siRNA-loaded poly(histidine-arginine)₆-modified chitosan nanoparticle with enhanced cell-penetrating and endosomal escape capacities for suppressing breast tumor metastasis

Abstract

An ideal carrier that delivers small interfering RNA (siRNA) should be designed based on two criteria: cellular-mediated internalization and endosomal escape. Poly(histidine-arginine) 6 (H6R6) peptide was introduced into chitosan (CS) to create a new CS derivative for siRNA delivery, 6-polyarginine (R6) as cell-penetrating peptides facilitated nanoparticle cellular internalization has been proved in our previous research, and 6-polyhistidine (H6) mediated the nanoparticle endosome escape resulted in the siRNA rapid releasing into tumor cytoplasm. H6R6-modified CS nanoparticles showed higher transfection efficiency and better endosomal escape capacity compared to ungroomed CS nanoparticle in vitro. Noticeably, H6R6-modified CS nanoparticles effectively inhibited tumor cell growth and metastases in vivo and significantly improved survival ratio. Therefore, we concluded that H6R6-modified CS copolymer can act as an ideal carrier for siRNA delivery and as a promising candidate in breast cancer therapy.

Targeted Delivery of siRNA with pH-Responsive Hybrid Gold Nanostars for Cancer Treatment

“…9R/DG-GNS (hydrazone) also showed uptake by tumor cells due to the targeting effect of DG. Positive 9R can bind the negative siRNA, used as a gene carrier [ 40 , 41 ], and it has been shown to have superior transmembrane transport ability [ 42 , 43 ]. In addition, the hydrazone bond was destroyed in the low endosomal pH microenvironment of tumor cells.…”

Application of the Nano-Drug Delivery System in Treatment of Cardiovascular Diseases

“…Combining chitosan with polyethylene glycol, the conjugate has a unique endocytosis and macrophage phagocytosis mechanism . In addition, the modification of chitosan with a polypeptide can improve its working efficiency (Ping et al, 2017).…”

Fundamentals of siRNA and miRNA therapeutics and a review of targeted nanoparticle delivery systems in breast cancer

“…They are usually positively charged and can bind to negatively charged siRNA to improve its stability in vivo (Jiang et al 2015;Raucher and Ryu 2015;Jing et al 2016). From a review of in vivo studies, we observed three design variations of delivery systems involving cell-penetrating peptides: cellpenetrating peptides modified with chitosan and then used to encapsulate the siRNA (Sun et al 2017a); some studies entrapped or loaded a cell-penetrating peptide onto another primary delivery vehicle (such as liposomes or ultrasoundsensitive nanobubbles) (Jing et al 2016;Xie et al 2016); others conjugated a cell-penetrating peptide with other cationic polymers (such as PEG) or micelles to form a nanocomplex for siRNA encapsulation (Wang et al 2015;Fang et al 2016;Yang et al 2016). All in vivo studies demonstrated positive outcomes by showing that tumor growth was inhibited by siRNA.…”