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Mathematical Modeling and Optimization of Drug Delivery from Intratumorally Injected Microspheres

¹ The Otto Loewi Minerva Center for Cellular and Molecular Neurobiology, Department of Neurobiology, The Hebrew University, Jerusalem, Israel; ² Research and Development Initiative, Teva Pharmaceutical Industries Ltd., Petah-Tiqva, Israel; ³ West Pharmaceutical Services Drug Delivery and Clinical Research Centre Ltd., Albert Einstein Centre, Nottingham Science and Technology Park, University Boulevard Nottingham, Nothingham, United Kingdom; and ⁴ Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts

Requests for reprints: Abraham Rami Tzafriri, Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Massachusetts Institute of Technology, Room 16-343, Cambridge, MA 02139. Phone: 617-252-1655; Fax: 617-253-2514; E-mail: ramitz{at}mit.edu.

Purpose: Paclitaxel is a highly promising phase-sensitive antitumor drug that could conceivably be improved by extended lower dosing as opposed to intermittent higher dosing. Although intratumoral delivery of paclitaxel to the whole tumor at different loads and rates has already been achieved, determining an optimal release mode of paclitaxel for tumor eradication remains difficult. This study set out to rationally design such an optimal microsphere release mode based on mathematical modeling.

Experimental Design: A computational reaction-diffusion framework was used to model drug release from intratumorally injected microspheres, drug transport and binding in tumor interstitum, and drug clearance by microvasculature and intracellular uptake and binding.

Results: Numerical simulations suggest that interstitial drug concentration is characterized by a fast spatially inhomogeneous rise phase, during which interstitial and intracellular binding sites are saturated, followed by a slow spatially homogeneous phase that is governed by the rate of drug release from microspheres. For zero-order drug release, the slow phase corresponds to a plateau drug concentration that is proportional to the ratio of the rate of blood clearance of drug to the rate of drug release from microspheres. Consequently, increasing the duration of intratumoral drug release extends the duration of cell exposure to the drug but lowers the plateau drug concentration. This tradeoff implies that intratumoral drug release can be designed to optimize tumor cell kill. Synthesizing our modeling predictions with published dose-response data, we propose an optimal protocol for the delivery of paclitaxel-loaded microspheres to small solid tumors.

Key Words: Breast Cancer • Computational methods • Adjuvant chemotherapy • Nonbiological delivery systems