机构：[a]Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115[b]West China School of Pharmacy, SichuanUniversity, Chengdu 610041, China[c]Vascular Biology Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115[d]Department ofTranslational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030[e]School of Life Sciences, Tsinghua University,Beijing 100084, China[f]Department of Chemical, Biological and Pharmaceutical Engineering, New Jersey Institute of Technology, Newark, NJ 07102[g]TheFirst Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China江苏省人民医院[h]Department of Chemistry, University of Waterloo,Waterloo, ON N2L 3G1, Canada[i]Department of Chemistry, University of Science and Technology of China, Hefei 230026, China[j]King AbdulazizUniversity, Jeddah 21589, Saudi Arabia
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.
基金：
This work was supported by the National Institutes
of Health (NIH) Grants R00CA160350 (to J.S.), R01CA37393 (to B.R.Z.),
EB015419 (to O.C.F.), and U54-CA151884 (to O.C.F.); the Movember-Prostate
Cancer Foundation (PCF) Challenge Award (to J.S. and O.C.F.); a PCF Young
Investigator Award (to J.S.) and the David Koch–PCF Program in Nanotherapeutics (O.C.F.); the National Research Foundation of Korea Grant
K1A1A2048701 (to O.C.F.); and the University of Texas Lung Specialized Programs of Research Excellence Grant P50CA70907 (to I.I.W.). X.Z., L.Z., and
L.W. received financial support from the China Scholarship Council. Y.X. received a Department of Defense Prostate Cancer Research Program Postdoctoral Training Award (W81XWH-14-1-0268). X.X. received postdoctoral
support from an NIH National Research Service Award (F32CA168163).
第一作者机构：[a]Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115[b]West China School of Pharmacy, SichuanUniversity, Chengdu 610041, China
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Xi Zhu,Yingjie Xu,Luisa M. Solis,et al.Long-circulating siRNA nanoparticles for validating Prohibitin1-targeted non-small cell lung cancer treatment.[J].PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA.2015,112(25):7779-7784.doi:10.1073/pnas.1505629112.
APA：
Xi Zhu,Yingjie Xu,Luisa M. Solis,Wei Tao,Liangzhe Wang...&Jinjun Shi.(2015).Long-circulating siRNA nanoparticles for validating Prohibitin1-targeted non-small cell lung cancer treatment..PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,112,(25)
MLA：
Xi Zhu,et al."Long-circulating siRNA nanoparticles for validating Prohibitin1-targeted non-small cell lung cancer treatment.".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 112..25(2015):7779-7784
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