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Murine Model for Non-invasive Imaging to Detect and Monitor Ovarian Cancer Recurrence
Published on: November 2, 2014
Spatial Modeling of Drug Delivery Routes for Treatment of Disseminated Ovarian Cancer
Kimberly Kanigel Winner1,2, Mara P Steinkamp3,4, Rebecca J Lee4
1Department of Biology, University of New Mexico, Albuquerque, NM USA.
Abstract:
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 or intraperitoneal 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 intravenously or intraperitoneally, as well as the subsequent exchange into the other delivery volume as a secondary route. By accounting for these dynamics, the model revealed that intraperitoneal 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% to 10%, also show enhanced drug delivery via the intraperitoneal 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. The use of both delivery routes may provide the best total coverage of tumors, depending on their size and vascularity.
Insights
Intraperitoneal infusion significantly enhances drug delivery to microscopic ovarian cancer tumors compared to intravenous administration. This route is superior for both small-molecule and antibody therapies targeting residual disease after surgery.
Area of Science:
- Oncology
- Pharmacology
- Computational Biology
Background:
- Ovarian cancer metastasis is often confined to the peritoneum, leaving microscopic disease after surgery.
- Targeting residual peritoneal disease requires effective drug delivery strategies beyond primary tumor removal.
- Intravenous (IV) and intraperitoneal (IP) infusion are potential routes for delivering therapeutics to peritoneal carcinomatosis.
Purpose of the Study:
- To compare the tumor penetration of small-molecule (cisplatin) and antibody (pertuzumab) drugs delivered via IV versus IP routes.
- To evaluate drug delivery dynamics considering primary and secondary routes of administration.
- To assess the efficacy of IP infusion for microscopic, avascular tumors and small, vascularized tumors in the peritoneum.
Main Methods:
- Utilized a cellular Potts model to simulate drug penetration into tumors.
- Modeled both IV and IP administration routes, including drug exchange between peritoneal cavity and systemic circulation.
- Integrated in silico and in vivo methods to assess antibody tumor entry.
Main Results:
- IP infusion demonstrated markedly superior delivery of both small-molecule and antibody therapies to microscopic, avascular tumors.
- IP delivery also enhanced drug penetration in small tumors (2-10% vascularity), despite potential drug sequestration by tumor vasculature.
- Antibody delivery optimization is crucial for the efficacy of biologic therapies.
Conclusions:
- Intraperitoneal infusion is the preferred route for delivering therapeutics to microscopic peritoneal ovarian cancer disease.
- Combining IV and IP routes may offer optimal tumor coverage depending on tumor size and vascularity.
- Computational modeling aids in optimizing drug delivery strategies for ovarian cancer treatment.
