“Click” chemistry for in situ formation of thermoresponsive P(NIPAAm‐co‐HEMA)‐based hydrogels

The strategy for in situ chemical gelation of poly(N‐isopropylacrylamide‐co‐hydroxylethyl methacrylate) [P(NIPAAm‐co‐HEMA)]‐based polymers was demonstrated. Two types of new P(NIPAAm‐co‐HEMA) derivatives with alkyne and azide pendant groups, respectively, were prepared. When the solutions of the two derivatives were mixed together, a crosslinking reaction, a type of Huisgen's 1,3‐dipolar azide‐alkyne cycloaddition, in the presence of Cu(I) catalyst occurs. The morphology, equilibrium swelling ratio, swelling kinetics, and temperature response kinetics of the in situ gelated hydrogels were studied. In comparison with the conventional PNIPAAm hydrogel, because of the spatial hindrance of polymeric chains, the resulted hydrogels had a macroporous structure as well as a fast shrinking rate. The strategy described here presents a potential alternative to the traditional synthesis techniques for the in situ formation of thermoresponsive hydrogels. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 5263–5277, 2008     

In situ fabrication of paclitaxel‐loaded core‐crosslinked micelles via thiol‐ene “click” chemistry for reduction‐responsive drug release

In this study, a facile method to fabricate reduction‐responsive core‐crosslinked micelles via in situ thiol‐ene “click” reaction was reported. A series of biodegradable poly(ether‐ester)s with multiple pendent mercapto groups were first synthesized by melt polycondensation of diol poly(ethylene glycol), 1,4‐butanediol, and mercaptosuccinic acid using scandium trifluoromethanesulfonate [Sc(OTf)₃] as the catalyst. Then paclitaxel (PTX)‐loaded core‐crosslinked (CCL) micelles were successfully prepared by in situ crosslinking hydrophobic polyester blocks in aqueous media via thiol‐ene “click” chemistry using 2,2′‐dithiodiethanol diacrylate as the crosslinker. These PTX‐loaded CCL micelles with disulfide bonds exhibited reduction‐responsive behaviors in the presence of dithiothreitol (DTT). The drug release profile of the PTX‐loaded CCL micelles revealed that only a small amount of loaded PTX was released slowly in phosphate buffer solution (PBS) without DTT, while quick release was observed in the presence of 10.0 mM DTT. Cell count kit (CCK‐8) assays revealed that the reduction‐sensitive PTX‐loaded CCL micelles showed high antitumor activity toward HeLa cells, which was significantly higher than that of reduction‐insensitive counterparts and free PTX. This kind of biodegradable and biocompatible CCL micelles could serve as a bioreducible nanocarrier for the controlled antitumor drug release. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 99–107     

Synthesis and functionalization of dendron‐polymer conjugate based hydrogels via sequential thiol‐ene “click” reactions

Fabrication and functionalization of hydrogels from well‐defined dendron‐polymer‐dendron conjugates is accomplished using sequential radical thiol‐ene “click” reactions. The dendron‐polymer conjugates were synthesized using an azide‐alkyne “click” reaction of alkene‐containing polyester dendrons bearing an alkyne group at their focal point with linear poly(ethylene glycol)‐bisazides. Thiol‐ene “click” reaction was used for crosslinking these alkene functionalized dendron‐polymer conjugates using a tetrathiol‐based crosslinker to provide clear and transparent hydrogels. Hydrogels with residual alkene groups at crosslinking sites were obtained by tuning the alkene‐thiol stoichiometry. The residual alkene groups allow efficient postfunctionalization of these hydrogel matrices with thiol‐containing molecules via a subsequent radical thiol‐ene reaction. The photochemical nature of radical thiol‐ene reaction was exploited to fabricate micropatterned hydrogels. Tunability of functionalization of these hydrogels, by varying dendron generation and polymer chain length was demonstrated by conjugation of a thiol‐containing fluorescent dye. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 926–934     

Hopping conduction in “pure” polypropylene

A recently developed theory of steady-state conduction in high-density polyethylene is applied to “pure” polypropylene (PP) in the temperature range 50–93°C. Morphological changes occur in PP, including a disordered-amorphous to monoclinic-amorphous transition between 50 and 80°C, where, with increasing temperature T, free volume increases, and decreases with decreasing amorphous fraction. The latter competing processes lead to large increases in hopping site separation, λ, in the transition region, followed either by saturation or a maximum in λ vs. T. We speculate that segmental and/or main chain molecular motions lower apparent activation energies, are “pinned“ by applied field, and impeded by dangling bonds in regions surrounding the surfaces of crystallites. Our analysis is semi-quantitative only, because the latter mechanisms have not been adequately quantified, and the relative contributions of each are unknown. Measurements were carried out on heated and cooled disordered-amorphous, and 106°C, 17-h annealed, 43% crystalline samples. Hopping distances, obtained from measured current vs. applied field characteristics, ranged from 1.2 to 5.2 nm. Apparent activation energies up to 1.80 eV were obtained from In (I/T) vs. (1/T) plots. Remarkable plateaus in the temperature range of the transition were observed in these plots, implying some carrier conduction with near zero activation energy. Possible explanations for the latter, and the electronic nature of the carriers are given. X-ray and density flotation measurements enabled crystallinity determinations. © 1994 John Wiley & Sons, Inc.     

