Fanbo Meng

Biodegradable amphiphilic copolymer containing nucleobase: synthesis, self-assembly in aqueous solutions, and potential use in controlled drug delivery.

Biodegradable nucleobase-grafted amphiphilic copolymer, the methoxyl poly (ethylene glycol)-b-poly (L-lactide-co-2-methyl-2(3-(2,3-dihydroxylpropylthio) propyloxycarbonyl)-propylene carbonate/1-carboxymethylthymine) (mPEG-b- P(LA-co-MPT)), was synthesized. (1)H NMR titration and FT-IR spectroscopy indicated that the hydrogen-bonding could be formed between mPEG-b-P(LA-co-MPT) and 9-hexadecyladenine (A-C16). The hydrophobic microenvironment of the amphiphilic copolymer can protect the complementary multiple hydrogen bonds between mPEG-b-P(LA-co-MPT) and A-C16 from water effectively. The addition of A-C16 not only lowered the critical aggregation concentration (CAC) of mPEG-b-P(LA-co-MPT)/A-C16 nanoparticles (NPs) in aqueous solution but also induced different morphologies, which can be observed by transmission electron microscopy (TEM). Meanwhile, dynamic light scattering (DLS) and turbidometry was utilized to evaluate the effect of temperature and pH change on the stability of mPEG-b-P(LA-co-MPT)/A-C16 NPs. Cytotoxicity evaluation showed good biocompatibility of the mPEG-b-P(LA-co-MPT)/A-C16 NPs. The in vitro drug release profile showed that with the increase of A-C16 content, the doxorubiucin (DOX) release at pH 7.4 decreased, while the faster release rate was observed with the addition of A-C16 with a pH of 5.0. Importantly, DOX-loaded NPs exerted comparable cytotoxicity against MDA-MB-231 cells. This work provided a new method to stabilize NP structure using hydrogen-bonds and would have the potential to be applied in controlled drug delivery.

A Polymer-(Tandem Drugs) Conjugate for Enhanced Cancer Treatment

A novel strategy for combination chemotherapy (platinum and demethylcantharidin) via a polymer-(tandem drugs) conjugate for enhanced cancer treatment is demonstrated. Cisplatin can be released inside cell by reduction to attack DNA, while DMC will be hydrolyzed subsequently to block DNA-damage-induced defense mechanisms by serine/threonine phosphatase PP2A inhibition. Synergistic effect of the polymer-(tandem drugs) conjugate causes complete suppression of H22 liver tumor xenografts without recurrence.

Doxorubicin-Loaded Carborane-Conjugated Polymeric Nanoparticles as Delivery System for Combination Cancer Therapy

Carborane-conjugated amphiphilic copolymer nanoparticles were designed to deliver anticancer drugs for the combination of chemotherapy and boron neutron capture therapy (BNCT). Poly(ethylene glycol)-b-poly(L-lactide-co-2-methyl-2(2-dicarba-closo-dodecarborane)propyloxycarbonyl-propyne carbonate) (PLMB) was synthesized via the versatile reaction between decaborane and side alkynyl groups, and self-assembled with doxorubicin (DOX) to form drug-loaded nanoparticles. These DOX@PLMB nanoparticles could not only suppress the leakage of the boron compounds into the bloodstream due to the covalent bonds between carborane and polymer main chains, but also protect DOX from initial burst release at physiological conditions because of the dihydrogen bonds between DOX and carborane. It was demonstrated that DOX@PLMB nanoparticles could selectively deliver boron atoms and DOX to the tumor site simultaneously in vivo. Under the combination of chemotherapy and BNCT, the highest tumor suppression efficiency without reduction of body weight was achieved. This polymeric nanoparticles delivery system could be very useful in future chemoradiotherapy to obtain improved therapeutic effect with reduced systemic toxicity.

