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.
- Truncated tissue factor
ASJC Scopus subject areas
- Environmental Chemistry
- Chemical Engineering(all)
- Industrial and Manufacturing Engineering