Combined Tumor- and Neovascular-"Dual Targeting" Gene/Chemo-Therapy Suppresses Tumor Growth and Angiogenesis.
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.
State Key Laboratory of Biotherapy/Geriatrics and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University , Chengdu 610041, China.
Bei
B
Xu
State Key Laboratory of Biotherapy/Geriatrics and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University , Chengdu 610041, China.
Quansheng
Q
Jin
State Key Laboratory of Biotherapy/Geriatrics and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University , Chengdu 610041, China.
Jun
J
Zeng
State Key Laboratory of Biotherapy/Geriatrics and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University , Chengdu 610041, China.
Ting
T
Yu
State Key Laboratory of Biotherapy/Geriatrics and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University , Chengdu 610041, China.
Yan
Y
Chen
State Key Laboratory of Biotherapy/Geriatrics and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University , Chengdu 610041, China.
Shuangzhi
S
Li
State Key Laboratory of Biotherapy/Geriatrics and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University , Chengdu 610041, China.
Daoqiong
D
Gong
College of Pharmacy, Southwest University for Nationalities , Chengdu 610041, China.
Lili
L
He
Department of Pathology/Collaborative Innovation Center of Biotherapy, Medical School of Nankai University , Tianjin 300071, China.
Xiaoyue
X
Tan
State Key Laboratory of Biotherapy/Geriatrics and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University , Chengdu 610041, China.
Li
L
Yang
State Key Laboratory of Biotherapy/Geriatrics and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University , Chengdu 610041, China.
Gu
G
He
State Key Laboratory of Biotherapy/Geriatrics and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University , Chengdu 610041, China.
Jinhui
J
Wu
State Key Laboratory of Biotherapy/Geriatrics and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University , Chengdu 610041, China.
Xiangrong
X
Song
D000818:Animals; D000970:Antineoplastic Agents; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D053758:Nanoparticles; D009369:Neoplasms; D009389:Neovascularization, Pathologic; D017239:Paclitaxel
D000970:Antineoplastic Agents; D017239:Paclitaxel
FGF receptors; active targeting nanoparticles; codelivery; paclitaxel; pigment epithelium-derived factor gene; truncated bFGF peptide