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Redox‐Responsive Nanoparticle‐Mediated Systemic RNAi for Effective Cancer Therapy
Author(s) -
Xu Xiaoding,
Wu Jun,
Liu Shuaishuai,
Saw Phei Er,
Tao Wei,
Li Yujing,
Krygsman Lisa,
Yegnasubramanian Srinivasan,
De Marzo Angelo M.,
Shi Jinjun,
Bieberich Charles J.,
Farokhzad Omid C.
Publication year - 2018
Publication title -
small
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.785
H-Index - 236
eISSN - 1613-6829
pISSN - 1613-6810
DOI - 10.1002/smll.201802565
Subject(s) - small interfering rna , rna interference , gene silencing , intracellular , systemic administration , ethylene glycol , chemistry , materials science , biophysics , transfection , nanotechnology , rna , biochemistry , biology , in vivo , gene , microbiology and biotechnology , organic chemistry
Biodegradable polymeric nanoparticles (NPs) have demonstrated significant potential to improve the systemic delivery of RNA interference (RNAi) therapeutics, such as small interfering RNA (siRNA), for cancer therapy. However, the slow and inefficient siRNA release inside tumor cells generally observed for most biodegradable polymeric NPs may result in compromised gene silencing efficacy. Herein, a biodegradable and redox‐responsive NP platform, composed of a solid poly(disulfide amide) (PDSA)/cationic lipid core and a lipid–poly(ethylene glycol) (lipid–PEG) shell for systemic siRNA delivery to tumor cells, is developed. This newly generated NP platform can efficiently encapsulate siRNA under extracellular environments and can respond to the highly concentrated glutathione (GSH) in the cytoplasm to induce fast intracellular siRNA release. By screening a library of PDSA polymers with different structures and chain lengths, the optimized NP platform shows the unique features of i) long blood circulation, ii) high tumor accumulation, iii) fast GSH‐triggered intracellular siRNA release, and iv) exceptionally effective gene silencing. Together with the facile polymer synthesis technique and robust NP formulation enabling scale‐up, this new redox‐responsive NP platform may become an effective tool for RNAi‐based cancer therapy.