Weipu Zhu

Drug-grafted seven-arm amphiphilic star poly(ε-caprolactone-co-carbonate)-b-poly(ethylene glycol)s based on a cyclodextrin core: synthesis and self-assembly behavior in water

Novel well-defined drug-grafted seven-arm amphiphilic star poly(e-caprolactone-co-carbonate)-b-poly(ethylene glycol)s based on a β-CD core [CDS-P(CL-co-DTC)-D-b-PEG] have been synthesized by the combination of controlled ring-opening polymerization (CROP), esterification coupling reactions and “click” reactions. First, 5,5-dibromomethyl-trimethylene carbonate (DBTC) bearing two bromide pendent groups was synthesized and used to copolymerize with CL to prepare seven-arm star random copolymers [CDS-P(CL-co-DBTC)] in the presence of per-2,3-acetyl-β-cyclodextrin and Sn(Oct)2. Second, esterification coupling reaction between CDS-P(CL-co-DBTC) and carboxyl-terminated mPEG led to amphiphilic seven-arm star copolymers [CDS-P(CL-co-DBTC)-b-PEG]. Subsequently, the bromide pendent groups on CDS-P(CL-co-DBTC)-b-PEG had been converted into azide groups by treating with NaN3. Finally, alkyne functionalized ibuprofen had been grafted onto the hydrophobic block of the star copolymers by copper(I)-catalyzed “click” reaction. 1H NMR, FT-IR and SEC analyses confirmed the well-defined drug grafted star architecture. These copolymers could self-assemble into multi-morphological aggregates in water, which were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM).

The construction of hierarchical structure on Ti substrate with superior osteogenic activity and intrinsic antibacterial capability

The deficient osseointegration and implant-associated infections are pivotal issues for the long-term clinical success of endosteal Ti implants, while development of functional surfaces that can simultaneously overcome these problems remains highly challenging. This study aimed to fabricate sophisticated Ti implant surface with both osteogenic inducing activity and inherent antibacterial ability simply via tailoring surface topographical features. Micro/submciro/nano-scale structure was constructed on Ti by three cumulative subtractive methods, including sequentially conducted sandblasting as well as primary and secondary acid etching treatment. Topographical features of this hierarchical structure can be well tuned by the time of the secondary acid treatment. Ti substrate with mere micro/submicro-scale structure (MS0-Ti) served as a control to examine the influence of hierarchical structures on surface properties and biological activities. Surface analysis indicated that all hierarchically structured surfaces possessed exactly the same surface chemistry as that of MS0-Ti, and all of them showed super-amphiphilicity, high surface free energy, and high protein adsorption capability. Biological evaluations revealed surprisingly antibacterial ability and excellent osteogenic activity for samples with optimized hierarchical structure (MS30-Ti) when compared with MS0-Ti. Consequently, for the first time, a hierarchically structured Ti surface with topography-induced inherent antibacterial capability and excellent osteogenic activity was constructed.

Reductively and hydrolytically dual degradable nanoparticles by “click” crosslinking of a multifunctional diblock copolymer

In this study, we report the synthesis of dual degradable nanoparticles by crosslinking a multifunctional amphiphilic block copolymer through “click” chemistry. Poly(ethylene glycol)-block-poly((e-caprolactone)-co-(5,5-dibromomethyl trimethylene carbonate)) (mPEG-b-PDBTCL), an amphiphilic block copolymer with multiple bromo groups, was synthesized first by the ring-opening copolymerization of 5,5-dibromomethyl trimethylene carbonate (DBTC) and e-caprolactone (CL) in the presence of methoxyl poly(ethylene glycol) as macroinitiator and stannous octanoate (Sn(Oct)2) as catalyst. Then the pendant bromo groups were partially transformed to the azide form by reacting with sodium azide under room temperature, to give partially azidated mPEG-b-PDBTCL (mPEG-b-PDBTCL-N3). Then “click” crosslinking was carried out using mPEG-b-PDBTCL-N3 as precursor and propargyl 3,3′-dithiopropionate as crosslinker, resulting in star-shaped nanoparticles bearing multiple bromo groups in the core. This kind of core crosslinked nanoparticle is biodegradable due to the hydrolysis of the poly(ester-carbonate) core. Additionally, depending on the redox-sensitive disulfide crosslinkers, the stable nanoparticles will dissociate into free block copolymers in the presence of 1,4-dithiothreitol (DTT). Furthermore, ammonium groups were introduced into the core covalently by the quaternization reaction between the remaining bromomethyl groups and N,N-dimethylbutylamine. These dual degradable nanoparticles are expected to have potential applications as smart nanovessels for both drug and gene delivery.

