title: Ultra-pH-Responsive and Tumor-Penetrating Nanoplatform for Targeted siRNA Delivery with Robust Anti-Cancer Efficacy.
abstract: RNA interference (RNAi) gene silencing technologies have shown significant potential for treating various diseases, including cancer. However, clinical success in cancer therapy remains elusive, mainly owing to suboptimal in vivo delivery of RNAi therapeutics such as small interference RNA (siRNA) to tumors. Herein, we developed a library of polymers that respond to a narrow pH change (ultra-pH-responsive), and demonstrated the utility of these materials in targeted and deep tumor-penetrating nanoparticle (NP) for in vivo RNAi. The new NP platform is mainly composed of the following key components: i) internalizing RGD (iRGD) to enhance tumor targeting and tissue penetration; ii) polyethylene glycol (PEG) chains to prolong blood circulation; and iii) sharp pH-responsive hydrophobic polymer to improve endosome escape. Through systematic studies of structure-function relationship, the optimized RNAi NPs (<70 nm) showed efficient gene silencing and significant inhibition of tumor growth with negligible toxicities in vivo.
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital Harvard Medical School, Boston, MA 02115 (USA).
authors.forename: Xiaoding
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital Harvard Medical School, Boston, MA 02115 (USA).
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital Harvard Medical School, Boston, MA 02115 (USA).
authors.forename: Yanlan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital Harvard Medical School, Boston, MA 02115 (USA).
authors.forename: Mikyung
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital Harvard Medical School, Boston, MA 02115 (USA).
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 (USA).
authors.forename: Xi
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital Harvard Medical School, Boston, MA 02115 (USA).
authors.forename: Sushant
authors.initials: S
authors.lastname: Bhasin
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital Harvard Medical School, Boston, MA 02115 (USA).
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital Harvard Medical School, Boston, MA 02115 (USA).
authors.forename: Emily
authors.initials: E
authors.lastname: Ha
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital Harvard Medical School, Boston, MA 02115 (USA).
authors.forename: Jinjun
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Anesthesiology, Brigham and Women's Hospital Harvard Medical School, Boston, MA 02115 (USA).|King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Omid C
authors.initials: OC
authors.lastname: Farokhzad
mesh_terms: D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000737:chemistry*; D018014:Gene Transfer Techniques; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D009842:Oligopeptides / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use; D000067492:RNAi Therapeutics / Q000379:methods*; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D003692:Delayed-Action Preparations; D051034:Inhibitor of Apoptosis Proteins; D009842:Oligopeptides; D011108:Polymers; D034741:RNA, Small Interfering; D000077022:Survivin; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid
keywords: cancer therapy; nanoparticles; pH-responsive; siRNA delivery; tumor penetration