store the drug at a lower temperature and release it at a higher temperature, possibly targeting at the lesion sites of human body. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41361.     

A convenient scheme for synthesizing reduction‐sensitive chitosan‐based amphiphilic copolymers for drug delivery

A novel type of reduction‐sensitive graft copolymers, chitosan‐S‐S‐poly(ε‐caprolactone) (CS‐S‐S‐PCL, here ‐S‐S‐ means PCL was conjugated onto chitosan backbone through disulfide linkage), was synthesized through a convenient route using dithiodipropionic anhydride (DTDPA) as a disulfide donor. Reaction of hydroxy‐terminated poly(ε‐caprolactone) (PCL) with DTDPA quantitatively yielded DTDPA functionalized PCL (PCL‐S‐S‐COOH). The disulfide‐containing polyester was regioselectively conjugated onto the hydroxy groups of chitosan under mild and homogeneous conditions, utilizing dodecyl sulfate‐chitosan complexes (SCC) as an intermediate. The self‐assembly and Doxorubicin (Dox) release behavior of the copolymers were investigated. Spherical micelles could be formed through self‐assembly of CS‐S‐S‐PCL in aqueous media. The reduction‐sensitive behavior of CS‐S‐S‐PCL micelles was investigated by using Dithiothreitol (DTT) as a reductive reagent. In the presence of 10 mM DTT, the micelles gradually lost their aggregation stability and were precipitated out after four days. In addition, the Dox release was accelerated when the micelles were treated with DTT. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Synthesis of biodegradable and biocompatible ABC triblock copolymers

A facile approach is offered to synthesize well‐defined amphiphilic ABC triblock copolymers composed of poly(ethylene glycol) monomethyl ether (MPEO) as A block, poly(L ‐lysine) (PLLys) as B block, and poly(ε‐caprolactone) (PCL) as C block by a combination of ring‐opening polymerization (ROP) and click reactions. The propargyl‐terminated poly(Z‐L ‐lysine)‐block‐poly(ε‐caprolactone) (MPEO‐PzLLys‐PCL) diblock copolymers were synthesized via the ring‐opening polymerization of N^ε‐carbobenzoxy‐L ‐lysine N‐carboxyanhydride (Z‐L ‐Lys NCA) in DMF at room temperature using propargyl amine as an initiator and the resulting amino‐terminated poly(Z‐L ‐lysine) then used in situ as a macroinitiator for the polymerization of ε‐caprolactone in the presence of stannous octoate as a catalyst. The triblock copolymers poly(ethylene glycol) monomethyl ether –block‐poly(Z‐L ‐lysine)‐block‐poly(ε‐caprolactone) (MPEO‐PzLLys‐PCL) were synthesized via the click reaction of the propargyl‐terminated PzLLys‐PCL and azido‐terminated poly(ethylene glycol) monomethyl ether (PEO‐N₃) in the presence of CuBr and 1,1,4,7,7‐pentamethyldiethylenetriamine (PMDETA) catalyst system. After the removal of Z groups of L ‐lysine units, amphiphilic and biocompatible ABC triblock copolymers MPEO‐PLLys‐PCL were obtained. The structural characteristics of these ABC triblock copolymers and corresponding precursors were characterized by NMR, IR, and GPC. These results showed the click reaction was highly effective. Therefore, a facile approach is offered to synthesize amphiphilic and biocompatible ABC triblock copolymers consisting of polyether, polypeptide and polyester. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Self‐assembling amphiphilic PEGylated block copolymers obtained through RAFT polymerization for drug‐delivery applications

In this work, ring‐opening polymerization and reversible addition‐fragmentation chain transfer polymerization (RAFT) have been employed for the production of block copolymers where the backbone is brushed with poly(ethylene glycol) (PEG) and polyester chains. Because of their amphiphilic properties, they are able to self‐assemble in water, forming micelles. Molecular dynamics simulations have been accomplished to study the behavior of the copolymer single chain in water, and the self‐assembly properties have been characterized and correlated to the copolymer structure in terms of critical micellar concentration and particle size. As a proof of their flexibility, these materials have been employed for the production of polymer–lipid hybrid nanoparticles with tunable dimensions (from 120 to 260 nm) adopted for the controlled release of anticancer compounds (paclitaxel and curcumin). © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43084.     

