Lilong Gao

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.

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.

An injectable drug-loaded hydrogel using a “clickable” amphiphilic triblock copolymer as a precursor

We developed a facile strategy to prepare an injectable drug-loaded hydrogel with chemical crosslinkages. A PCL-POEGM-PCL amphiphilic triblock copolymer was synthesized in “one pot” by a combination of polycondensation and ring-opening polymerization, which can disperse hydrophobic drugs in aqueous solution and be crosslinked by POEGMS under physiological conditions.

Injectable camptothecin conjugated hydrogels with simultaneous drug release and degradation

Hydrogels loaded with anticancer drugs can be regarded as depots for intratumoral chemotherapy to downsize tumors. However, the low drug loading content, the rapid drug release, and the subsequently undegraded blank hydrogel matrix may limit their applications. In this work, we prepared an injectable camptothecin (CPT) conjugated hydrogel with simultaneous drug release and degradation to resolve these problems. Poly[oligo(ethylene glycol) maleate] (POEGM) with two terminal hydroxyl groups was first synthesized by the direct polycondensation of oligo(ethylene glycol) (OEG) with maleic acid (MA). CPT, a highly hydrophobic anticancer drug, was conjugated to the chain end of POEGM via carbonic ester bond. The resultant water-soluble CPT–polymer conjugate could be in situ crosslinked by poly[oligo(ethylene glycol) mercaptosuccinate] (POEGMS) rapidly through thiol-ene “click” reaction under physiological conditions, which can be used as injectable CPT conjugated hydrogels. Bright blue fluorescence emitted from CPT-conjugated hydrogel under UV lamp demonstrated the homogeneity of CPT loading. The CPT release by the breakage of carbonic ester bond and the degradation of hydrogels by the breakage of ester bonds were observed simultaneously within one week to 16 days, depending on the solid content of hydrogels. The CPT-conjugated hydrogels exhibited significant cytotoxicity to HepG2 cells based on in vitro cell viability assays. As a contrast, the blank hydrogels without CPT conjugation showed excellent biocompatibility under the same conditions. This kind of CPT conjugated hydrogels could be a potential candidate for intratumor drug delivery.