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Liposomal encapsulation of irinotecan and potential for the use of liposomal drug in the treatment of liver metastases associated with advanced colorectal cancer Messerer, Corrie Lynn

Abstract

Colorectal cancer is the second leading cause of cancer mortality in North America, primarily because of a high incidence of hepatic metastases, which are relatively unresponsive to the systemic chemotherapy. Irinotecan, a camptothecin analogue recently approved for used in conjunction with 5-fluorouricil/leucovorin, is a marginal improvement but toxic and by no means curative. Liposomal drug formulations are argued to be more effective at treating liver-localised carcinomas when compared with their free drug counterparts, because of their intrinsic affinity for the liver and extended lifespan. This work examined the suitability o f a liposomal irinotecan formulation in the treatment of colorectal liver metastases. Irinotecan was encapsulated in DSPC/cholesterol liposomes using an ionophore-generated transmembrane proton gradient. After i.v. injection, liposomal drug was eliminated from the plasma much more slowly than free drag, and after 1 h circulating levels of liposome-associated drug were 10 fold greater. In addition, high-performance liquid chromography analysis of plasma samples revealed that liposome-associated irinotecan is protected from inactivating hydrolysis with > 80 % remaining in the active lactone form up to 24 h after administration. These improved pharmacokinetics observed for the liposomal drug were associated with increased efficacy in both solid tumour and orthotopic human models of colorectal metastases. Using a model (LS180) of colorectal metastases in SCID/RAG2M mice it was demonstrated that liposome-encapsulated drug was more effective at arresting tumour growth than was free drug. Further, in the human model of colorectal liver metastases (LS174T), liposomal irinotecan substantially increase life span relative to free drug with all members surviving long-term (75 days) as compared to a survival time of 30 and 50 days for the control and free drug treated groups. These results illustrate that liposomal encapsulation can substantially enhance the therapeutic activity of irinotecan, and emphasize the potential for liposomal irinotecan in the treatment of liver metastases.

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