Photo‐initiated thiol–ene “click” hydrogels from RAFT‐synthesized poly(N‐isopropylacrylamide)

Despite the efficiency and robustness of the widely used copper‐catalyzed 1,3‐dipolar cycloaddition reaction, the use of copper as a catalyst is often not attractive, particularly for materials intended for biological systems. The use of photo‐initiated thiol‐ene as an alternative “click” reaction to synthesize “model networks” is investigated here. Poly(N‐isopropylacrylamide) precursors were synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization and were designed to have trithiocarbonate moieties as end groups. This structure design provides opportunity for subsequent end‐group modifications in preparation for thiol‐ene “click.” Two reaction routes have been proposed and studied to yield thiol and ene moieties. The advantages and disadvantages of each reaction path were investigated to propose a simple but efficient route to prepare copper‐free “click” hydrogels. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 4626–4636     

Modulating catalytic activity of polymer‐based cuAAC “click” reactions

The copper(I)‐catalyzed azide–alkyne cycloaddition (CuAAC) reaction is used to synthesize complex polymer architectures. In this work, we demonstrate the control of this reaction at 25 °C between polystyrene (PSTY) chains through modulating the catalytic activity by varying the combinations of copper source (i.e., Cu(I)Br or copper wire), ligand (PMDETA and/or triazole ligand), and solvent (toluene or DMF). The fastest rate of CuAAC was found using Cu(I)Br/PMDETA ligand in toluene, reaching near full conversion after 15 min at 25 °C. For the same catalysts system, DMF also gave fast rates of “click” (95% conversion in 25 min). Cu(0) wire in toluene gave a conversion of 98% after 600 min, a much higher rate than that observed for the same catalyst system used in DMF. When the PSTY had a chemically bound triazole ring close to the site of reaction, the rate of CuAAC in toluene increased significantly, 97% in 180 min at 25 °C, in agreement with our previously published results. This suggests that rapid rates can be obtained using copper wire and will have direct applications to the synthesis of compound where air, removal of copper, and reuse of the copper catalyst are required. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Synthesis of pH‐responsive photocrosslinked hyaluronic acid‐based hydrogels for drug delivery

Photocrosslinked hyaluronic acid/poly(vinyl alcohol)‐styrylpyridinium (HA/PVA‐SbQ) hydrogels were synthesized for controlled antitumor drug delivery. The photocrosslinking reaction was rapid, and the time required for completely converting into the insoluble hydrogels was less than 500 s on exposure to 5 mW/cm² UV light irradiation. The resulting hydrogels exhibited sensitivity to the pH value of the surrounding environment. Scanning electron microscopic analysis revealed that the morphology and the pore size of the hydrogels could be controlled by changing the ratio of HA and PVA‐SbQ in the formulations. Paclitaxel (PTX)‐loaded hydrogel could also be formed rapidly by UV irradiation of a mixed solution of HA/PVA‐SbQ and PTX. Release profiles of PTX from the hydrogels showed pH‐dependent and sustained manner. Moreover, our data revealed that PTX released from the HA hydrogels remained biologically active and had the capability to kill cancer cells. In contrast, control groups of HA hydrogels without PTX did not exhibit any cytotoxicity. This study demonstrates the feasibility of using HA‐based hydrogels as a potential carrier for chemotherapeutic drugs for cancer treatments. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Drug Design of “Undruggable” Targets

Drug innovation is not only reflected in the discovery of new chemotypes of active compounds against existing targets but also more dependent on the innovation of drug targets. Currently, a number of attractive and validated targets could not be targeted pharmacologically. Some have been described as “undruggable”. In this review, we summarized the current situation of “undruggable” targets, and the design strategies for “undruggable” targets, hoping to provide references for the development of innovative drugs.     

