OX26/CTX-conjugated PEGylated liposome as a dual-targeting gene delivery system for brain glioma

Molecular Cancer

Research

Xiang-pen Li¹  Lei He¹  Yi Li¹  Pei-jian Yue¹  Shu-wei Qiu¹  Ying Peng²  Dan Xie³  Yi-ji Liao³ 

[1] Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, NO.107, Yan Jiang Xi Road of Guangzhou, 510120, Guangzhou, China;Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, NO.107, Yan Jiang Xi Road of Guangzhou, 510120, Guangzhou, China;Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen University, 510120, Guangzhou, China;State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, NO.651, Dongfeng Road East, 510060, Guangzhou, China;

关键词: Dual-targeting;    Gene therapy;    Chlorotoxin;    Blood–brain barrier;    Glioma;   

DOI  :  10.1186/1476-4598-13-191

 received in 2014-01-18, accepted in 2014-08-08,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundThe successful gene delivery into the brain is a major challenge due to the presence of the blood–brain barrier (BBB). In order to transport plasmid DNA across the BBB and target the brain glioma, the PEGylated liposomes (PLs) modified with OX26 and chlorotoxin (CTX) were developed as a dual-targeting gene delivery system, and the therapeutic efficacy of OX26/CTX-PL/pC27 against glioma was evaluated using in vitro and in vivo experimental models.MethodsThe PEGylated liposome complexes were prepared by the reverse phase evaporation method, and their physicochemical properties were examined. The transfection efficiency, intracellular distribution, in vitro effects of OX26/CTX-PL/pC27 were determined on C6, F98 and HEK293T cell lines. The dual-targeting therapeutic efficacy of OX26/CTX-PL/pC27 against glioma were assessed using the BMVECs/C6 cells co-culture model and the rat orthotopic glioma model.ResultsThe OX26/CTX-PL/pDNA complexes exhibited a subglobose shape, and possessed notably low toxicities to HEK293T and C6 cells post 4 h incubation. In the in vitro transfection experiment, gene expressions of hTERTC27 from C6 and F98 cells were significantly improved by OX26 and CTX modification. Our in vitro results also showed that OX26 endowed the PLs with the transport ability across the BBB. Using the BMVECs/C6 cells co-culture model, the viability of C6 cells was decreased to 46.0% after OX26/CTX-PL/pC27 transfection. The OX26/CTX-PL/pC27 complexes exhibited enhanced therapeutic effects on C6 cells. Moreover, the dual-targeting therapeutic effects were further conformed with diminished tumor volumes (18.81 ± 6.15 mm3) and extended median survival time (46 days) in C6 glioma-bearing rats. Immunohistochemical analysis revealed the therapeutic effects derived from enhanced hTERTC27 expression in the tumor site.ConclusionsThe PEGylated liposomes modified with OX26 and CTX are able to significantly promote cell transfection, increase the transport of plasmid DNA across the BBB and afterwards target the brain glioma cells in vitro and in vivo, exhibit the most significant therapeutic efficacy. The ligand OX26 plays a critical role in transporting the lipoplexes across the BBB, and CTX acts as a major role in targeting brain glioma cells. The results would encourage further developments for non-invasive targeting therapy of brain gliomas by intravenous injection.

【 授权许可】

Unknown   
© Yue et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.