Shudong Lin

Interlayer‐Crosslinked Micelle with Partially Hydrated Core Showing Reduction and pH Dual Sensitivity for Pinpointed Intracellular Drug Release

Although the utilization of polymeric micelles has demonstrated great potential in delivering anticancer drugs, this technique is facing tremendous challenges. In particular, polymeric micelles usually show a drug-release profile that is not in favor of achieving optimal drug availability inside tumor cells. That is, a “burst release” of up to 20–30 % of the encapsulated drug within several hours post micelle formation, followed by a slow diffusional drug release lasting for many days. The premature burst release leads to drug loss in micelle storage and blood circulation. Meanwhile, the secondstage slow drug release results in low intracellular drug availability insufficient for killing cancer cells. Therefore, development of delivery systems with better drug-release properties is still of great importance. One of the most promising strategies is to construct polymeric micelles that respond to specific stimulation, such as light exposure, enzymatic degradation, redox reaction, or change in pH or temperature. Acid-triggered rapid release of drugs can be achieved inside tumor tissue (pH below 6.8) or lysosomal compartments (pH about 5.0) of cancer cells by using micelles of copolymers bearing pH-sensitive blocks, such as poly(lhistidine) and poly(b-amino ester). Nevertheless, these pH-sensitive micelles were not designed to avoid the premature burst release of drugs. In addition, supramolecular nanoassemblies de-micellize when the polymer concentration drops below the critical micelle concentration (CMC), which is another underlying cause for the loss of drugs during blood circulation. Recently, covalent crosslinking of the core or shell of selfassembled polymeric micelles has emerged as a viable strategy to prevent de-micellization-associated drug loss. 11] Among various approaches, the utilization of disulfide-containing reversible crosslinkers is of particular importance, owing to the fact that the disulfide bond is reducible and therefore can be cleaved by glutathione (GSH), a thiol-containing oligopeptide predominantly found inside cells (up to the millimolar scale). Indeed, shell-crosslinked micelles (SCMs) obtained using disulfide-containing agents have demonstrated great potential for specifically releasing the loaded cargos inside cells. 13] In spite of their potential in reducing premature drug leakage, these SCMs cannot rapidly release drugs inside cells because drug release from their nonsensitive cores still follows a diffusion-controlled mechanism. Herein, we describe the first example of a highly packed interlayer-crosslinked micelle (HP-ICM) with reduction and pH dual sensitivity, which comprises a polyethylene glycol (PEG) corona to stabilize the particles, a highly compressed pH-sensitive partially hydrated core to load anticancer drugs, and a disulfide-crosslinked interlayer to tie up the core against expansion at neutral pH. The HP-ICM was stable and drug leakage free in a neutral pH environment without reducing agent. However, when the HP-ICM was internalized into cells and trapped inside lysosomes featuring low pH ( 5) and enriched reducing agent (GSH), the pH-sensitive core was unpacked and thus erupted to burst release the anticancer drug (Figure 1). The reductionand pH-sensitive interlayer-crosslinked micelle with partially hydrated core was prepared from a triblock copolymer of monomethoxy polyethylene glycol (mPEG), 2-mercaptoethylamine (MEA)-grafted poly(laspartic acid) (PAsp(MEA)), and 2-(diisopropylamino)ethylamine (DIP)-grafted poly(l-aspartic acid) (PAsp(DIP)). The copolymer was synthesized by ring-opening polymerization of b-benzyl l-aspartate N-carboxy-anhydride (BLA-NCA) in combination with click and aminolysis reactions (see the Supporting Information, Figure S1). So far, most reported shell-crosslinked nanoparticles have been based on polyacrylate or polyacrylamide. 14] We chose biodegradable polypeptide as the copolymer backbone in consideration of biocompatibility requirements in drug delivery. Poly(BLA) aminolysis with MEA and DIP introduced the crosslinkable thiol and pH-sensitive tertiary amino groups onto the middle and end blocks of the copolymer, respectively. NMR and FTIR analyses confirmed the chemical structures of the polymers (see the Supporting Information, Figures S3–S6). Gel permeation chromatography measurements also evidenced the successful synthesis of mPEG[*] Dr. J. Dai, S. Lin, Dr. D. Cheng, Prof. X. Shuai PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering Sun Yat-sen University, Guangzhou 510275 (China) E-mail: shuaixt@mail.sysu.edu.cn

Simple approach towards fabrication of highly durable and robust superhydrophobic cotton fabric from functional diblock copolymer

