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Elucidating Chemotherapeutic Drug Transport of Different Agents and of Antiangiogenic Therapy against a Brain Tumor

Davis Yohanes Arifin, Chemical and Pharmaceutical Engineering, Singapore-MIT Alliance, 4 Engineering Drive 3, Singapore 117576, Singapore, Singapore, Kam Yiu Timothy Lee, Brain and Spine Clinic, Gleneagles Hospital, 6A Napier Road, Singapore 258500, Singapore, Singapore, Chi-Hwa Wang, Chemical and Biomolecular Engineering, National University of Singapore, WS2-06-15, 4 Engineering Drive3, Singapore, 118431, Singapore, and Kenneth A. Smith, Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139.

Treatment against brain tumors usually involves surgical removal, chemotherapy, and radiotherapy. For chemotherapy, the first FDA-approved treatment is the Gliadel wafer [1]. This wafer is able to provide sustained release of carmustine locally to the remnant tumor. However, results have been highly variable due to the significant loss of carmustine to blood capillaries, resulting in a limited (millimeter) penetration distance [2]. This suggests that the cause of poor performance for this drug delivery device is related to the drug transport mechanism in the tumor tissue, not the local delivery concept.

The above example shows how drug transport properties are often overlooked. Though the drug is clinically effective against the tumor tissue, insufficient penetration will yield an ineffective therapy. Many new chemotherapeutic agents have been developed and might also be administered by local polymeric delivery. These drugs include paclitaxel, 4-hydroperoxy-cyclophosphamide (4-HC), 5-fluoroacil (5-FU), and methotrexate (MTX). There is a need to analyze their transport mechanisms in brain tumor. A related issue is the use of antiangiogenic agents to enhance the performance of chemotherapy. It has been hypothesized that this therapy could renormalize the tumor vasculature and, hence, improves the localization of the drug by decreasing convection [3]. However, this concept needs to be further explored for the case of brain tumor.

To address these questions, a simulation analysis has been performed. This analysis has the advantages of being able to decouple and isolate different aspects of drug transport. Thus, we are able to elucidate (a) which chemotherapeutic agent is more favorable from a transport perspective, and (b) how the antiangiogenic agents could enhance the overall therapy. In addition, recent advances in patient-specific imaging techniques, e.g. magnetic resonance images (MRI) and computed tomography (CT), allow the extraction of brain tissue geometry as well as precise tumor size and location. Here, the simulation utilizes a three-dimensional geometry constructed from MRI of a brain tumor patient so that the possible effect of brain fluid flow can be examined.

[1] H. Brem and P. Gabikian. Biodegradable polymer implants to treat brain tumors Journal of Controlled Release 74 (2001) 63-67.

[2] A.B. Fleming and W.M. Saltzman. Pharmacokinetics of the carmustine implant. Clinical Pharmacokinetics 41 (2002) 403-419.

[3] R.K. Jain, R.T. Tong, L.L. Munn. Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: Insights from a mathematical model. Cancer Research 67 (2007) 2729-2735.