Core-crosslinked amphiphilic biodegradable copolymer based on the complementary multiple hydrogen bonds of nucleobases: synthesis, self-assembly and in vitro drug delivery

Nucleobases (adenine and thymine) were conjugated to the amphiphilic biodegradable copolymers methoxyl poly(ethylene glycol)-b-poly(L-lactide-co-2-methyl-2-allyloxycarbonylpropylene carbonate) (mPEG-b-P(LA-co-MAC)). The hydrogen bonds between adenine (A) and thymine (T) were confirmed by 1H NMR titration experiments and FT-IR. It was found that the incorporation of nucleobases into the hydrophobic segment of the amphiphilic copolymers could be used for core-crosslinking of the formed micelles containing a lowered critical micelle concentration (CMC) via hydrogen bond interaction between A and T in aqueous solution. The anticancer drug doxorubicin (DOX) was encapsulated into the copolymer micelles. The in vitro drug release profile showed that the incorporation of nucleobases significantly restricted DOX release at pH 7.4, because of the compact crosslinking structure of micelles. However, a much faster release rate was observed at pH 5.0, due to the dissociation of hydrogen bonds between nucleobases. This character facilitates drug delivery in the acidic tumor micro-environment inside the endosome. Meanwhile, the DOX-loaded core-cross-linked micelles could be efficiently internalized into cancer cells and exhibit similar anticancer efficacy as free DOX against MDA-MB-231 cells. Therefore, the complementary multiple hydrogen bonds of nucleobases provided a convenient tool to stabilize the micelle structures by forming core-crosslinking, and could be further applied for controlled drug delivery.

A novel amphiphilic copolymer poly(ethylene oxide-co-allyl glycidyl ether)-graft-poly(ε-caprolactone): synthesis, self-assembly, and protein encapsulation behavior

New amphiphilic graft copolymers with hydrophilic poly(ethylene oxide-co-allyl glycidyl ether) (PEAG) as the backbone and hydrophobic poly(e-caprolactone) (PCL) as the side chains (PEAG-g-PCL) were designed and synthesized. For this purpose, the combined techniques of anionic copolymerization, radical mediated thiol–ene reaction and ring-opening polymerization were employed. The properties of the graft copolymer were characterized by 1H NMR, 13C NMR, GPC and MALDI-TOF-MS. The self-assembly of the copolymers in aqueous solution was examined by fluorescence spectroscopy, DLS and TEM. The results showed that with a relatively low critical aggregation concentration (CAC), the graft copolymers could form different morphologies including vesicles (polymersomes). The formed polymersomes had the capacity to encapsulate protein molecules (like hemoglobin, Hb) through a modified lyophilization–rehydration method as analyzed via TEM and SDS-PAGE. Furthermore the gas-binding capacity of the encapsulated Hb was assayed via UV-vis spectroscopy. The characteristic absorption peak of the encapsulated Hb in different gas-binding states (CO, O2, N2) showed no significant change by comparison with that of free Hb. These Hb encapsulated PEAG-g-PCL polymersomes could have the potential to be applied as an artificial oxygen carrier for transfusion.

Layer-by-Layer Assembled Polypeptide Capsules for Platinum-Based Pro-Drug Delivery

Platinum(IV), a pro-drug of platinum(II), was conjugated to poly(l-lysine) (PLL), and then assembled with poly(glutamic acid) (PGA) through a layer-by-layer (LbL) approach on colloidal silica templates. After removal of the templates, biodegradable PGA/PLL-Pt(IV) multilayer capsules (diameter = 0.5 μm) with 10 μg of platinum incorporated into each bilayer were obtained. Under acidic and/or reductive conditions, the amount and rate of platinum released from the capsules were increased, which are desirable traits for platinum-based anticancer drug delivery systems. Furthermore, in vitro evaluation showed that the PGA/PLL-Pt(IV) multilayer microcapsules displayed higher cytotoxicity (IC(50Pt) = 3.5 μg/mL) against colon cancer cells CT-26 than that of free cisplatin (IC(50Pt) = 8.6 μg/mL). This enhanced cytotoxicity was attributed to the effective internalization of the capsules by the cancer cells, which was observed by confocal laser scanning microscopy (CLSM) imaging.