We report here a simple and reproducible strategy for fabricating highly durable and robust superhydrophobic cotton fabrics (SCFs) from a series of functional diblock copolymers. These diblock copolymers consisted of both poly(glycidyl methacrylate) (PGMA) and poly(2,2,2-trifluoroethyl methacrylate) (PTFEMA) blocks that were synthesized via sequential atom transfer radical polymerization (ATRP). While the PTFEMA block provides the low surface free energy, the PGMA block serves as an anchor and forms covalent bonds with the surfaces of cotton fibers. These covalent bonds are formed via the epoxy ring-opening reaction between the epoxy groups of the PGMA block and the hydroxyl groups on the surface of the cotton fiber, and self-crosslinking of epoxy groups from PGMA chains. Structures exhibiting nano- and microscale roughness were created in one-step by combining copolymer-based nanobumps onto surfaces of micro-sized fibers of the cotton fabric, as confirmed by SEM and AFM analysis. The modified cotton fabrics show excellent water repellency with water contact angles (WCAs) of ∼163° and water sliding angles (WSAs) of ∼3° under optimized conditions. Since the low-fluorinated PTFEMA chains are chemically bound to the cotton fibers, the SCFs possess long-term stability, ultra-high durability and robustness. In particular, these SCFs withstood mechanical abrasion by sandpaper, strong laundering conditions, ultrasonication treatment in tetrahydrofuran (THF) or trifluorotoluene (TFT), soaking in a wide range of organic solvents, as well as acidic and basic aqueous solutions, exposure to UV-irradiation and even refluxing in TFT or THF.

Simultaneous diagnosis and gene therapy of immuno-rejection in rat allogeneic heart transplantation model using a T-cell-targeted theranostic nanosystem.

As the final life-saving treatment option for patients with terminal organ failure, organ transplantation is far from an ideal solution. The concomitant allograft rejection, which is hardly detectable especially in the early acute rejection (AR) period characterized by an intense cellular and humoral attack on donor tissue, greatly affects the graft survival and results in rapid graft loss. Based on a magnetic resonance imaging (MRI)-visible and T-cell-targeted multifunctional polymeric nanocarrier developed in our lab, effective co-delivery of pDNA and superparamagnetic iron oxide nanoparticles into primary T cells expressing CD3 molecular biomarker was confirmed in vitro. In the heart transplanted rat model, this multifunctional nanocarrier showed not only a high efficiency in detecting post-transplantation acute rejection but also a great ability to mediate gene transfection in T cells. Upon intravenous injection of this MRI-visible polyplex of nanocarrier and pDNA, T-cell gathering was detected at the endocardium of the transplanted heart as linear strongly hypointense areas on the MRI T(2)*-weighted images on the third day after cardiac transplantation. Systematic histological and molecular biology studies demonstrated that the immune response in heart transplanted rats was significantly suppressed upon gene therapy using the polyplex bearing the DGKα gene. More excitingly, the therapeutic efficacy was readily monitored by noninvasive MRI during the treatment process. Our results revealed the great potential of the multifunctional nanocarrier as a highly effective imaging tool for real-time and noninvasive monitoring and a powerful nanomedicine platform for gene therapy of AR with high efficiency.

Fabrication of fluorinated raspberry particles and their use as building blocks for the construction of superhydrophobic films to mimic the wettabilities from lotus leaves to rose petals

Reported herein is the preparation of poly((glycidyl methacrylate)-co-(ethylene glycol dimethacrylate)) raspberry-like colloidal particles (also denoted as RPs) bearing micro-/nano-scale surface roughness and the fabrication of superhydrophobic films with tunable adhesion derived from the RPs after their fluorination. The RPs were prepared via the one-pot dispersion polymerization of glycidyl methacrylate (GMA) and ethylene glycol dimethacrylate (EGDMA). The size and the surface roughness of the RPs can be readily tuned by adjusting the polymerization parameters, including the temperature, the feed monomer mole ratio, the initiator concentration, and so on. A possible mechanism of the formation of RPs was proposed according to the morphological evolution observed during the polymerization process as monitored via transmission electron microscopy (TEM), scanning electron microscopy (SEM), and size variation as evaluated with dynamic light scattering (DLS) measurements. Fluorinated RPs (also denoted as FRPs) with various fluorination degrees were further prepared by reaction between the epoxy groups of the RPs and the thiol group of perfluorodecanethiol (PFDT). The raspberry-like morphology of the FRPs was maintained as confirmed via SEM observation. By only changing the surface chemistry rather than the roughness, superhydrophobic films with tunable superhydrophobic properties capable of mimicking wettabilities ranging from those of lotus leaves to those of rose petals were easily prepared by drop-casting dispersions of FRPs onto glass substrates.