Crosslinkable micelles from diblock amphiphilic copolymers based on vinylbenzyl thymine and vinylbenzyl triethylammonium chloride

Polymeric micelles (PMs) composed of self‐assembled amphiphilic block copolymers were synthesized from vinylbenzyl thymine (VBT) and vinylbenzyl triethylammonium chloride (VBA) exhibiting improved physical stability. Three diblock copolymers of different chemical compositions and similar molecular weights (polydispersities below 1.5) were obtained via nitroxide mediated radical polymerization. Critical micelle concentration (CMC) was determined by dye micellization method, the shift of the absorption peak of the anionic (EY) due to the interactions with non‐assembled chains and auto‐assembled copolymers was followed. Polymeric systems exhibited good stability revealing that a higher proportion of cationic monomers in the diblock reduce the CMC. Furthermore, after the core of PMs was photocrosslinked by UV irradiation, the CMC decreases notably. Kinetic release studies using EY dye as probe demonstrated that both, higher VBA ratios in the polymer and higher UV‐irradiation, slow down the dye release. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41947.     

Preparation and properties of crosslinked chitosan thermosensitive hydrogel for injectable drug delivery systems

The aim of this study was to prepare and investigate the physical properties of a thermosensitive crosslinked chitosan pregel solution, and evaluate the in vitro release profiles of macromolecules from this sol–gel transition system. Chitosan and poly (vinyl alcohol) were used to form an interpenetrating polymeric network with glutaraldehyde as the crosslinker, and glycerophosphate (GP) was added to transform the pH‐dependent solutions into thermosensitive pH‐dependent solutions. Rheological study showed that the gelation was dependent on the crosslink degree and GP concentration of the solution. The crosslinked gel had excellent mechanic properties and no apparent “pores” and formed an integrated hydrogel texture according to scanning electronic micrograph. Gas chromatography test guaranteed the medication safety with no detection of glutaraldehyde remnants in the hydrogels. In vitro release study showed that the gelation does not significantly affect the macromolecules diffusion but the crosslinking degree does. These results indicated that the hydrogel formed an intensified three‐dimensional hybrid network with interpenetrating molecules, which effectively buffered or delayed the macromolecules diffusion. The hydrogels sustained the drug release over 30 days and could be potentially used as in situ gelling implants. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 101: 1892–1898, 2006     

含磷酸钠基的SBS两亲离聚体的合成、表征及性质

环氧化SBS在甲苯中与磷酸氢二钠水溶液,以N,N-二甲基苯胺及四乙基溴化铵为催化剂,通过开环反应合成了含磷酸二钠基的两亲性SBS离聚体。离聚体采用FTIR进行表征。研究了开环反应条件及该离聚体的乳化性、吸水性、耐油性和稀溶液粘度。结果表明开环率可以达到32%,该离聚体具有很好的乳化性、明显的吸水性和耐油性,其乳化性、吸水性、耐油性及稀溶液粘度随离子含量增加而增大,随一价阳离子的离子电位增加而增加。     

Characterization and emulsifying properties of block copolymers prepared from lactic acid and poly(ethylene glycol)

Block copolymers were prepared by the direct polycondensation of an aqueous lactic acid solution on monomethoxy or dihydroxyl poly(ethylene glycol) (PEG) in the absence of a catalyst. The resulting poly(lactic acid) (PLA)–PEG diblock and PLA–PEG–PLA triblock copolymers were characterized by various analytical techniques, including matrix‐assisted laser desorption/ionization time of flight mass spectrometry (MALDI‐TOF MS), gel permeation chromatography, and ¹H‐NMR. The molecular structure between PLA–PEG and PLA–PEG–PLA could be distinguished after the calculation of the repeat unit masses and end‐group masses through the MALDI‐TOF MS spectra. Interestingly, both copolymers could serve as a hydrophilic emulsifier to stabilize the squalene/water interfaces and yield narrowly distributed oil‐in‐water nanoparticles. In contrast, the prepolymer PEG failed to stabilize the squalene/water interface under the same homogenization conditions. These features are of great interest for applications as bioactive agent delivery, especially for candidate vaccine antigens and lipophilic anticancer drugs. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Ring‐opening copolymerization and properties of polycarbonate copolymers

