Hypoxic targeting and activating TH-302 loaded transcatheter arterial embolization microsphere

• Main Authors: Pengkai Ma (Author), Jianhua Chen (Author), Haixian Qu (Author), Ye Li (Author), Xiaohui Li (Author), Xuemei Tang (Author), Zhigang Song (Author), Hainan Xin (Author), Jinbang Zhang (Author), Jingxue Nai (Author), Zhiping Li (Author), Zhijun Wang (Author)
• Format: Book
• Published: Taylor & Francis Group, 2020-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1071-7544; 1521-0464; 10.1080/10717544.2020.1831102
• Keywords: hepatocellular carcinoma; tace; hypoxia; chemoembolization microsphere; th-302; Therapeutics. Pharmacology; RM1-950
• Source: Drug Delivery, Vol 27, Iss 1, Pp 1412-1424 (2020)

The tumor-derived and transcatheter arterial chemoembolization (TACE) induced hypoxia microenvironment is closely related to the poor prognosis of hepatocellular carcinoma (HCC). In this study, hypoxia-activated prodrug TH-302 loaded poly(lactic-co-glycolic acid) (PLGA)-based TACE microspheres were prepared to treat HCC through localized and sustained drug delivery. TH-302 microspheres with three different sizes were fabricated by an oil-in-water emulsion solvent evaporation method and characterized by scanning electron microscopy (SEM), infrared spectra (IR), X-ray diffractometer (XRD), and drug release profiles. The in vitro antitumor potential was firstly evaluated in an HepG2 cell model under normoxic and hypoxic conditions. Then, a VX-2 tumor-bearing rabbit model was established and performed TACE to investigate the in vivo drug tissue distribution and antitumor efficiency of TH-302 microspheres. Blood routine examination and histopathological examinations were also conducted to evaluate the safety of TH-302 microspheres. TH-302 microspheres with particle size 75-100 μm, 100-200 μm, and 200-300 μm were prepared and characterized by sphere morphology and sustained drug release up to 360 h. Compared with TH-302, the microspheres exhibited higher cytotoxicity, cell apoptosis, and cell cycle S phase retardation in HepG2 cells under hypoxic conditions. The microspheres also displayed continuous drug release in the liver tissue and better anti-tumor efficiency compared with TH-302 injection and lipiodol. Meanwhile, no serious toxicity appeared in the duration of treatment. Therefore, TH-302 microspheres showed to be feasible and effective for TACE and hold promise in the clinical for HCC chemoembolization therapy.