The characteristics and performance of a multifunctional nanoassembly system for the co-delivery of docetaxel and iSur-pDNA in a mouse hepatocellular carcinoma model

Human hepatocellular carcinoma (HCC) is one of the most causes of cancer-related death and is well known because of resistant to chemotherapeutic drug. Co-delivery of antitumor agent docetaxel and iSur-pDNA, a suppressor of metastatic and resistance-related protein survivin, was postulated to achieve synergistic/combined effect of antitumor drug and gene therapeutics. To valid this hypothesis, a folate-modified multifunctional nanoassembly (FNA) loading both docetaxel and iSur-pDNA was constructed and evaluated as a therapeutic approach for HCC. The FNAs were prepared with folate-modified lipid FA-PEG-DSPE as the target to tumor, protamine sulfate (PS) as the condenser to protect and enhance the nuclear transfer of iSur-pDNA, and DOPE-based lipid envelope as the carrier of doctaxel and PS/DNA complex to achieve their co-delivery and enhance internalization into hepatoma cells. FNAs showed the particle size about 200 nm with encapsulation efficiency >90%. Blank nanoassemblies (BNAs) loading only reporter gene revealed higher transfection efficiency with neglectable cytotoxicity compared with Lipofectamine (TM) 2000, which could result from enhanced cellular uptake via ligand-receptor recognition and efficient nuclear delivery mediated by PS. Cytotoxicity of FNAs against hepatocellular carcinoma cell line BEL 7402 was much higher than either docetaxel or non-docetaxel FNAs (nFNAs) loading only iSur-pDNA, and was also superior to the combined treatment with free docetaxel and nFNAs. Better antitumor efficacy of FNAs with low systemic toxicity was also observed on mouse hepatocellular carcinoma xenograft model. These results suggested that co-delivery of docetaxel and iSur-pDNA with FNAs could be a safer and more efficient strategy for the treatment of locally advanced and metastatic HCC. (C) 2009 Elsevier Ltd. All rights reserved.