title: Targeted Dual pH-Sensitive Lipid ECO/siRNA Self-Assembly Nanoparticles Facilitate In Vivo Cytosolic sieIF4E Delivery and Overcome Paclitaxel Resistance in Breast Cancer Therapy.
abstract: RNAi-mediated knockdown of oncogenes associated with drug resistance can potentially enhance the efficacy of chemotherapy. Here, we have designed and developed targeted dual pH-sensitive lipid-siRNA self-assembly nanoparticles, RGD-PEG(HZ)-ECO/siRNA, which can efficiently silence the oncogene, eukaryotic translation initiation factor 4E (eIF4E), and consequently resensitize triple-negative breast tumors to paclitaxel. The dual pH-sensitive function of these nanoparticles facilitates effective cytosolic siRNA delivery in cancer cells, both in vitro and in vivo. Intravenous injection of RGD-PEG(HZ)-ECO/siRNA nanoparticles (1.0 mg-siRNA/kg) results in effective gene silencing for at least one week in MDA-MB-231 tumors. In addition, treatment of athymic nude mice with RGD-PEG(HZ)-ECO/sieIF4E every 6 days for 6 weeks down-regulates the overexpression of eIF4E and resensitizes paclitaxel-resistant MDA-MB-231 tumors to paclitaxel, resulting in significant tumor regression at a low dose, with negligible side effects. Moreover, repeated injections of the RGD-PEG(HZ)-ECO/siRNA nanoparticles in immunocompetent mice result in minimal immunogenicity, demonstrating their safety and low toxicity. These multifunctional lipid/siRNA nanoparticles constitute a versatile platform of delivery of therapeutic siRNA for treating cancer and other human diseases.
authors.affiliation: Case Center for Biomolecular Engineering, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 44106, USA.
authors.forename: Maneesh
authors.initials: M
authors.lastname: Gujrati
authors.affiliation: Case Center for Biomolecular Engineering, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 44106, USA.
authors.forename: Amita M
authors.initials: AM
authors.lastname: Vaidya
authors.affiliation: Case Center for Biomolecular Engineering, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 44106, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Mack
authors.affiliation: Case Center for Biomolecular Engineering, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 44106, USA.
authors.forename: Dayton
authors.initials: D
authors.lastname: Snyder
authors.affiliation: Case Center for Biomolecular Engineering, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 44106, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Malamas
authors.affiliation: Case Center for Biomolecular Engineering, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 44106, USA.
authors.forename: Zheng-Rong
authors.initials: ZR
authors.lastname: Lu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005260:Female; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008055:Lipids / Q000008:administration & dosage*; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage*; D017239:Paclitaxel / Q000008:administration & dosage*; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D008055:Lipids; D034741:RNA, Small Interfering; D017239:Paclitaxel
keywords: ECO; cytosolic siRNA delivery; drug resistance; dual pH-sensitive; eIF4E