A Theoretical Model for Intraperitoneal Delivery of Cisplatin and the Effect of Hyperthermia on Drug Penetration Distance

Abstract

A theoretical model for the intraperitoneal (i.p.) delivery of cisplatin and heat to tumor metastases in tissues adjacent to the peritoneal cavity is presented. The penetration distance (the depth to which drug diffuses directly from the cavity into tissues) is predicted to be on the order of 0.5 mm. The model shows that exchange with the microvasculature has more effect than cellular uptake in limiting the penetration distance. Possible effects of hyperthermia are simulated, including increased cell uptake of drug, increased cell kill at a given level of intracellular drug, and decreased microvascular density. The model suggests that the experimental finding of elevated intracellular platinum levels up to a depth of 3 to 5 mm when drug is delivered i.p. by a heated infusion solution is due to penetration of heat to this distance, causing increased cell uptake of drug. Beyond a depth of about 0.5 mm, the drug is delivered mainly through the circulation. Use of sodium thiosulfate to deactivate systemic cisplatin may therefore be counterproductive when heat is delivered locally. The model suggests that i.p. delivery of heat, combined with systemic delivery of drug, may be as effective as i.p. delivery of heat and drug.

Keywords

• Intraperitoneal delivery
• chemotherapy
• cisplatin
• hyperthermia
• continuous hyperthermic peritoneal perfusion