We propose to extend our previous preliminary in vitro targeting studies to in vivo models to develop a new receptor-mediated approach to chemotherapy of hepatocellular carcinoma. The concept is based on the use of hepatotoxins, to destroy malignant cells, in combination with specific targeted-antagonists to achieve exclusive rescue of normal hepatocytes. This targeting is dependent on the ability of normal hepatocytes, and the inability of the majority of hepatocellular carcinomas to take up and degrade, intracellularly, galactose-terminal (asialo-) glycoproteins by a specific receptor-mediated endocytosis. Linkage of an appropriate antagonist to such glycoproteins could result in specific binding and release of antagonist with subsequent rescue of only normal, differentiated hepatocytes. We also propose to investigate new strategies to enhance the effectiveness of targeted rescue: 1) increased delivery of rescue agents to normal hepatocytes using asialoglycoprotein-polylysine carrier molecules to increase the amount of antagonists capable of being coupled to the carrier molecule 2) increased efficiency of antagonist release by the interposition of labile linkages. We will use two animal models to test these approaches: 1) inbred Buffalo rats implanted with a rat hepatoma cell line 2) rats bearing carcinogen-induced hepatomas. We will use serological and pathological measurements to determine the feasibility of the use of targeted rescue as an effective modality for the treatment of hepatocellular carcinoma.
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