Combined delivery of a TGF-β inhibitor and an adenoviral vector expressing interleukin-12 potentiates cancer immunotherapy

被引：32

作者：

Jiang, Jiayu ^{[1
]}

Zhang, Yuandong ^{[1
]}

Peng, Ke ^{[1
]}

Wang, Qin ^{[1
]}

Hong, Xiaoyu ^{[1
]}

Li, Hanmei ^{[1
]}

Fan, Gerui ^{[1
]}

Zhang, Zhirong ^{[1
]}

Gong, Tao ^{[1
]}

Sun, Xun ^{[1
]}

机构：

[1] Sichuan Univ, West China Sch Pharm, Minist Educ, Key Lab Drug Targeting & Drug Delivery Syst, Chengdu 610041, Sichuan, Peoples R China

来源：

ACTA BIOMATERIALIA | 2017年 / 61卷

基金：

中国国家自然科学基金;

关键词：

Cancer immunotherapy; Transforming growth factor-beta; Adenovirus; Interleukin-12; beta-Cyclodextrin-PEI; Melanoma; GROWTH-FACTOR-BETA; RECOMBINANT HUMAN INTERLEUKIN-12; DENDRITIC CELLS; GENE-TRANSFER; ANTITUMOR IMMUNITY; PHASE-I; RECEPTOR; THERAPY; IL-12; CYCLODEXTRINS;

D O I：

10.1016/j.actbio.2017.05.009

中图分类号：

R318 [生物医学工程];

学科分类号：

0831 ;

摘要：

Cancer immunotherapy appears to have a promising future, but it can be thwarted by secretion of immunosuppressive factors, such as transforming growth factor-beta (TGF-beta), which inhibits local immune responses to tumors. To weaken immune resistance of tumors and simultaneously strengthen immune responses, we developed a multifunctional polymer that could co-deliver hydrophobic TGF-beta inhibitor and an adenovirus gene vector to tumor sites. This co-delivery system sustainably released TGF-beta inhibitor SB-505124 and effectively transferred the adenovirus vector carrying the interleukin-12 gene. In addition, it significantly delayed growth of B16 melanoma xenografts in mice and increased animal survival. Mechanistic studies showed that this combination therapy enhanced anti-tumor immune response by activating CD4(+) and CD8(+) T cells, natural killer cells and interferon-gamma secretion in the tumor microenvironment. Statement of Significance To weaken immune resistance of tumors and simultaneously strengthen tumors' immune responses, we synthesized a structurally simple, low-toxic but functional polymer 6-cyclodextrin-PEI to encapsulate a hydrophobic TGF-beta inhibitor SB-505124 and to complex adenovirus vectors expressing IL-12. This is the first report demonstrating that combining TGF-beta inhibitor with IL-12 could provide effective immunotherapy against melanoma by the sustainable release of SB-505124 and the effectible transduction of IL-12 gene in tumor cells. The rational delivery system presented a comprehensive and valued platform to be a candidate vector for co-delivering hydrophobic small-molecule drugs and therapeutic genes for treating cancer, providing a new approach for cancer immunotherapy. (C) 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

引用

页码：114 / 123

页数：10

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