Improved tumor-targeting drug delivery and therapeutic efficacy by cationic liposome modified with truncated bFGF peptide.

Abstract

Fibroblast growth factor receptors (FGFRs), overexpressed on the surface of a variety of tumor cells and on tumor neovasculature in situ, are potential targets for tumor- and vascular-targeting therapy. This study aimed to develop a FGFR-mediated drug delivery system to target chemotherapeutic agents to FGFR-overexpressed tumor cells and tumor neovasculature endothelial cells in vitro and in vivo. Here we designed a truncated human basic fibroblast growth factor peptide (tbFGF), which was attached to the surface of cationic liposomal doxorubicin (LPs-DOX) and paclitaxel (LPs-PTX) via electrostatic force. Then we characterized the tbFGF-modified liposome (tbFGF-LPs) and examined internalization of doxorubicin in tumor cells (TRAMP-C1, B16) and HUVEC cells in vitro. In vivo, we evaluated the biodistribution and antitumor efficacy of tbFGF-LPs-DOX and tbFGF-LPs-PTX in C57BL/6J mice bearing TRAMP-C1 prostate carcinoma and B16 melanoma, respectively. The tbFGF-LPs-DOX significantly improved the uptake of doxorubicin in TRAMP-C1, B16 and HUVEC cells, respectively. Biodistribution study in B16 tumor-bearing mice showed that tbFGF-LPs-PTX achieved 7.1-fold (72.827+/-7.321mgh/L vs 10.292+/-0.775mgh/L, mean+/-SD, P<0.01) accumulation of paclitaxel in tumor tissue than those of free paclitaxel. More importantly, treatment of tumor-bearing mice with tbFGF-LPs-DOX and tbFGF-LPs-PTX showed the significant inhibition in tumor growth and improvement in survival rate as compared with mice treated with free and liposomal drugs in TRAMP-C1 and B16 tumor models, respectively. Furthermore, repeated intravenous administration of tbFGF-LPs-DOX/PTX did not induce anti-bFGF antibodies. These results suggested that this FGFR-mediated drug delivery system may provide a new treatment strategy for tumors which overexpress FGFRs.

• Authors: Xiang Chen, Xianhuo Wang, Yongsheng Wang, Li Yang, Jia Hu, Wenjing Xiao, Afu Fu, Lulu Cai, Xia Li, Xia Ye, Yalin Liu, Wenshuang Wu, Ximing Shao, Yongqiu Mao, Yuquan Wei, Lijuan Chen
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 145 Issue 1 Pg. 17-25 (Jul 01 2010) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 20307599 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2010 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cations
• Drug Carriers
• Liposomes
• Receptors, Fibroblast Growth Factor
• Fibroblast Growth Factor 2
• Doxorubicin
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics, therapeutic use)
• Cations
• Cell Line, Tumor
• Doxorubicin (administration & dosage, pharmacokinetics, therapeutic use)
• Drug Carriers (chemistry)
• Female
• Fibroblast Growth Factor 2 (chemistry)
• Flow Cytometry
• In Situ Nick-End Labeling
• Injections, Intravenous
• Liposomes
• Male
• Melanoma, Experimental (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Microscopy, Atomic Force
• Neoplasm Transplantation
• Paclitaxel (administration & dosage, pharmacokinetics, therapeutic use)
• Particle Size
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Protein Binding
• Receptors, Fibroblast Growth Factor (metabolism)
• Surface Properties