Novel aramid nanofiber-coated polypropylene separators for lithium ion batteries

Aramid nanofiber (ANF)-coated separators were successfully prepared by the dip-coating of a cationized polypropylene (PP) porous separator in an ANF dispersion in DMSO. The ANFs were successfully coated onto the surface of the cationized PP separator as demonstrated by FT-IR and XPS measurements and the ANFs could be directly observed on the surface of the composite separator via SEM and AFM. The ANF-based coating layers became more uniform and denser as more dip-coating cycles were employed. The gas permeabilities of the separators were strongly influenced by the concentrations of the ANF dispersion and the number of dip-coating cycles. The porosity decreased and a narrower pore size distribution was obtained after the ANFs were coated onto the cationized PP separator. The ANF-coated separators were found to exhibit higher dimensional stabilities than the pristine PP separator. The separators exhibited almost identical endothermic peaks in the DSC experiment and a similar shrink temperature in the DMA experiment but the ANF-coated separator exhibited a higher rupture temperature. The ANF-coated separator retained a comparable mechanical strength with that of the pristine PP separator. The ANF coating layer was mechanically stable and durable in the electrolyte. The ANF-coated separator exhibited comparable C-rate performance and cycling performance in LMO/Li cell systems to that of the PDA–PP separator, and showed significantly better C-rate performance and cycling performance than that of the pristine PP separator. The ANF-coated PP separators exhibited improved safety in a hot oven test in comparison with the pristine PP separator. Thus the ANF-coated separators have great potential for use in lithium ion batteries.

pH-Responsive Nanoemulsions for Controlled Drug Release

Three ternary graft copolymers bearing polystyrene (PS), poly(ethylene glycol) methyl ether (MPEG), and poly(acrylic acid) (PAA) side chains were synthesized and characterized. At pH = 7.4, these copolymers stabilized doxorubicin (DOX)-containing benzyl benzoate (BBZ) nanoemulsion droplets in water and formed a compact polymer layer to inhibit DOX release. Upon lowering the solution pH to 5.0, the AA groups dissociated less and became less soluble. Moreover, the neutralized AA groups formed presumably H-bonded complexes with the EG units, reducing the solubility of the EG units. This dual action drastically shifted the hydrophilic and hydrophobic balance of the copolymer and caused the original stabilizing polymer layer to rupture and the nanoemulsion droplets to aggregate, releasing DOX. The rate and extent of DOX release could be increased by matching the numbers of PAA and MPEG chains per graft copolymer. In addition, these nanoemulsions were not toxic and entered human carcinoma cells, releasing DOX there. Thus, these nanoemulsions have potential as drug delivery vehicles.

Emulsion and nanocapsules of ternary graft copolymers

Alkyne end-tagged poly(ethylene glycol) methyl ether, polystyrene, and poly(tert-butyl acrylate) (denoted as MPEG–CCH, PS–CCH, and PtBA–CCH, respectively) were grafted randomly onto a (PGMA–N3) backbone via “click” chemistry to produce a series of ternary graft copolymers PGMA-g-(MPEG-r-PtBA-r-PS). The selective hydrolysis of the PtBA chains into poly(acrylic acid) (PAA) yielded PGMA-g-(MPEG-r-PAA-r-PS). Since MPEG and PAA were soluble in water while PS was soluble in decahydronaphthalene (DN), the graft copolymers were good surfactants for emulsifying DN in water. Various factors affecting the emulsification were examined, including the stirring rate, the copolymer composition, and the concentration. Crosslinking of the PAA chains, which were distributed among MPEG chains in the coronas of the emulsion droplets, with a diamine produced a novel structure – “nanocapsules” bearing partially crosslinked coronas.

