Development of in Situ Forming Thermosensitive Hydrogel for Radiotherapy Combined with Chemotherapy in a Mouse Model of Hepatocellular Carcinoma

• Published in: Molecular pharmaceutics 2013-05, Vol.10 (5), p.1854-1864
• Main Authors: Peng, Cheng-Liang, Shih, Ying-Hsia, Liang, Kuo-Sheng, Chiang, Ping-Fang, Yeh, Chung-Hsin, Tang, I-Chang, Yao, Cheng-Jung, Lee, Shin-Yi, Luo, Tsai-Yueh, Shieh, Ming-Jium
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Chemoradiotherapy - methods; Colloids - chemistry; Combined Modality Therapy; Doxorubicin - administration & dosage; Drug Delivery Systems; Hydrogels - chemistry; Liposomes - chemistry; Liver Neoplasms, Experimental - pathology; Liver Neoplasms, Experimental - therapy; Male; Mice; Mice, Inbred BALB C; Polyesters - chemistry; Polyethylene Glycols - chemistry; Radiopharmaceuticals - administration & dosage; Rhenium - administration & dosage; Temperature; Tin - administration & dosage
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/mp3006424

This study evaluated a system for local cancer radiotherapy combined with chemotherapy. The delivery system is a thermosensitive hydrogel containing a therapeutic radionuclide (188Re-Tin colloid) and a chemotherapeutic drug (liposomal doxorubicin). The thermosensitive PCL-PEG-PCL copolymer was designed to spontaneously undergo a sol–gel phase transition in response to temperature, remaining liquid at room temperature and rapidly forming a gel at body temperature. A scanning electron microscope was used to observe the microstructure of the fully loaded hydrogel. Release of radionuclide and doxorubicin from the hydrogel was slow, and the system tended to remain stable for at least 10 days. After the intratumoral administration of Lipo-Dox/188Re-Tin hydrogel in mice with hepatocellular carcinoma (HCC), its retention by the tumor, spatiotemporal distribution, and therapeutic effect were evaluated. The residence time in the tumor was significantly longer for 188Re-Tin loaded hydrogel than for Na 188Re perrhenate (Na 188ReO4). The hydrogel after thermal transition kept the radionuclide inside the tumor, whereas free 188Re perrhenate (188ReO4) diffused quickly from the tumor. The tumor growth was more profoundly inhibited by treatment with Lipo-Dox/188Re-Tin hydrogel (with up to 80% regression of well-established tumors on day 32) than treatment with either 188Re-Tin hydrogel or Lipo-Dox hydrogel. Therefore, this injectable and biodegradable hydrogel may offer the advantage of focusing radiotherapy and chemotherapy locally to maximize their effects on hepatocellular carcinoma.