Star-branched amphiphilic PLA-b-PDMAEMA copolymers for co-delivery of miR-21 inhibitor and doxorubicin to treat glioma

• Published in: Biomaterials Vol. 35; no. 7; pp. 2322 - 2335
• Main Authors: Qian, Xiaomin, Long, Lixia, Shi, Zhendong, Liu, Chaoyong, Qiu, Mingzhe, Sheng, Jing, Pu, Peiyu, Yuan, Xubo, Ren, Yu, Kang, Chunsheng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.02.2014
• Subjects: Advanced Basic Science; Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - therapeutic use; Brain Neoplasms - drug therapy; Brain Neoplasms - pathology; Co-delivery; Dentistry; Doxorubicin - administration & dosage; Doxorubicin - therapeutic use; Glioma - drug therapy; Glioma - pathology; In Situ Hybridization, Fluorescence; Methacrylates - administration & dosage; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - antagonists & inhibitors; Microscopy, Electron, Transmission; miR-21; Polydimethylaminoethyl methacrylate; Polyesters - administration & dosage; Polylactic acid; Star-branched copolymer; Synergistic effects; Synergistic effects; Co-delivery; Polydimethylaminoethyl methacrylate; miR-21; Star-branched copolymer; Polylactic acid
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2013.11.039

Abstract The combined treatment of chemotherapeutant and microRNA (miR) has been proven to be a viable strategy for enhancing chemosensitivity due to its synergistic effect for tumor therapy. However, the co-delivery of drugs and genes remains a major challenge as they lack efficient co-delivery carriers. In this study, three amphiphilic star-branched copolymers comprising polylactic acid (PLA) and polydimethylaminoethyl methacrylate (PDMAEMA) with AB3 , (AB3 )2 ,and (AB3 )3 molecular architectures were synthesized respectively by a combination of ring-opening polymerization, atom transfer radical polymerization, and click chemistry via an “arm-first” approach. The star copolymers possessed a low critical micelle concentration (CMC) and formed nano-sized micelles with positive surface charges in water as well as exhibiting a much lower cytotoxicity than PEI 25 kDa. Nevertheless, their gene transfection efficiency and tumor inhibition ability showed a remarkable dependence on their molecular architecture. The (AB3 )3 architecture micelle copolymer exhibited the highest transfection efficiency, about 2.5 times higher than PEI. In addition, after co-delivering DOX and miR-21 inhibitor (miR-21i) into LN229 glioma cells, the micelles could mediate escaping miR-21i from lysosome degradation and the release of DOX to the nucleus, which significantly decreased the miR-21 expression. Moreover, co-delivery of DOX and miR-21i surprisingly exhibited an anti-proliferative efficiency compared with DOX or the miR-21i treatment alone. These results demonstrated that amphiphilic star-branched copolymers are highly promising for their combinatorial delivery of genes and hydrophobic therapeutants.