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Targeted Dual pH‐Sensitive Lipid ECO/siRNA Self‐Assembly Nanoparticles Facilitate In Vivo Cytosolic sieIF4E Delivery and Overcome Paclitaxel Resistance in Breast Cancer Therapy
Author(s) -
Gujrati Maneesh,
Vaidya Amita M.,
Mack Margaret,
Snyder Dayton,
Malamas Anthony,
Lu ZhengRong
Publication year - 2016
Publication title -
advanced healthcare materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.288
H-Index - 90
eISSN - 2192-2659
pISSN - 2192-2640
DOI - 10.1002/adhm.201600677
Subject(s) - paclitaxel , gene silencing , in vivo , gene knockdown , cancer research , small interfering rna , chemistry , rna interference , oncogene , nanocarriers , drug delivery , cancer , pharmacology , transfection , apoptosis , medicine , biology , cell cycle , biochemistry , rna , microbiology and biotechnology , organic chemistry , gene
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.