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Rational design of temperature-sensitive blood-vessel-embolic nanogels for improving hypoxic tumor microenvironment after transcatheter arterial embolization.

ABSTRACT: Transcatheter arterial embolization (TAE) plays an important role in clinical tumor therapy by accomplishing vessel-casting embolization of tumor arteries at all levels and suppressing tumor collateral circulation and vascular re-canalization. In this study, we describe smart blood-vessel-embolic nanogels for improving the anti-tumor efficacy of TAE therapy on hepatocellular carcinoma (HCC). Methods: In this study, an in vitro model composed of two microfluidic chips was used for simulating the tumor capillary network and analyzing artery-embolization properties. Also, blood-vessel-casting embolization of renal arteries was evaluated in normal rabbits. Using a VX2 tumor-bearing rabbit model, the therapeutic efficacy of TAE on HCC was investigated for tumor growth, necrosis, and proliferation. Neovascularization and collateral circulation were evaluated by immunofluorescent detection of hypoxia-inducible factor-1? (HIF-1?), vascular endothelial growth factor (VEGF), and CD31 following the TAE therapy of VX2 tumor-bearing rabbits. Results: Sufficient embolization of all eight levels of micro-channels was achieved in a tumor-vessel-mimetic model with two microfluidic chips using PIBI-2240, and was further confirmed in renal arteries of normal rabbit. Effective inhibition of tumor collateral circulation and vascular re-canalization was observed in VX2 tumor-bearing rabbits due to the reduced expression levels of HIF-1?, VEGF, and CD31. Conclusions: The exceptional anti-tumor effect of PIBI-2240 observed in this study suggested that it is an excellent blood-vessel-embolic material for tumor TAE therapy.

SUBMITTER: Li L

PROVIDER: S-EPMC6299701 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Rational design of temperature-sensitive blood-vessel-embolic nanogels for improving hypoxic tumor microenvironment after transcatheter arterial embolization.

Li Ling L Liu Yiming Y Li Han H Guo Xiaopeng X He Xiaojun X Geng Shinan S Zhao Hao H Peng Xiaole X Shi Dingwen D Xiong Bin B Zhou Guofeng G Zhao Yanbing Y Zheng Chuansheng C Yang Xiangliang X

Theranostics 20181129 22

Transcatheter arterial embolization (TAE) plays an important role in clinical tumor therapy by accomplishing vessel-casting embolization of tumor arteries at all levels and suppressing tumor collateral circulation and vascular re-canalization. In this study, we describe smart blood-vessel-embolic nanogels for improving the anti-tumor efficacy of TAE therapy on hepatocellular carcinoma (HCC). <b>Methods:</b> In this study, an <i>in vitro</i> model composed of two microfluidic chips was used for s ...[more]

PMID: 30613298

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Project description:Purpose:Transcatheter arterial embolization or transcatheter arterial chemoembolization has become a critical therapy for unresectable hepatocarcinoma. Although hypoxia caused by embolization can induce apoptosis and necrosis of the majority of tumor cells, a small proportion of cells can survive with hypoxia and chemotherapy resistance. HIF-1? induced by hypoxia is the key factor rendering surviving tumor cells invasive and metastatic properties. Thus, we generated a synthetic hypoxia-replicative oncolytic adenovirus (HYAD) expecting to further eliminate the surviving tumor cells, which expressed HIF-1?. Materials and methods:In our study, we detected protein expression, proliferation, apoptosis, and necrosis of hepatic tumor cell line when infected with HYAD under hypoxia and normoxia. And we constructed VX2 hepatic cancer rabbit models to explore the therapeutic effect of transcatheter arterial embolization combined with HYAD perfusion under digital subtraction angiography. Inhibition of tumor growth and invasion was detected by histopathological examination and contrast-enhanced CT scan. Results:Experiments in vitro verified that HYAD expressed and replicated along with HIF-1? expression or hypoxia. Compared with wild adenovirus type 5 (WT), HYAD expressed much more under hypoxia, which was the main principle of HYAD killing surviving tumor cells posttransarterial embolization. In vivo experiment of VX2 models, HYAD perfusion combined with polyvinyl alcohol (PVA) embolization achieved the highest expression quantity and the longest expression duration compared with simple HYAD perfusion, WT perfusion combined with PVA embolization, and simple WT perfusion. Because adenovirus expression protein E1A had the properties of promoting apoptosis, inhibiting invasion, and inhibiting metastasis, HYAD perfusion combined with PVA embolization group efficiently repressed tumor growth and intrahepatic metastases compared to other processing groups. Conclusion:HYAD can overcome the hypoxic tumor microenvironment postembolization and target the surviving tumor cells with specificity. In turn, HYAD perfusion combined with PVA embolization can bring out the best effect in each other.

Dataset Information

Rational design of temperature-sensitive blood-vessel-embolic nanogels for improving hypoxic tumor microenvironment after transcatheter arterial embolization.

Publications

Rational design of temperature-sensitive blood-vessel-embolic nanogels for improving hypoxic tumor microenvironment after transcatheter arterial embolization.

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