A series of polycarbonate copolymers were synthesized by the ring‐opening bulk polymerization of 2‐phenyl‐5,5‐bis(hydroxymethyl) trimethylene carbonate (PTC) and 5,5‐dimethyl trimethylene carbonate (DTC) with tin(II) 2‐ethylhexanoate and aluminum isopropoxide as initiators. The copolymers obtained were characterized by ¹H‐NMR, Fourier transform infrared, and ultraviolet. The influence of the molar ratio of the monomers, the initiators, and their concentrations, the reaction time, and the reaction temperature on the copolymerization was also studied. The copolymerization of monomers DTC and PTC was a nonideal copolymerization, and the copolymerization reactivity ratio of the monomer DTC was higher than that of PTC in the copolymerization process. In vitro release profiles of fluorouracil from the copolymers showed that the copolymer had a steady drug‐release rate and good controlled‐release property. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2008     

Synthesis and characterization of a new amphiphilic copolymer containing multihydroxyl segments for drug carrier

A new amphiphilic copolymer (copoly‐(MR‐BMA‐HEA‐MAA), PRBHM) containing multihydroxyl segments was designed and synthesized for application in drug carrier. PRBHM can be dissolved in water to form aggregates directly with a critical aggregate concentration (CAC) of 0.0138 mg mL^?1. The chains of PRBHM can be collapsed into hydrophobic globules when pH decreases from neutral to slightly acid condition (pH = 5.0–7.0) in water. Since the hydrophilic hydroxyl group is independent on pH, PRBHM can keep stable both in neutral and slightly acid aqueous solutions. The hydrophobic small molecules such as 5‐(4‐(4‐vinylbenzyloxy) phenyl)‐4,5‐dihydro‐1,3‐diphenyl‐1H‐pyrazole (PY) can be loaded into PRBHM aggregates via ultrasonic treatment in water, and can be internalized into BEL‐7402 cancer cells. The cytotoxicity determination also indicates the good biocompatibility of PRBHM in potential application as a drug carrier. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Stimuli-responsive hybrid microgels for controlled drug delivery: Sorafenib as a model drug

Microgels (MGs) are synthetic colloidal hydrogel particles made of three dimensional polymer networks. Their chemical composition is crucial for their use as intelligent drug release systems operated by temperature control. Herein, several MGs using N-isopropylacrylamide (Nipam)/N-isopropylmethacrylamide (Nipmam), chitosan and acrylic/methacrylic acid have been synthesized by free radical polymerization reactions (NC MGs) and the effects of surfactants and different reaction times on size and swelling properties have been investigated. MGs have been identified and characterized by dynamic light scattering and atomic force microscopy, and finally used to optimize the encapsulation protocol of the hydrophobic drug sorafenib. The drug delivery system here described has encapsulation efficiency of 40% and releases 10% of the entrapped drug over about 16 h after the temperature is raised above the volume phase transition temperature. Data suggest that MGs with optimized composition may act as properly instructed entities able to trap and release biomolecules following external stimuli.     

Positively charged nanomicelles in water of amphiphilic copolymer chitosan-g-polylactide as drug carrier of photoporphyrin IX for photodynamic therapy

Preparation of amphiphilic graft copolymers of chitosan-g-methacrylate-terminated poly(lactic acid) (CS-g-MPLA_n) with various chain length of lactic acid monomers in the copolymers (n = 20, 40, and 70) has been successfully carried out by “grafting on” free radical polymerization. Beside to offer a tunable and easy preparation of chitosan (CS)-based amphiphilic copolymers, the specific purpose is to study the effects of poly(lactic acid) chain length on the micelle properties of the copolymers in water. First, oligomer CS was synthesized by partial oxidation. Second, the methacrylate-terminated poly(lactic acid) with different chain length were synthesized by ring opening polymerization of lactide monomer using 2-hydroxyethyl methacrylate and Sn(Oct)₂ as initiator and catalyst, respectively. Finally, the grafting process was carried out by free radical copolymerization using cerium(IV) sulfate as initiator at 70°C for 24 h. The CS-g-MPLA_n amphiphilic copolymers were characterized by Fourier transform infrared and proton nuclear magnetic resonance. The hydrophobic drug nanomicelles in water with a narrow-size distribution, positively charged and high stability have been confirmed. The micelle size is significantly bigger on longer chain of poly(lactic acid); however, the stability, loading capacity, and encapsulation efficiency are independent on the chain length. The high-loading capacity and encapsulation efficiency for hydrophobic drug protoporphyrin IX as the model are ensuring the hydrophobic drugs efficacy in photodynamic therapy applications.     

