title: Long-circulating siRNA nanoparticles for validating Prohibitin1-targeted non-small cell lung cancer treatment.
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.
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; West China School of Pharmacy, Sichuan University, Chengdu 610041, China;
authors.forename: Xi
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Solis
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; School of Life Sciences, Tsinghua University, Beijing 100084, China;
authors.forename: Wei
authors.initials: W
authors.lastname: Tao
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Liangzhe
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; Department of Chemical, Biological and Pharmaceutical Engineering, New Jersey Institute of Technology, Newark, NJ 07102;
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China;
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; Department of Chemistry, University of Waterloo, Waterloo, ON N2L 3G1, Canada;
authors.forename: Danny
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Chemistry, University of Science and Technology of China, Hefei 230026, China;
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; King Abdulaziz University, Jeddah 21589, Saudi Arabia.
authors.forename: Omid C
authors.initials: OC
authors.lastname: Farokhzad
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Zetter
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; jinjun.shi@zeus.bwh.harvard.edu.
authors.forename: Jinjun
authors.initials: J
authors.lastname: Shi
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood*; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy*; D053758:Nanoparticles; D000091402:Prohibitins; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000097:blood* / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: C000717328:PHB protein, human; D000091402:Prohibitins; D034741:RNA, Small Interfering; D012097:Repressor Proteins
keywords: Prohibitin1; nanoparticle; non-small cell lung cancer; siRNA delivery