Combined Tumor- and Neovascular-"Dual Targeting" Gene/Chemo-Therapy Suppresses Tumor Growth and Angiogenesis.

Abstract

A rational combination is critical to achieve efficiently synergistic therapeutic efficacy for tumor treatment. Hence, we designed novel antitumor combinations (T-NPs) by integrating the tumor vascular and tumor cells dual-targeting ligand with antiangiogenesis/antitumor agents. The truncated bFGF peptide (tbFGF), which could effectively bind to FGFR1 overexpressed on tumor neovasculature endothelial cells and tumor cells, was selected to modify PLGA nanoparticles (D/P-NPs) simultaneously loaded with PEDF gene and paclitaxel in this study. The obtained T-NPs with better pharmaceutical properties had elevated cytotoxicity and enhanced expression of PEDF and α-tubulin on FGFR1-overexpressing cells. The uptake of T-NPs increased in C26 cells, probably mediated by tbFGF via specific recognization of the overexpressed FGFR1. T-NPs dramatically disrupted the tube formation of primary human umbilical vein endothelial cells (HUVECs) and displayed improved antiangiogenic activity in the transgenic zebrafish model and the alginate-encapsulated tumor cell model. More importantly, T-NPs achieved a markedly higher antitumor efficacy in the C26 tumor-bearing mice model. The antitumor effect involved the inhibition of tumor cell proliferation and angiogenesis, induction of apoptosis, and down-regulation of FGFR1. The enhanced antitumor activity of T-NPs probably resulted from the raised distribution in tumor tissues. In addition, T-NPs had no obvious toxicity as evaluated by weight monitoring, serological/biochemical analyses, and H&E staining. These results revealed that T-NPs, an active targeting gene/chemo-therapy, indeed had superior antitumor efficacy and negligible side effect, suggesting that this novel combination is a potential tumor therapy and a new treatment strategy and that the tbFGF modified nanoparticles could be applied to a wide range of tumor-genetic therapies and/or tumor-chemical therapies.

• Authors: Bei Xu, Quansheng Jin, Jun Zeng, Ting Yu, Yan Chen, Shuangzhi Li, Daoqiong Gong, Lili He, Xiaoyue Tan, Li Yang, Gu He, Jinhui Wu, Xiangrong Song
• Journal: ACS applied materials & interfaces (ACS Appl Mater Interfaces) Vol. 8 Issue 39 Pg. 25753-25769 (Oct 05 2016) ISSN: 1944-8252 [Electronic] United States
• PMID: 27615739 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents
• Cell Line, Tumor
• Humans
• Mice
• Nanoparticles
• Neoplasms
• Neovascularization, Pathologic
• Paclitaxel