Semifluorinated ABA triblock copolymers: Synthesis,characterization, and amphiphilic properties

In this study a series of novel semifluorinated ABA triblock copolymers with different fluorinated segment lengths and different fluorocarbon side‐chain structures were synthesized via atom transfer radical polymerization (ATRP) and macroinitiator techniques. The macroinitiator, telechelic bromine terminated polystyrene, was obtained from bulk ATRP of styrene with α,α′‐dibromo‐p‐xylene as the initiator and cuprous bromide/α,α′‐bispyridine complex as the catalyst. The polymerization reactions of 2‐[(perfluorononenyl)oxy] ethyl methacrylate and ethylene glycol monomethacrylate monoperfluorooctanoate were initiated by the macroinitiator in the presence of additional catalyst. The characterization of the block copolymers was performed by gel permeation chromatography, ¹H‐NMR spectroscopy, and differential scanning calorimetry. The surface activities of the block copolymers in toluene were investigated with the Wilhelmy plate method. The solid surface energy of the block copolymers was determined by measurement of the contact angles. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 83: 2625–2633, 2002     

Preparation and characterization of pH responsive poly(methacrylic acid‐acrylamide‐N‐hydroxyethyl acrylamide) hydrogels for drug delivery systems

In this study, pH responsive polymers composed of methacrylic acid, acrylamide, and N‐hydroxyethyl acrylamide were synthesized by free radical polymerization technique. The characterization was done with Fourier transform infrared spectroscopy and scanning electron microscopy. The swelling and drug release behavior of the hydrogels was determined as a function of time at 37°C in pH 2.1 and 7.4. The swelling and drug release studies showed that increased methacrylic acid amount caused a higher increase in swelling and drug release values at pH 7.4 than those at pH 2.1. In addition, the drug release data were applied to kinetic models such as zero order, first order, and Higuchi equations, and it fit well in the Higuchi model of the hydrogel. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43226.     

Preparation of phenylboronic acid-based hydrogel microneedle patches for glucose-dependent insulin delivery

There is a problem with directly loading insulin into the polymerized glucose-responsive microneedle (MN) patch due to that polymerization conditions and solvents may damage the activity of insulin. In this study, we report a totally polymerized phenylboronic acid-based MN patch, and insulin was directly loaded in MNs by a mild drop/dry procedure. MN patch was prepared by copolymerization of N-isopropyl acrylamide, N-vinyl-2-pyrrolidone, and 3-acrylamidoephenylboronic acid in MN mold. The MN patch showed good glucose-dependent swelling behavior in pH 9.0 at 27°C. After insulin loading procedure, insulin was distributed on and within the MNs. About 43.2% of total insulin was diffused into MNs' interior. As a result, the release of insulin on MNs' surface was uncontrolled by MNs and rapidly finished after ~10 min. However, the release of insulin within MNs was depended on glucose concentration, and insulin was released 1.6 times more at 4 g/L than at 1 g/L glucose concentration after 12 h. Although further improvements are needed to make MN patch responding in physiological environment, this work suggests a solution for directly loading insulin in polymerized glucose-responsive MNs.     

In vitro evaluation of efficacy of dihydroartemisinin‐loaded methoxy poly(ethylene glycol)/poly(l‐lactic acid) amphiphilic block copolymeric micelles

Dihydroartemisinin (DHA)‐loaded methoxy poly(ethylene glycol)/poly(l ‐lactic acid) (mPEG₅₀₀₀—PLLA₃₂₀₀) amphiphilic block copolymeric micelles (DHA‐CM) have been prepared using modified solvent evaporation method. Physicochemical properties of DHA‐CM were investigated by using dynamic light scattering, transmission electron microscopy, high‐performance liquid chromatography, and Fourier transform infrared. Polymers formed stable, spherical, and worm‐like micelles with mean sizes smaller than 130 nm. In vitro release experiments revealed that DHA‐CM provided a more solubilizing effect than DHA suspension; in addition, it was showed that drug release profiles highly depended on pH values of dissolution media. Various types of lyoprotectants were tested to improve the redispersion performance of the freeze‐dried products. 3‐(4, 5‐dimethyl‐ thiazol‐2‐yl)‐2, 5‐diphenyl tetrazolium bromide assay was used to evaluate the cytotoxicity of micellar solutions of freeze‐dried DHA‐CM. The results showed that the IC₅₀ values of DHA‐CM and DHA suspension for KB cell lines were 18.70 and 24.55 μM, respectively. However, DHA‐CM had little cytotoxicity for L02 cell lines. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Effect of network mesh size and swelling to the drug delivery from pH responsive hydrogels