Fully biodegradable antibacterial hydrogels via thiol–ene “click” chemistry

In this work, fully biodegradable antimicrobial hydrogels were prepared facilely via a thiol–ene “click” reaction under human physiological conditions using multifunctional poly(ethylene glycol) (PEG) derivatives as precursors. Water soluble and degradable PEG derivatives with multi-enes and multi-thiols, respectively, were synthesized by polycondensation of oligo(ethylene glycol) (OEG) with “clickable” monomers. Ammonium groups with long alkyl chains were incorporated into one of the precursors covalently, using dodecyl bis(2-hydroxyethyl) methylammonium chloride as a comonomer. Proton nuclear magnetic resonance (1H-NMR) spectroscopy, gel permeation chromatography (GPC) and Fourier transform infrared spectroscopy (FT-IR) were used to characterize the precursors and hydrogels. These types of cationic PEG-type hydrogels showed strong antibacterial abilities against both Gram-negative and Gram-positive bacteria due to the ammonium moieties. Moreover, the hydrogel with fewer ammonium moieties still possessed significant antibacterial abilities, but low toxicity, and has the potential to be used as a medical material.

Acid-triggered drug release from micelles based on amphiphilic oligo(ethylene glycol)–doxorubicin alternative copolymers

We report a facile strategy to synthesize pH-sensitive amphiphilic oligo(ethylene glycol) (OEG)-doxorubicin (DOX) alternative conjugates. Poly[oligo(ethylene glycol) malicate] (POEGM) with numerous pendent hydroxyl groups was first synthesized by the direct polycondensation of oligo(ethylene glycol) (OEG) with malic acid under mild conditions. Then, benzaldehyde groups were introduced into the POEGM backbone via esterification between the pendant hydroxyl groups and 4-formylbenzoic acid. DOX moieties were finally attached to the polymeric backbone via benzoic imine linkages to obtain the OEG-DOX conjugates. Because of the high molecular weight and alternate architecture, this type of amphiphilic OEG-DOX alternative conjugates can form stable micelles in aqueous solution with a high DOX loading content (38.2 wt%) and low critical micelle concentrations (0.021 mg mL-1). Due to the pH-sensitive benzoic imine linkages between the DOX moieties and polymeric backbone, DOX could be rapidly released from the micelles at pH 5.8, whereas only a minimal amount of DOX was released at pH 7.4 under the same conditions. The cytotoxicity assay indicates that the OEG-DOX conjugates show cytotoxic effects to MCF-7 tumor cells, while the corresponding polymer material POEGM-CHO exhibits a great biocompatibility for MCF-7 tumor cells. These pH-sensitive and high drug loading nano-carriers based on the OEG-DOX alternative conjugates provide a promising platform for targeted cancer therapy.

Facile preparation of shell crosslinked micelles for redox-responsive anticancer drug release

We report a “one-pot” method to synthesize an amphiphilic triblock copolymer with multiple pendant mercapto groups in the hydrophilic block. Shell crosslinked micelles were prepared in a facile manner via the self-assembly of this copolymer in aqueous solution and crosslinking of the micellar shell by H2O2. These shell crosslinked micelles show rapid bioreductive responsiveness for anticancer drug release.

