Cell-penetrating peptide-siRNA conjugate loaded YSA-modified nanobubbles for ultrasound triggered siRNA delivery.
Due to the absence of effective in vivo delivery systems, the employment of small interference RNA (siRNA) in the clinic has been hindered. In this paper, a new siRNA targeting system for EphA2-positive tumors was developed, based on ultrasound-sensitive nanobubbles (NBs) and cell-permeable peptides (CPPs). Here, a CPP-siRNA conjugate (CPP-siRNA) was entrapped in an ephrin mimetic peptide (YSA peptide)-modified NB (CPP-siRNA/YSA-NB) and the penetration of the CPP-siRNA was temporally masked; local ultrasound stimulation triggered the release of CPP-siRNA from the NBs and activated its penetration. Subsequent research demonstrated that the CPP-siRNA/YSA-NBs had particle sizes of approximately 200 nm and a siRNA entrapment efficiency of more than 85%. The in vitro release results showed that over 90% of the encapsulated CPP-siRNA released from the NBs in the presence of ultrasound, while less than 1.5% of that (30 min) released without ultrasound. Cell experiments showed a the higher CPP-siRNA cellular uptake of CPP-siRNA/YSA-NB among the various formulations in human breast adenocarcinoma cells (MCF-7, EphA2 positive cells). Additionally, after systemic administration in mice, CPP-siRNA/YSA-NB accumulated in the tumor, augmented c-Myc silencing and delayed tumor progression. In conclusion, the application of CPP-siRNA/YSA-NB with ultrasound may provide a strategy for the selective and efficient delivery of siRNA.
Department of Pharmacy, Wuhan General Hospital of Guangzhou Command, Wuhan 430070, PR China.
Xiangyang
X
Xie
Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
Yanfang
Y
Yang
Department of Clinical Laboratory, Huangshi Love & Health Hospital of Hubei Province, Huangshi 435000, PR China.
Wen
W
Lin
Department of Pharmacy, Wuhan General Hospital of Guangzhou Command, Wuhan 430070, PR China.
Hui
H
Liu
Department of Pharmacy, Wuhan General Hospital of Guangzhou Command, Wuhan 430070, PR China.
Hong
H
Liu
Beijing Institute of Pharmacology and Toxicology, No. 27 Taiping Road, Beijing 100850, PR China. Electronic address: amms2013@126.com.
Yang
Y
Yang
Department of Pharmacy, Wuhan General Hospital of Guangzhou Command, Wuhan 430070, PR China.
Ying
Y
Chen
Department of Pharmacy, Wuhan General Hospital of Guangzhou Command, Wuhan 430070, PR China.
Xudong
X
Fu
Department of Clinical Laboratory, Huangshi Love & Health Hospital of Hubei Province, Huangshi 435000, PR China. Electronic address: jpdeng@126.com.
Jianping
J
Deng
D000818:Animals; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D049329:Nanostructures; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage*
D034741:RNA, Small Interfering
Cell-penetrating peptides; EphA2; Nanobubbles; Ultrasound; siRNA delivery