Intratumoral Administration of Thermosensitive Hydrogel Co-Loaded with Norcantharidin Nanoparticles and Doxorubicin for the Treatment of Hepatocellular Carcinoma

Benjian Gao,1– 3,* Jia Luo,4,* Ying Liu,1– 3,* Song Su,1– 3 Shaozhi Fu,4 Xiaoli Yang,1– 3 Bo Li1– 3 1Department of General Surgery (Hepatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People’s Republic of China; 2Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan Province, People’s Republic of China; 3Academician (Expert) Workstation of Sichuan Province, Luzhou, Sichuan Province, People’s Republic of China; 4Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoli Yang; Bo LiDepartment of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, No. 25 Taiping Road, Luzhou, Sichuan, 646000, People’s Republic of ChinaTel +86-15086878251; +86-13518371998Email 344920646@qq.com; liboer2002@126.comBackground: The efficacy of systemic chemotherapy for hepatocellular carcinoma (HCC) is predominantly hampered by low accumulation in tumor tissue and the high systemic toxicity of anticancer drugs. In this study, we designed an in situ drug-loaded injectable thermosensitive hydrogel system for the simultaneous delivery of norcantharidin-loaded nanoparticles (NCTD-NPs) and doxorubicin (Dox) via intratumoral administration to HCC tumors.Methods: NCTD-NPs were prepared by the thin film dispersion method using PCEC polymers as the carrier. Then, NCTD-NPs and Dox were co-encapsulated in a thermosensitive hydrogel based on Pluronic F127 (PF127) to construct a dual drug-loaded hydrogel system. The rheological properties of the drug-loaded hydrogel were studied using a rheometer. Drug release of the drug-loaded hydrogel and cytotoxicity in HepG2 cells were evaluated in vitro. An H22 tumor-bearing mice model was used to assess the in vivo antitumor activity of the drug-loaded hydrogel via intratumoral administration.Results: The prepared drug-loaded hydrogel exhibited good thermal-sensitive properties, which remained liquid at room temperature and rapidly transformed into a non-flowing gel at body temperature, and released the drugs in a sustained manner. In vitro studies revealed that the drug-loaded hydrogel exhibited remarkable antiproliferative activity in HepG2 cells compared to free drugs. In vivo antitumor efficacy experiments showed that the drug-loaded hydrogel significantly suppressed tumor growth, alleviated side effects, and prolonged the survival time of mice bearing H22 tumors compared to the other groups. Moreover, immunohistochemical staining revealed that the expression of Ki-67 and CD31 in the drug-loaded hydrogel group was significantly lower than that in the other groups (P < 0.05), indicating that the drug-loaded hydrogel effectively inhibited tumor proliferation and angiogenesis.Conclusion: The formulated hybrid thermosensitive hydrogel system with sustained drug release and enhanced therapeutic efficacy was demonstrated to be a promising strategy for the local-regional treatment of HCC via intratumoral administration.Keywords: Norcantharidin, Doxorubicin, Nanoparticles, Thermosensitive hydrogel, Hepatocellular carcinoma, Intratumoral injectio