Metal and light free “click” hydrogels for prevention of post-operative peritoneal adhesions

This study presented a facile method to prepare two PEG derivatives with multi-thiols or multi-enes by polycondensation on a large scale using scandium trifluoromethanesulfonate (Sc(OTf)3) as highly efficient and chemoselective catalyst. A novel type of biodegradable and biocompatible PEG hydrogel was easily obtained through the thiol–ene “click” reaction under physiological conditions. 1H NMR spectra and GPC were used to characterize the chemical compositions and molecular weights of the two PEG derivatives. FT-IR and rheological experiments were used to investigate the gelation behavior of the PEG hydrogel. Degradation studies revealed a precursor concentration-dependent degradation behavior of the resultant PEG hydrogel. In vitro cell viability assay showed the excellent biocompatibility of the two precursors and also the resultant hydrogel. Furthermore, the rat model of abdominal sidewall defect-cecum abrasion suggested that the PEG hydrogel developed in the present study is a promising physical barrier for the prevention of post-operative peritoneal adhesion.

Facile fabrication of reduction-responsive nanocarriers for controlled drug release

An amphiphilic multiblock poly(ether–ester) containing multiple thiols was facilely synthesized by “one-pot” polycondensation of dihydroxyl poly(ethylene glycol), 1,4-butanediol and mercaptosuccinic acid, which could be used to fabricate reduction-responsive core-crosslinked micelles for controlled drug release.

Facile fabrication of ultrathin antibacterial hydrogel films via layer-by-layer “click” chemistry

We report a facile strategy to fabricate ultrathin hydrogel films via a layer-by-layer (LbL) technique and “click” chemistry. Poly[oligo(ethylene glycol)fumarate]-co-poly[dodecyl bis(2-hydroxyethyl)methylammonium fumarate] (POEGDMAM) containing multi-enes and poly[oligo(ethylene glycol)mercaptosuccinate] (POEGMS) containing multi-thiols were synthesized by polycondensation, which were used as precursors for a LbL thiol–ene “click” reaction under ambient conditions without any metal catalyst or light irradiation. Due to the presence of ammonium groups with long alkyl chains in the POEGDMAM, the ultrathin hydrogel films exhibited excellent antibacterial activity against both Staphylococcus aureus and Escherichia coli, which was enhanced by increasing the number of layers. These kinds of biocompatible, antibacterial, ultrathin hydrogel films are promising candidates for biomedical applications.

Facile synthesis and characterization of biodegradable antimicrobial poly(ester-carbonate)

Biodegradable antimicrobial poly(ester-carbonate)s were prepared facilely via a simple two-step process with low cost. First, poly(5,5-dibromomethyl trimethylene carbonate-co-e-caprolactone) (PDBTCL) with pendant bromo groups was synthesized by the direct ring-opening copolymerization of 5,5-dibromomethyl trimethylene carbonate (DBTC) and e-caprolactone (CL) in the presence of stannous octanoate (Sn(Oct)2) as catalyst. Then, the quaternization reaction between PDBTCL and a series of N,N-dimethyl alkylamines was performed under mild conditions, resulting in biodegradable poly(ester-carbonate)s with pendant ammonium salts (QPDBTCL). The chemical structure and composition of QPDBTCLs were characterized by 1H NMR. The influences of alkyl chain length and charge density on the antimicrobial activity of QPDBTCLs against Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria were evaluated by OD600 and zone of inhibition methods. It was observed that QPDBTCLs with long alkyl chain on the ammonium groups exhibit significantly higher antimicrobial activity than those with short alkyl chain for both Gram-negative and Gram-positive bacteria. QPDBTCL with quaternary N,N-dimethyldodecylammonium groups shows strong antimicrobial activity even with very low charge density (4.3 mol%). This kind of biodegradable antimicrobial material may have potential applications as biomaterials.