Synthesis and characterization of star graft copolymers with asymmetric mixed “V‐shaped” side chains via “click” chemistry on a hyperbranched polyglycerol core

The star graft copolymers composed of hyperbranched polyglycerol (HPG) as core and well defined asymmetric mixed “V‐shaped” identical polystyrene (PS) and poly(tert‐butyl acrylate) as side chains were synthesized via the “click” chemistry. The V‐shaped side chain bearing a “clickable” alkyne group at the conjunction point of two blocks was first prepared through the combination of anionic polymerization of styrene (St) and atom transfer radical polymerization of tert‐butyl acrylate (tBA) monomer, and then “click” chemistry was conducted between the alkyne groups on the side chains and azide groups on HPG core. The obtained star graft copolymers and intermediates were characterized by gel permeation chromatography (GPC), GPC equipped with a multiangle laser‐light scattering detector (GPC‐MALLS), nuclear magnetic resonance spectroscopy and fourier transform infrared. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 1308–1316, 2009     

Preparation of phenolic microspheres in water/“water” system

Phenolic microspheres were obtained by condensation of resorcinol and formaldehyde via a novel water/“water” suspension polymerization (WWSP) system, which was proposed and constructed for the first time. Resorcinol/formaldehyde aqueous solutions, ammonium sulfate aqueous solution, hydroxyethyl cellulose (HEC), and sodium hydroxyl were employed as water phase, “water” phase, stabilizer for protecting colloid, and catalyst, respectively. Stable and perfect phenolic microspheres were prepared in this special WWSP system. Particle sizes, size distribution, as well as morphology of microspheres were investigated by scanning electron microscope and computerized image analysis program. The results showed that particle size increased from 0.38 to 2.22 µm along with the increase of concentration of ammonium sulfate in “water” phase from 1.5% to 12.5% and the ratio of resorcinol to formaldehyde from 1:1.5 to 1:4. On the contrary, the particle size decreased from 1.80 to 0.30 µm with the increase of the amount of HEC from 0.1 to 1.0 g and amount of catalyst from 0.05 to 0.2 g. The polydispersity index value of the resulting microspheres is quite narrow, ranging from 1.01 to 1.30, which meant that the morphology of phenolic microspheres was unique. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis of a Novel Oligoaniline: “Dumbbell‐Shaped” Oligoaniline

Summary: A new kind of aniline oligomer with a “dumbbell” shape was synthesized through a simple oxidative coupling reaction with a new rigid aromatic amine as starting material. The oligomer was characterized with mass spectrometry, IR and NMR spectroscopies. Its redox property was checked by cyclic voltammetry and chemical oxidation/reduction process was monitored by UV spectroscopy. We found it has a reversible electrochemical property like common oligoanilines. Combined with its well‐defined structure, it is expected to act as a model compound for a molecular electronic switch.

The “dumbbell‐shaped” oligoaniline compound synthesized here.     

Efficient synthesis of monodisperse,highly crosslinked,and “living” functional polymer microspheres by the ambient temperature iniferter‐induced “living” radical precipitation polymerization

The facile and efficient one‐pot synthesis of monodisperse, highly crosslinked, and “living” functional copolymer microspheres by the ambient temperature iniferter‐induced “living” radical precipitation polymerization (ILRPP) is described for the first time. The simple introduction of iniferter‐induced “living” radical polymerization (ILRP) mechanism into precipitation polymerization system, together with the use of ethanol solvent, allows the direct generation of such uniform functional copolymer microspheres. The polymerization parameters (including monomer loading, iniferter concentration, molar ratio of crosslinker to monovinyl comonomer, and polymerization time and scale) showed much influence on the morphologies of the resulting copolymer microspheres, thus permitting the convenient tailoring of the particle sizes by easily tuning the reaction conditions. In particular, monodisperse poly(4‐vinylpyridine‐co‐ethylene glycol dimethacrylate) microspheres were prepared by the ambient temperature ILRPP even at a high monomer loading of 18 vol %. The general applicability of the ambient temperature ILRPP was confirmed by the preparation of uniform copolymer microspheres with incorporated glycidyl methacrylate. Moreover, the “livingness” of the resulting polymer microspheres was verified by their direct grafting of hydrophilic polymer brushes via surface‐initiated ILRP. Furthermore, a “grafting from” particle growth mechanism was proposed for ILRPP, which is considerably different from the “grafting to” particle growth mechanism in the traditional precipitation polymerization. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

Facile synthesis of polyester dendrimer via combining thio‐bromo “Click” chemistry and ATNRC

