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

Yujuan Zhang; Xuelin Zhan; Shanshan Peng; Ying Cai; Yu Shrike Zhang; Yanling Liu; Zhigang Wang; Yanrong Yu; Yifan Wang; Qiaofa Shi; Xiaoping Zeng; Keng Yuan; Nanjin Zhou; Rakesh Joshi; Meng Zhang; Zhuxu Zhang; Weiping Min

doi:10.1016/j.nano.2018.04.010

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

Nanomedicine. 2018 Jul;14(5):1679-1693. doi: 10.1016/j.nano.2018.04.010. Epub 2018 Apr 21.

Authors

Yujuan Zhang¹, Xuelin Zhan², Shanshan Peng³, Ying Cai², Yu Shrike Zhang⁴, Yanling Liu², Zhigang Wang², Yanrong Yu², Yifan Wang², Qiaofa Shi⁵, Xiaoping Zeng⁵, Keng Yuan², Nanjin Zhou², Rakesh Joshi⁶, Meng Zhang³, Zhuxu Zhang⁶, Weiping Min⁷

Affiliations

¹ Institute of immunotherapy and College of Basic Medicine of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China; Jiangxi Provincial Key Laboratory of Immunotherapy, Nanchang, China; Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA. Electronic address: yujuanzhang@ncu.edu.cn.
² Institute of immunotherapy and College of Basic Medicine of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China; Jiangxi Provincial Key Laboratory of Immunotherapy, Nanchang, China.
³ Institute of immunotherapy and College of Basic Medicine of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China; Jiangxi Provincial Key Laboratory of Immunotherapy, Nanchang, China; Department of Surgery, Pathology and Oncology, University of Western Ontario, London, Canada.
⁴ Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA.
⁵ Institute of immunotherapy and College of Basic Medicine of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China.
⁶ Department of Surgery, Pathology and Oncology, University of Western Ontario, London, Canada.
⁷ Institute of immunotherapy and College of Basic Medicine of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China; Jiangxi Provincial Key Laboratory of Immunotherapy, Nanchang, China; Department of Surgery, Pathology and Oncology, University of Western Ontario, London, Canada. Electronic address: weiping.min@uwo.ca.

PMID: 29684526
DOI: 10.1016/j.nano.2018.04.010

Abstract

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.

Keywords: BRAF; Gold nanorods; melanoma; photothermal effects; siRNA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Combined Modality Therapy
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
Extracellular Signal-Regulated MAP Kinases / genetics
Female
Folic Acid / chemistry*
Gene Silencing*
Gold / chemistry
Hyperthermia, Induced*
MAP Kinase Kinase 1 / antagonists & inhibitors
MAP Kinase Kinase 1 / genetics
Melanoma, Experimental / therapy*
Mice
Mice, Inbred C57BL
Nanotubes / chemistry*
Phototherapy
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Proto-Oncogene Proteins B-raf / genetics
RNA, Small Interfering / genetics*
Tumor Cells, Cultured

Substances

RNA, Small Interfering
Gold
Folic Acid
Braf protein, mouse
Proto-Oncogene Proteins B-raf
Extracellular Signal-Regulated MAP Kinases
MAP Kinase Kinase 1
Map2k1 protein, mouse