Spatial modeling of drug delivery routes for treatment of disseminated ovarian cancer

In ovarian cancer, metastasis is typically confined to the peritoneum. Surgical removal of the primary tumor and macroscopic secondary tumors is a common practice, but more effective strategies are needed to target microscopic spheroids persisting in the peritoneal fluid after debulking surgery. To treat this residual disease, therapeutic agents can be administered by either intravenous (IV) or intraperitoneal (IP) infusion. Here, we describe the use of a cellular Potts model to compare tumor penetration of two classes of drugs (cisplatin and pertuzumab) when delivered by these two alternative routes. The model considers the primary route when the drug is administered either IV or IP, as well as the subsequent exchange into the other delivery volume as a secondary route. By accounting for these dynamics, the model revealed that IP infusion is the markedly superior route for delivery of both small molecule and antibody therapies into microscopic, avascular tumors typical of patients with ascites. Small tumors attached to peritoneal organs, with vascularity ranging from 2-10%, also show enhanced drug delivery via the IP route, even though tumor vessels can act as sinks during the dissemination of small molecules. Furthermore, we assessed the ability of the antibody to enter the tumor by in silico and in vivo methods and suggest that optimization of antibody delivery is an important criterion underlying the efficacy of these and other biologics. Use of both delivery routes may provide the best total coverage of tumors, depending on their size and vascularity.

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