OX26/CTX-conjugated PEGylated liposome as a dual-targeting gene delivery system for brain glioma.
OX26/CTX-conjugated PEGylated liposome as a dual-targeting gene delivery system for brain glioma.
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OX26/CTX 缀合的聚乙二醇化脂质体作为脑胶质瘤的双靶向基因递送系统
DOI：
10.1186/1476-4598-13-191
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发表时间：
2014-08-13
期刊：
影响因子：
37.3
通讯作者：
Peng Y
中科院分区：
文献类型：
--
作者：
Yue PJ;He L;Qiu SW;Li Y;Liao YJ;Li XP;Xie D;Peng Y
由于血脑屏障（BBB）的存在，成功地将基因递送到脑中是一个重大挑战。为了实现质粒DNA跨血脑屏障的靶向治疗，本研究设计了OX26/CTX修饰的聚乙二醇化脂质体（PL）作为双靶向基因递送系统，并采用体内外实验模型评价了OX26/CTX-PL/pC27对脑胶质瘤的治疗效果。采用逆相蒸发法制备了聚乙二醇化脂质体复合物，并对其理化性质进行了考察。检测OX26/CTX-PL/pC27在C6、F98和HEK293T细胞系中的转染效率、细胞内分布和体外作用。采用BMVECs/C6细胞共培养模型和大鼠原位胶质瘤模型评价OX26/CTX-PL/pC27双靶向治疗胶质瘤的疗效。OX26/CTX-PL/pDNA复合物呈亚球形，孵育4 h后对HEK293T和C6细胞的毒性明显降低。在体外转染实验中，OX26和CTX修饰后的C6和F98细胞hTERTC27基因表达量明显增加。我们的体外实验结果也表明，OX26赋予PLs跨血脑屏障的转运能力。采用BMVECs/C6细胞共培养模型，转染OX26/CTX-PL/pC27后C6细胞存活率下降至46.0%。OX26/CTX-PL/pC27复合物对C6细胞的治疗作用增强。双靶向治疗C6胶质瘤大鼠的肿瘤体积缩小（18.81 ± 6.15 mm 3），中位生存期延长（46 d）。免疫组化分析显示，肿瘤部位的hTERTC 27表达增强产生的治疗效果。用OX26和CTX修饰的聚乙二醇化脂质体能够显着促进细胞转染，增加质粒DNA穿过BBB的转运，然后在体外和体内靶向脑胶质瘤细胞，表现出最显着的治疗效果。配体OX26在将脂质复合物转运穿过BBB中起关键作用，而CTX在靶向脑胶质瘤细胞中起主要作用。这一结果将促进脑胶质瘤静脉注射无创靶向治疗的进一步发展。本文的在线版本（doi：10.1186/1476 - 4598 - 13 - 191）包含补充材料，可供授权用户使用。
The 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. The 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. The 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. The 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. The online version of this article (doi:10.1186/1476-4598-13-191) contains supplementary material, which is available to authorized users.
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