title: Therapeutic potential of targeted multifunctional nanocomplex co-delivery of siRNA and low-dose doxorubicin in breast cancer.
abstract: Malignant tumors remain a major health burden throughout the world, and effective therapeutic strategies are urgently needed. Combining gene therapy with chemotherapeutics in a single delivery system is more effective than co-treatment of cancer with individual delivery systems carrying either gene or drug. In this study, a multifunctional folate-decorated and pH-responsive PHD/PPF/siVEGF nanocomplex is developed via a self-assembly process utilizing ternary pre-functionalized polymers with vascular endothelial growth factor targeted siRNA. Antitumor effects of the combination therapy are evaluated in both in vitro and in vivo orthotopic xenograft models of breast cancer with systemic administration. The improved therapeutic response was supported by the observation of over 70% and 55% down-regulation of VEGF mRNA expressed in vitro and in vivo, effective antiproliferation and inhibition of tumor spheroids in vitro, significant decrease in tumor microvessel density in vivo, dramatic increase in life span of mice with a tumor xenograft and a decrease in toxicity in vivo. In addition, the current studies demonstrated the potential of combination of antiangiogenic therapy of siVEGF and killing off tumor cells of DOX, with the incorporation of tumor microenvironment sensitivity and target modified into a single nanoparticulate formulation for profound therapeutic effect.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Dawen
authors.initials: D
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: qixr@bjmu.edu.cn.
authors.forename: Xian-Rong
authors.initials: XR
authors.lastname: Qi
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058726:Nanoconjugates / Q000008:administration & dosage; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D018874:Spheroids, Cellular / Q000187:drug effects; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D058726:Nanoconjugates; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D004317:Doxorubicin
keywords: Antiangiogenic; Co-delivery of siRNA and doxorubicin; Cytotoxicity; Multifunctional nanocomplex; Synergistic treatment