PEGylated Click Polypeptides Synthesized by Copper-Free Microwave-Assisted Thermal Click Polymerization for Selective Endotoxin Removal from Protein Solutions

PEGylated click polypeptides (PEG-CPs) containing α-amino side groups as well as PEG segments are designed for selective endotoxin removal from protein solutions. The PEG-CPs are synthesized via copper-free thermal click copolymerization from aspartic (or glutamic) acid-based dialkyne and diazide monomers (containing free amino side groups) and alkyne-terminated mPEGs or dialkyne-terminated PEGs. Microwave-assisting technology is introduced into thermal click chemistry to improve the reaction efficiency. The monomers and polymers are fully characterized using NMR, XPS, and MALDI-TOF MS. After immobilizing the PEGylated click polypeptides onto polystyrene microspheres, the adsorbents exhibit good endotoxin removal selectivity from BSA solutions.

A reduction-sensitive carrier system using mesoporous silica nanospheres with biodegradable polyester as caps

Mesoporous silica nanoparticles (MSN)-polymer hybrid combined with the aliphatic biodegradable polyester caps on the surface were first developed in order to manipulate the smart intracellular release of anticancer drugs. First, poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-PCL) was successfully grafted on the surface of MSN via disulfide bonds which could cleave under a reduction environment in tumor cells. The anticancer drug doxorubicin (DOX) was encapsulated into the particle pores. The in vitro drug release profile showed that DOX release was significantly restricted by the polymer caps at pH 7.4, while it was greatly accelerated upon the addition of GSH. Cytotoxicity evaluation showed good biocompatibility with the hybrid particles. Fast endocytosis and intracellular DOX release were observed by confocal laser scanning microscopy (CLSM). The DOX-loaded particles exhibited comparable antitumor activity with free DOX towards HeLa cells and showed in a time-dependent manner. This work developed an extensive method of utilizing aliphatic biodegradable polyesters as polymer caps for MSN to control drug delivery. The paper might offer a potential option for cancer therapy.

Facile preparation of core cross-linked micelles from catechol-containing amphiphilic triblock copolymer

Efficient delivery of anti-cancer drugs into tumor cells for enhancing the intracellular drug concentration is a major challenge for cancer therapy due to the instability of drug-loading vehicle. In this report, we developed a simple method to stabilize the nanostructure of micelles only by bubbling air to crosslink the outer layer of the micelle core. Dopamine was conjugated to a biodegradable triblock copolymer monomethoxy poly(ethylene glycol)-b-poly(2-methyl-2-carboxyl-propylene carbonate)-b-poly(L-lactide) (mPEG-b-PMCC-b-PLA) to obtain dopamine grafted copolymer mPEG-b-P(MCC-g-dopamine)-b-PLA. After self-assembly, the core cross-linked micelles were then prepared by the oxidative self-polymerization of dopamine in the middle hydrophobic phase of the micelles. The cross-linked micelles had smaller sizes and narrower particle size distributions than their uncross-linked precursors. The improved stability was confirmed by critical micelle concentration (CMC) experiments and 1H NMR spectra. The kinetics and processes of oxidative cross-linking of micelles under air flux were monitored by UV-Vis spectroscopy and transmission electron microscopy (TEM). These core cross-linked micelles were able to load doxorubicin (DOX) with superior loading capacity of up to 19.5% (w/w, drug/micelle) with high drug loading efficiency (97.5%). Compared with the uncross-linked ones, drug release efficacy from the cross-linked micelles extremely decreased at pH 7.4. However, a properly sustained release occurred at pH 5.0, which is very favorable for drug delivery in tumor cells. The DOX-loaded micelles had similar cytotoxicity as the free drug and could be effectively internalized into MDA-MB-231 cells. This controllable and convenient approach for preparing core cross-linked micelles will have a pragmatic future in stabilizing the architecture of nanocarriers for drug delivery.