Redox-Responsive Nanoparticle-Mediated Systemic RNAi for Effective Cancer Therapy

Xiaoding Xu, Jun Wu, Shuaishuai Liu, Phei Er Saw, Wei Tao, Yujing Li, Lisa Krygsman, Srinivasan Yegnasubramanian, Angelo M. De Marzo, Jinjun Shi, Charles J. Bieberich, Omid C. Farokhzad

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number1802565
JournalSmall
Volume14
Issue number41
DOIs
StatePublished - Oct 11 2018

Keywords

  • biodegradable nanoparticle
  • cancer therapy
  • redox-responsive
  • siRNA delivery

ASJC Scopus subject areas

  • Biotechnology
  • Biomaterials
  • Chemistry(all)
  • Materials Science(all)

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