Long-circulating siRNA nanoparticles for validating Prohibitin1-targeted non-small cell lung cancer treatment

Xi Zhu, Yingjie Xu, Luisa M. Solis, Wei Tao, Liangzhe Wang, Carmen Behrens, Xiaoyang Xu, Lili Zhao, Danny Liu, Jun Wu, Ning Zhang, Ignacio I. Wistuba, Omid C. Farokhzad, Bruce R. Zetter, Jinjun Shi

Research output: Contribution to journalArticlepeer-review

106 Scopus citations

Abstract

RNA interference (RNAi) represents a promising strategy for identification and validation of putative therapeutic targets and for treatment of a myriad of important human diseases including cancer. However, the effective systemic in vivo delivery of small interfering RNA (siRNA) to tumors remains a formidable challenge. Using a robust self-assembly strategy, we develop a unique nanoparticle (NP) platform composed of a solid polymer/cationic lipid hybrid core and a lipid-poly(ethylene glycol) (lipid-PEG) shell for systemic siRNA delivery. The new generation lipid-polymer hybrid NPs are small and uniform, and can efficiently encapsulate siRNA and control its sustained release. They exhibit long blood circulation (t1/2 ∼8 h), high tumor accumulation, effective gene silencing, and negligible in vivo side effects. With this RNAi NP, we delineate and validate the therapeutic role of Prohibitin1 (PHB1), a target protein that has not been systemically evaluated in vivo due to the lack of specific and effective inhibitors, in treating non-small cell lung cancer (NSCLC) as evidenced by the drastic inhibition of tumor growth upon PHB1 silencing. Human tissue microarray analysis also reveals that high PHB1 tumor expression is associated with poorer overall survival in patients with NSCLC, further suggesting PHB1 as a therapeutic target. We expect this long-circulating RNAi NP platform to be of high interest for validating potential cancer targets in vivo and for the development of new cancer therapies.

Original languageEnglish (US)
Pages (from-to)7779-7784
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number25
DOIs
StatePublished - Jun 23 2015

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Nanoparticle
  • Non-small cell lung cancer
  • Prohibitin1
  • siRNA delivery

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