The synergistic blood-vessel-embolization of coagulation fusion protein with temperature sensitive nanogels in interventional therapies on hepatocellular carcinoma

As one of the most extensively used clinical treatments for many solid tumors such as liver cancer, trans-arterial embolization (TAE) was greatly limited by postoperative recurrence and metastasis and poor long-term efficacy. In present work, tTF-pHLIPs was entrapped into 3D networks of poly(N-isopropylacrylamide-co-butyl methacrylate) (PIB) nanogels, named as TF-Nanogels, for improving their sustained release and in vivo PK/PD properties by temperature sensitive sol–gel transition of PIB nanogels. TF-Nanogels exhibited a synergistic effect between the extrinsic coagulation of tTF-pHLIPs and intrinsic coagulation of PIB nanogels with negative charges in in vitro clotting assays, and a distinct activation on platelets by CD62P pathways at above 0.1 mg/mL of nanogel concentration. The resultant blood fibril clots by TF-Nanogels showed thicker fibrin networks than those by free tTF-pHLIPs in SEM pictures (400 nm vs. 60 nm of fibrin diameters), suggesting the interpenetrating networks of fibril clots, platelets/ hemocytes and PIB nanogels. Compared to i.v. injection of tTF-pHLIPs, TF-Nanogels exihited an long-term vascular occlusion in VX2 tumor-bearing rabbits only at a half dose (250 μg) of i.v. injection, indicating the synergistic antitumor efficacy between PIB nanogels and tTF-pHLIPs. TF-Nanogels showed favorable supression on tumor angiogenesis and metastasis due to far lower levels of HIF-1α, VEGFs and MMP-9 than tTF-pHLIPs, and distinct antitumor immune response (higher levels of CD3⁺ and CD8⁺ T cells). TF-Nanogels were promising embolic agents to enhance TAE antitumor efficacy (angiogenesis inhibition, metastasis inhibition, antitumor immune activation, etc.) by the synergistic effect between coagulative artery infraction of tTF-pHLIPs and temperature sensitive artery embolization of PIB nanogels in interventional therapies on hepatocellular carcinoma.