Targeted-gene silencing of BRAF to interrupt BRAF/MEK/ERK pathway synergized photothermal therapeutics for melanoma using a novel FA-GNR-siBRAF nanosystem

• Published in: Nanomedicine Vol. 14; no. 5; pp. 1679 - 1693
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2018
• Subjects: Animals; Apoptosis; BRAF; Combined Modality Therapy; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - genetics; Female; Folic Acid - chemistry; Gene Silencing; Gold - chemistry; Gold nanorods; Hyperthermia, Induced; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase 1 - genetics; melanoma; Melanoma, Experimental - therapy; Mice; Mice, Inbred C57BL; Nanotubes - chemistry; Phototherapy; photothermal effects; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; RNA, Small Interfering - genetics; siRNA; Tumor Cells, Cultured; melanoma; GNR; siRNA; LSPR; BRAF; CTAB; siBRAF; PTT; NMR; PEI; MUA; FA; Gold nanorods; TEM; photothermal effects
• ISSN: 1549-9634; 1549-9642
• DOI: 10.1016/j.nano.2018.04.010

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. [Display omitted]