pH responsive hydrogels are ideal platforms for numerous therapeutic delivery applications, including oral delivery, as they are capable of overcoming the many barriers that must be considered when creating an effective drug delivery system. Understanding of the innate hydrogel network structure and its swelling behavior at environmentally relevant conditions is vital for designing hydrogel network capable of effective controlled drug release. Herein, we explored how to expand traditional techniques of swelling and pore characterization to gain better insight into the performance of anionic microparticles composed of the poly(methyl methacrylate-co-acrylic acid) with varying molar percentage of 10, 20, and 30 mol% of MMA, for controlled release of low-molecular-weight drugs. By evaluating these carrier systems at environmental conditions, we can observe changes in swelling and pore size of the anionic hydrogel networks as a function of MMA, which was then correlated with the release profiles of the small-molecular-weight drug sodium nitrate. With the correlation of the swelling behavior of the networks and the release profiles, we demonstrated how the expansion of swelling parameters at relevant pH values provides further incite for evaluating for the optimal blend for controlled release. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48767.     

Modeling and closed‐loop control of particle size and initial burst of PLGA biodegradable nanoparticles for targeted drug delivery

An in‐house computer code based on artificial intelligence has been developed and applied in modeling and closed‐loop optimization of release behavior of Poly(lactic‐co‐glycolic acid) (PLGA) biodegradable particles. A series of micro‐ and nanoparticles were prepared via water‐in‐oil‐in‐water double emulsion to be loaded with albumin–fluorescein isothiocyanate conjugate as a typical drug. The interrelationship between input variables (molecular weight of polymer and stabilizer, polymer concentration, and sonication rate) and outputs (PLGA particle size and percentage of initial burst) was uncovered with the aid of artificial neural network modeling. The regression analysis confirmed acceptable correlation coefficients for the aforementioned responses, where the PLGA molecular weight played the most important role among the studied variables. Input variables needed to minimize PLGA size and PLGA initial burst were then obtained via multiobjective optimization performed by a genetic algorithm. PLGA nanoparticles were checked for particle size and particle size distribution using scanning electron micrographs. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45145.     

Design and study of the potential of crosslinked cationic polymers as drug delivery systems for dermal application

Crosslinked carriers based on cationic monomer [2‐(acryloyloxy)ethyl]trimethylammonium chloride or 2‐(dimethylamino)ethyl methacrylate were developed and investigated as new platform for ibuprofen transdermal delivery. Series of networks of varied composition and structure were synthesized and characterized by FTIR spectroscopy and following swelling kinetics in different solvents. Dermal safety tests to examine the skin irritation and sensitization potential of the network films were performed in vivo. Chosen network compositions were loaded with ibuprofen by swelling in its ethanol solution. The structures of the drug carriers were investigated by scanning electron microscopy. Ibuprofen release from the developed drug delivery systems was followed in phosphate buffer solution at 37 °C. The investigation proved the feasibility of the developed cationic copolymer networks as effective platforms with modified ibuprofen release for potential dermal application. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46420.     

Nonfouling biomaterials based on polyethylene oxide‐containing amphiphilic triblock copolymers as surface modifying additives: Synthesis and characterization of copolymers and surface properties of copolymer–polyurethane blends

The objective of this work is to develop nonfouling biomaterials by blending polyethylene oxide (PEO)‐containing block copolymers with a polyurethane (PU) matrix; it is expected that the PEO component will migrate to the tissue‐material interface. Three amphiphilic triblock copolymers, PEO‐PU‐PEO, in which the PEO MW was 550 (copolymer 1), 2000 (copolymer 2), and 5000 (copolymer 3), respectively, were synthesized. XPS data showed that the polymer/vacuum interfaces of copolymers 2 and 3 were enriched in the PU block, whereas that of copolymer 1 was enriched in the PEO block. In contact with water, the PEO blocks for all three copolymers migrated to the surface as indicated by water contact angles. Blends of the copolymers with a segmented polyurethane were investigated. Surface enrichment of the copolymers occurred and increased over time up to a limit; the degree of enrichment was dependent on PEO block size and copolymer content. At copolymer content <10%, enrichment decreased with increasing PEO block size. For the copolymer 2 and copolymer 3 blends, enrichment increased with increasing copolymer content; at 20% copolymer the surfaces consisted essentially of pure copolymer. For the copolymer 1 blends, the surface was completely covered by copolymer at content ≥ 1%. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008