【摘 要】
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Nucleoside analogues are a significant class of anticancer agents.As prodrugs, they terminate the DNA synthesis upon transforming to their active triphosphate metabolites.However,several in vivo deliv
【机 构】
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Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology, USA
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Nucleoside analogues are a significant class of anticancer agents.As prodrugs, they terminate the DNA synthesis upon transforming to their active triphosphate metabolites.However,several in vivo delivery hurdles compromise their application in clinical settings.To address these delivery problems, we encapsulated the phosphorylated nucleoside analogues (i.e.gemcitabine triphosphate (GTP), or gemcitabine monophosphate (GMP), or acyclovir monophosphate) into a novel Lipid/Calcium/Phosphate nanoparticle (LCP) platform.The therapeutic efficacy of drug loaded LCPs was evaluated in a panel of human non-small-cell lung cancer (NSCLC) or human pancreatic cancer xenograft models.In order to suppress the tumor progression more effectively, gene therapy by RNAi was combined with gemcitabine chemotherapy, by formulating multiple therapeutic agents into one single nanoparticle.LCP encapsulating both VEGF siRNA and GMP, or LCP encapsulating both c-Myc siRNA and GMP were constructed.In vivo responses of combined therapies were compared with individual monotherapies in NSCLC xenograft model or NSCLC orthotopic model.In vivo efficacies of LCP formulations were evaluated by caspase activation, apoptosis induction and proliferation reduction, as well as tumor growth inhibition.Cell cycle progression,pharmacokinetic profiles, anti-angiogenic effects and in vivo toxicities were also discussed.Broadly speaking, the current study offers preclinical proof-of-principle that many phosphorylated nucleoside analogues and nucleic acid therapeutics could be encapsulated in the LCP nanoplatform and systemically administered to modulate multiple therapeutic pathways simultaneously.
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