Development of PLGA Nanoparticles Simultaneously Loaded with Vincristine and Verapamil for Treatment of Hepatocellular Carcinoma

Hpatocellular carcinoma (HCC) is one of the malignant tumors with poor chemosensitivity to vincristine sulfate (VCR) due to multi-drug resistance (MDR). Combinations of encapsulated VCR and verapamil hydrochloride (VRP, a chemo-sensitizer) might be a potential strategy to improve HCC therapeutic efficacy of VCR. PLGA nanoparticles (PLGANPs) simultaneously loaded with VCR and VRP (CVn) were prepared. The entrapment efficiencies of VCR and VRP were 70.92 +/- 3.78% and 85.78 +/- 3.23%, respectively (n = 3). The HCC therapeutic activity of CVn was assessed using MTT assay. In BEL7402 and BEL7402/5-FU human hepatocarcinoma cell lines, CVn had the same antitumor effect as one free drug/another agent-loaded PLGANPs (C+Vn or Cn+V) combination and coadministration of two single-agent- loaded PLGANPs (Cn+Vn), which was slightly higher than that of the free VCR/VRP combination (C-V). CVn might cause lower normal tissue drug toxicity by the enhanced permeation and retention effect in vivo. Additionally, CVn might cause fewer drug-drug interaction and be the most potential formulation to simultaneously deliver VCR and VRP to the target cell in vivo than the other three nanoparticle formulations (C+Vn, Cn+V, and Cn+Vn). Therefore, we speculate that CVn might be the most effective preparation in the treatment of drug-resistant human HCC in vivo. (C) 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4874-4879, 2010