Hydrophilization of polysulfone membranes using a binary graft copolymer

An amphiphilic binary graft copolymer polysulfone-graft-[poly(methyl methacrylate)-random-poly(acrylic acid)], PSf-g-(PMMA-r-PAA), was synthesized via a combination of atom transfer radical polymerization (ATRP) and click chemistry. This copolymer and polysulfone (PSf) were used to prepare porous membranes through the phase inversion method, which involved dissolving the polymers in a common solvent N-methyl pyrrolidone (NMP), casting the solution onto a glass plate to obtain a film, and subsequently immersing this film into a coagulant (a mixture of dimethylformamide and water at a given pH). The surfaces of the membrane and its pore walls were covered by the copolymer, and these surfaces were enriched with PAA domains due to the immiscibility of PAA and PSf and the miscibility of PMMA and PSf. More specifically, while the hydrophobic PMMA component served as an anchor to fix the graft copolymer onto the PSf bulk substrate, the hydrophilic PAA component assembled and became exposed at the surfaces of the membrane and the pore walls. Factors influencing this surface AA concentration or carboxyl group content (CGC) enrichment and the surface and pore morphologies of the membranes include the ratio between the amount of the copolymer and PSf in the mixture, the solvent quality of the coagulant for PSf, and the temperature as well as the pH of the coagulant. These factors have been systematically adjusted to optimize the hydrophilization of the PSf membrane and the resultant membranes have been characterized by water contact angle (WCA) measurements, scanning electron microscopy (SEM), atomic force microscopy (AFM), and X-ray photoelectron spectroscopy (XPS). Optimization of the phase inversion process yielded membranes with nearly complete surface coverage by PAA, even when the graft copolymer represented only 8 wt% of the membranes composition. The hydrophilized membranes exhibited increased water flux and even pH-responsive water flow without adversely affecting their mechanical properties. In addition, these hydrophilic membranes exhibited long-term stability. Therefore, this novel binary amphiphilic graft copolymer-based approach for membrane modification may be of commercial value.

Metal ion induced-assembly of amylose in aqueous solution

Cu(2+)/amylose assemblies of various sizes were prepared through the Cu(2+) ion induced-assembly of amylose. These assembly structures were characterized via transmission electronic microscopy (TEM), scanning electronic microscopy (SEM), dynamic light scattering (DLS), (1)H NMR analysis, fluorescence spectroscopy (FL) and UV-vis absorption spectroscopy (UV-vis). The results from these characterizations revealed the existence of a complexation effect and/or a bridging effect between the hydroxyl groups of amylose and Cu(2+) ions, and that the formation of the hydrophobic domains promoted the formation of Cu(2+)/amylose assemblies. The use of other metal ions to induce the formation of spherical, flower- and wire-like amylose assemblies was investigated as well. A preliminary investigation on the ability of amylose to capture various metal ions was also performed, and the results of this work demonstrated that amylose could bind quantitatively metal ions that were at low concentrations. This work provided an alternative strategy for the recovery of precious metals from metal ion-containing aqueous solutions and the reduction of water pollution.

Synthesis of poly(2-hydroxyethyl methacrylate) end-capped with asymmetric functional groups via atom transfer radical polymerization

Poly(2-hydroxyethyl methacrylate) (PHEMA) end-capped with living chloride and alkyne groups was synthesized via ATRP of HEMA using CuCl/CuCl2/2,2′-bipyridine as a catalyst in a solvent mixture of methanol and 2-butanone. The effects of parameters including the initiator, solvent, temperature and initial monomer to initiator ratios on polymerization were studied in terms of polymerization kinetics, the degree of polymerization (DP) and molar mass dispersity (Đ) of the resulting PHEMA polymer. ATRP of HEMA using propargyl 2-bromoisobutyrate (PBiB) as an initiator was poorly controlled, but those using 3-(trimethylsilyl)propargyl 2-bromoisobutyrate (TMSPBiB) and 3-(triisopropysilyl)propargyl 2-bromoisobutyrate (TiPSPBiB) as initiators were well-controlled. Moreover, the apparent propagation rate constant for ATRP of HEMA using the TMSPBiB initiator was higher than that using the TiPSPBiB initiator. The solvent mixture of methanol–2-butanone at different compositions greatly affected the polymerization controllability. A high molecular weight PHEMA sample with a DP of 1000 and a Đ of 1.34 was obtained under appropriate conditions. The poly(2-hydroxyethyl methacrylate)-block-poly(butyl acrylate) (PHEMA-b-PBA) diblock copolymer was prepared through ATRP of BA using (CH3)3Si–CC–PHEMA–Cl as a macroinitiator. The methoxyl polyethylene glycol-block-poly(2-hydroxyethyl methacrylate) (MPEG-b-PHEMA) diblock copolymer was prepared by click reaction between MPEG-N3 and HCC–PHEMA–Cl. These two reactions demonstrated the reactivity of the asymmetric functional groups end-capping the PHEMA, and further provided modular examples for the synthesis of a novel well-defined (co)polymer with complex architectures.