Core-crosslinked pH-sensitive degradable micelles: A promising approach to resolve the extracellular stability versus intracellular drug release dilemma.

The extracellular stability versus intracellular drug release dilemma has been a long challenge for micellar drug delivery systems. Here, core-crosslinked pH-sensitive degradable micelles were developed based on poly(ethylene glycol)-b-poly(mono-2,4,6-trimethoxy benzylidene-pentaerythritol carbonate-co-acryloyl carbonate) (PEG-b-P(TMBPEC-co-AC)) diblock copolymer that contains acid-labile acetal and photo-crossslinkable acryloyl groups in the hydrophobic polycarbonate block for intracellular paclitaxel (PTX) release. The micelles following photo-crosslinking while displaying high stability at pH 7.4 were prone to rapid hydrolysis at mildly acidic pHs of 4.0 and 5.0, with half lives of ca. 12.5 and 38.5h, respectively. Notably, these micelles showed high drug loading efficiencies of 76.0-93.2% at theoretical PTX loading contents of 5-15wt.%. Depending on drug loading contents, PTX-loaded micelles had average sizes varying from 132.2 to 171.6nm, which were decreased by 17-22nm upon photo-crosslinking. The in vitro release studies showed that PTX release at pH 7.4 was greatly inhibited by crosslinking of micelles. Notably, rapid drug release was obtained under mildly acidic conditions, in which 90.0% and 78.1% PTX was released in 23h at pH 4.0 and 5.0, respectively. MTT assays showed that PTX-loaded crosslinked micelles retained high anti-tumor activity with a cell viability of 9.2% observed for RAW 264.7 cells following 72h incubation, which was comparable to PTX-loaded non-crosslinked counterparts (cell viability 7.5%) under otherwise the same conditions, supporting efficient drug release from PTX-loaded crosslinked micelles inside the tumor cells. These core-crosslinked pH-responsive biodegradable micelles with superior extracellular stability and rapid intracellular drug release provide a novel platform for tumor-targeting drug delivery.

Wu Y ，Chen W ，Meng F ，Wang Z ，Cheng R ，Deng C ，Liu H ，Zhong Z ... -  《-》

Galactose-installed photo-crosslinked pH-sensitive degradable micelles for active targeting chemotherapy of hepatocellular carcinoma in mice.

In this study, we designed and developed galactose-installed photo-crosslinked pH-sensitive degradable micelles (Gal-CLMs) for active targeting chemotherapy of hepatocellular carcinoma in mice. Gal-CLMs were readily obtained from co-self-assembly of poly(ethylene glycol)-b-poly(mono-2,4,6-trimethoxy benzylidene-pentaerythritol carbonate-co-acryloyl carbonate) (PEG-b-P(TMBPEC-co-AC)) and Gal-PEG-b-poly(ε-caprolactone) (Gal-PEG-b-PCL) copolymers followed by photo-crosslinking. Notably, paclitaxel (PTX)-loaded Gal-CLMs (Gal-PTX-CLMs) showed a narrow distribution (PDI=0.08-0.12) with average sizes ranging from 92.1 to 136.3nm depending on the Gal contents. The release of PTX from Gal-CLMs while inhibited at physiological pH was enhanced under endosomal pH conditions. MTT assays in asialoglycoprotein receptor (ASGP-R) over-expressing HepG2 cells demonstrated that half-maximal inhibitory concentration (IC50) values of Gal-PTX-CLMs decreased from 11.7 to 2.9 to 1.1μg/mL with increasing Gal contents from 10% to 20% to 30%, supporting receptor-mediated endocytosis mechanism. The in vivo biodistribution studies in human hepatoma SMMC-7721 tumor-bearing nude mice displayed that Gal20-PTX-CLMs resulted in significantly enhanced drug accumulation in the tumors over non-targeting PTX-CLM counterpart. In accordance, Gal20-PTX-CLMs caused much greater tumor growth inhibition than non-targeting PTX-CLMs as well as non-crosslinking Gal20-PTX-NCLM controls (average tumor volume: ca. 35mm(3)versus 144mm(3) and 130mm(3), respectively). Histological analysis showed that Gal20-PTX-CLMs induced more extensive apoptosis of tumor cells while less damage to normal liver and kidney compared to Taxol. Ligand-installed photo-crosslinked pH-responsive degradable micelles have a great potential for targeted cancer chemotherapy.

Zou Y ，Song Y ，Yang W ，Meng F ，Liu H ，Zhong Z ... -  《-》

Thermosensitive and biodegradable polymeric micelles for paclitaxel delivery.

Soga O ，van Nostrum CF ，Fens M ，Rijcken CJ ，Schiffelers RM ，Storm G ，Hennink WE ... -  《JOURNAL OF CONTROLLED RELEASE》

Galactose-decorated cross-linked biodegradable poly(ethylene glycol)-b-poly(ε-caprolactone) block copolymer micelles for enhanced hepatoma-targeting delivery of paclitaxel.

Yang R ，Meng F ，Ma S ，Huang F ，Liu H ，Zhong Z ... -  《-》

pH-Sensitive degradable polymersomes for triggered release of anticancer drugs: a comparative study with micelles.

pH-Sensitive degradable polymersomes and micelles were prepared based on diblock copolymer of poly(ethylene glycol) (PEG) and an acid-labile polycarbonate, poly(2,4,6-trimethoxybenzylidenepentaerythritol carbonate) (PTMBPEC). Polymersomes of PEG(1.9k)-PTMBPEC(6k) revealed average sizes of 100-200 nm. The acetals of polymersomes, similar to those of PEG(5k)-PTMBPEC(5.8k) micelles, though stable at pH 7.4 were prone to fast hydrolysis at mildly acidic pH of 4.0 and 5.0, with half lives of 0.5 and 3d, respectively. The acetal hydrolysis resulted in significant size increase of polymersomes, to over 1000 nm in 24h at pH 4.0. Drug encapsulation studies revealed that polymersomes were able to simultaneously load paclitaxel (PTX, hydrophobic) and doxorubicin hydrochloride (DOX.HCl, hydrophilic), whereas micelles loaded PTX only. Notably, polymersomes showed lower drug loading efficiencies for PTX than micelles (30.0-37.7% versus 61.4-65.2%). The in vitro release studies demonstrated that release of PTX and DOX.HCl from polymersomes was highly pH-dependent, i.e. significantly faster drug release at mildly acidic pH of 4.0 and 5.0 compared to physiological pH. Furthermore, much higher release rates were observed for PTX release from the polymersomes compared to that from the micelles under otherwise the same conditions. These pH-sensitive nano-sized degradable polymersomes hold great promise for combination therapy for cancers.

Chen W ，Meng F ，Cheng R ，Zhong Z ... -  《-》