Systemic delivery of phosphorylated nucleoside analogues and siRNA via LCP nanoparticles for cancer therapy

Zhang, Yuan

Download PDF

Request Version for Screen Reader

Last Modified

March 21, 2019

Creator

Zhang, Yuan
- Affiliation: Eshelman School of Pharmacy

Abstract

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)) 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. Drug-loaded LCPs induced cell death and arrested the cell cycle in the S phase. In vivo efficacy studies showed that intravenously injected drug-loaded LCPs triggered effective apoptosis of tumor cells, significant reduction of tumor cell proliferation and cell cycle progression, leading to dramatic inhibition of tumor growth, with little in vivo toxicity. Additionally, LCPs significantly prolonged the blood circulation of the entrapped GTP as compared to the free drug. The current study offers preclinical proof-of-principle that many active nucleotide or phosphorylated nucleoside analogues could be encapsulated in the LCP nanoplatform for systemic delivery. 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. Anti-angiogenic effects and in vivo toxicities were also discussed. 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.

Date of publication