Targeted-gene silencing of BRAF to interrupt BRAF/MEK/ERK pathway synergized photothermal therapeutics for melanoma using a novel FA-GNR-siBRAF nanosystem
Targeted-gene silencing of BRAF to interrupt BRAF/MEK/ERK pathway synergized photothermal therapeutics for melanoma using a novel FA-GNR-siBRAF nanosystem
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使用新型 FA-GNR-siBRAF 纳米系统对 BRAF 进行靶向基因沉默以中断 BRAF/MEK/ERK 通路协同光热疗法治疗黑色素瘤
DOI：
10.1016/j.nano.2018.04.010
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Min Weiping
中科院分区：
文献类型：
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作者：
Zhang Yujuan;Zhan Xuelin;Peng Shanshan;Cai Ying;Zhang Yu Shrike;Liu Yanling;Wang Zhigang;Yu Yanrong;Wang Yifan;Shi Qiaofa;Zeng Xiaoping;Yuan Keng;Zhou Nanjin;Joshi Rakesh;Zhang Meng;Zhang Zhuxu;Min Weiping
黑色素瘤与突变BRAF基因显著相关，突变BRAF基因是基于siRNA的抗黑色素瘤治疗的合适靶点。然而，肿瘤特异性递送系统是临床应用的主要障碍。在这里，我们开发了一种新型的纳米载体FA-GNR-siBRAF，用于安全的局部应用，其由作为肿瘤靶向部分的叶酸（FA）、在激光照射下提供光热杀死肿瘤细胞的能力的金纳米棒（GNR）和特异性沉默BRAF（siBRAF）的siRNA组成。体外和体内结果显示，FA-GNR-siBRAF显示出高转染率，随后诱导BRAF的显著基因敲低，导致由于MEK/ERK通路的中断而抑制黑色素瘤生长。组合光热效应和FA-GNR-siBRAF敲低的BRAF通过凋亡有效地杀死肿瘤细胞，效率比单独治疗提高。因此，FA-GNR-siBRAF同时诱导BRAF基因沉默和光热效应，在黑色素瘤的治疗中达到协同功效，为开发黑色素瘤的临床治疗方法铺平了新的道路。
Melanoma is significantly associated with mutant BRAF gene, a suitable target for siRNA-based anti-melanoma therapy. However, a tumor-specific delivery system is a major hurdle for clinical applications. Here, we developed a novel nano-carrier, FA-GNR-siBRAF for safe topical application, which consists of folic acid (FA) as the tumor-targeting moiety, golden nanorods (GNR) providing photothermal capability to kill tumor cells under laser irradiation, and siRNA specifically silencing BRAF (siBRAF). The in vitro and in vivo results revealed that FA-GNR-siBRAF displayed high transfection rates, and subsequently induced remarkable gene knockdown of BRAF, resulting in suppression of melanoma growth due to the interruption of the MEK/ERK pathway. Combinatorial photothermal effects and BRAF knockdown by FA-GNR-siBRAF effectively killed tumor cells through apoptosis, with enhanced efficiency than individual treatments. Therefore, the FA-GNR-siBRAF simultaneously induced BRAF gene silencing and photothermal effects which achieved synergistic efficacy in the treatment of melanoma, paving a new path for developing clinical treatment methods for melanoma.