title: Codelivery of VEGF siRNA and gemcitabine monophosphate in a single nanoparticle formulation for effective treatment of NSCLC.
abstract: There is an urgent need for new therapeutics for the treatment of aggressive and metastatic refractory human non-small-cell lung cancer (NSCLC). Antiangiogenesis therapy and chemotherapy are the two major treatment options. Unfortunately, both types of therapies when used individually have their disadvantages. Integrating antiangiogenesis therapy with chemotherapy is expected to target the tumor's vascular endothelial cells and the tumor cells simultaneously. In this study, we coformulated Vascular endothelial growth factor (VEGF) siRNA targeting VEGFs and gemcitabine monophosphate (GMP) into a single cell-specific, targeted lipid/calcium/phosphate (LCP) nanoparticle formulation. Antitumor effect of the combination therapy using LCP loaded with both VEGF siRNA and GMP was evaluated in both subcutaneous and orthotopic xenograft models of NSCLC with systemic administration. The improved therapeutic response, as compared with either VEGF siRNA or GMP therapy alone, was supported by the observation of 30-40% induction of tumor cell apoptosis, eightfold reduction of tumor cell proliferation and significant decrease of tumor microvessel density (MVD). The combination therapy led to dramatic inhibition of tumor growth, with little in vivo toxicity. In addition, the current studies demonstrated the possibility of incorporating multiple nucleic acid molecules and phosphorylated small-molecule drugs, targeting to different pathways, into a single nanoparticle formulation for profound therapeutic effect.
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7571, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Nicole Mj
authors.initials: NM
authors.lastname: Schwerbrock
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Rogers
authors.forename: William Y
authors.initials: WY
authors.lastname: Kim
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; D020169:Caspases; D000093542:Gemcitabine