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-1α (HIF-1α), 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-1α, 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.

Assessment of embolization effect with temperature-sensitive p(N-isopropylacrylamide-co-butyl methylacrylate) nanogels in rabbit renal artery by CT perfusion and pathology

“…A smart polymer material can remain in a liquid solution state at LCST and become a gelatinous solid above LCST. With a transition temperature close to physiological temperature, smart polymer materials have been reported in blood vessel embolic materials 13,16 , drug delivery [17][18][19] , precise cancer therapy 20,21 , tissue engineering 22 , and cell sheet engineering 23,24 . Most of the studies have focused on phase behaviour theory, drug delivery and promising biomedical applications.…”

“…Temperature-sensitive p(N-isopropylacrylamide-co-butyl methylacrylate) nanogels have been used as novel blood vessel embolic materials to solve the dilemma of peripheral artery embolization and permanent embolization [11][12][13] . With the progress in preparation technology, materials have become more compatible and more convenient.…”

“…Some researchers have attempted to use digital subtraction angiography (DSA) to assess the long-term effect of embolization [11][12][13][14] . However, a major drawback of DSA is invasion.…”

Assessment of the embolization effect of temperature-sensitive p(N-isopropylacrylamide-co-butyl methylacrylate) nanogels in the rabbit renal artery by CT perfusion and confirmed by macroscopic examination

“…In addition to good dispersibility and permanent embolism, the p ( N -isopropylacrylamide- co -butyl methylacrylate) (PIB) nanogels developed by us exhibited a lower inflammatory vascular response, better fluidity, and better operability than PVA-embolized particles and Lipiodol 12 , 13 . Temperature-sensitive PIB nanogels have been used as novel blood vessel embolic materials to solve the dilemma of peripheral artery embolization and permanent embolization 12 – 14 . With the progress of preparation technology, the resultant PIB nanogels have become more biocompatible, and the convenience of operation has been markedly improved.…”

“…Digital subtraction angiography (DSA) has long been the imaging gold standard in the evaluation, treatment, and follow-up of vascular disorders 15 . Some researchers have attempted to use DSA to assess the long-term effect of embolization 12 – 14 , 16 . However, a major drawback of DSA is the invasiveness of vascular puncture.…”