This article reports on developing an efficient synthesis approach to aliphatic polyester dendrimer, poly(thioglycerol‐2‐propionate) (PTP), by combination of thio‐bromo “Click” chemistry with atom transfer nitroxide radical coupling (ATNRC). Through the one‐pot two‐step method, linear polystyrene with hydroxyl end groups (l‐PS‐2OH) was obtained by first atom transfer radical polymerization of styrene and following termination using 4‐(2,3‐dihydroxypropoxy)‐TEMPO (DHP‐TEMPO) to capture the PS macroradicals via ATNRC method. Using l‐PS‐2OH as support, the dendritic repeating units divergently were grown from the hydroxyl end groups via esterification and thio‐bromo “Click” reaction two‐step process. In every generation, the resulting intermediates l‐PS‐d‐PTP (G1‐G4) can be easily isolated from the excessive unreacted monomers by simple precipitation in ethanol without help of time, labor and solvent consuming column chromatographic purification. At last, cleavage of the alkoxyamine group between the PS support and dendrimer at elevated temperature (125 °C) provided the targeted polyester dendrimer PTP up to the fourth generation. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1762–1768     

Azide/Alkyne‐“Click”‐Reactions of Encapsulated Reagents: Toward Self‐Healing Materials

The successful encapsulation of reactive components for the azide/alkyne‐“click”‐reaction is reported featuring for the first time the use of a liquid polymer as reactive component. A liquid, azido‐telechelic three‐arm star poly(isobutylene) ( = 3900 g · mol⁻¹) as well as trivalent alkynes were encapsulated into micron‐sized capsules and embedded into a polymer‐matrix (high‐molecular weight poly(isobutylene), = 250 000 g · mol⁻¹). Using (Cu^IBr(PPh₃)₃) as catalyst for the azide/alkyne‐“click”‐reaction, crosslinking of the two components at 40 °C is observed within 380 min and as fast as 10 min at 80 °C. Significant recovery of the tensile storage modulus was observed in a material containing 10 wt.‐% and accordingly 5 wt.‐% capsules including the reactive components within 5 d at room temperature, thus proving a new concept for materials with self‐healing properties.

     

Synthesis and properties of novel aromatic polyamides based on “multi-ring” flexible dicarboxylic acids

The five benzene rings-containing (hereafter referred to as “five-ring”) dicarboxylic acids α,α′-bis[4-(4-carboxyphenoxy)phenyl]-1,4-diisopropylbenzene (p- III ) and α,α′-bis[4-(4-carboxyphenoxy)phenyl]-1,3-diisopropylbenzene (m- III ) were prepared by the fluoro-displacement of α,α′-bis(4-hydroxyphenyl)-1,4-diisopropylbenzene and α,α′-bis(4-hydroxyphenyl)-1,3-diisopropylbenzene with p-fluorobenzonitrile, and subsequent alkaline hydrolysis of the intermediate dinitriles. A number of high-molecular-weight polyamides based on these two “five-ring” dicarboxylic acids (p- III and m- III ) and various aromatic diamines were directly synthesized in N-methyl-2-pyrrolidone (NMP) containing lithium chloride (LiCl) or calcium chloride (CaCl₂) using triphenyl phosphite and pyridine as condensing agents. These polyamides were obtained with inherent viscosities above 0.51 and up to 0.91 dL/g. The weight-average molecular weight were in the range of 51,000–211,000. Most of these polyamides were amorphous and readily soluble in polar solvents such as NMP, N,N-dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO), and afforded tough, flexible, and transparent films by solution-casting. The films had tensile strength of 50–83 MPa, elongation to break of 4–8%, and tensile modulus of 1.3–2.0 GPa. Most polyamides showed distinct glass transitions on the differential scanning calorimetry (DSC) curves ranging from 147 to 177°C. In nitrogen or air, all the polymers showed no significant weight loss up to 490°C, as indicated by thermogravimetric analysis (TG). © 1996 John Wiley & Sons, Inc.     

“Bottom‐Up” Fabrication of BODIPY‐Functionalized Fluorescent Hyperbranched Glycopolymers for Hepatoma‐Targeted Imaging

A novel type of multivalent and highly specific fluorescent hyperbranched glycopolymers h‐P(GalEA‐co‐VBPT‐co‐BYMA) (hPGVB) is designed and prepared successfully via a facile “bottom‐up” strategy. The acetylated hPGVB is prepared by one‐pot reversible addition‐fragmentation chain transfer (RAFT) copolymerization of acrylate‐type galactose monomers AcGalEA and methacrylate‐type fluorescent monomers BYMA in presence of an inimer‐type RAFT chain transfer agent. After deacetylation, the resulting amphiphilic hPGVB can self‐assemble into stable nanoparticles in aqueous media, showing strong green fluorescence with relative high quantum yields and good photostability. The cell viability study indicates the excellent biocompatibility of the hPGVB fluorescent nanoparticles (FNPs) against HepG2 and NIH3T3 cells. More importantly, comparing with the galactose‐free fluorescent hyperbranched polymers h‐P(OEGMA‐co‐VBPT‐co‐BYMA), hPEVB FNPs can be selectively internalized by asialoglycoprotein (ASGP) receptor‐rich HepG2 cells, indicating their potential application in the bioimaging fields.