Mathematical Modeling and Optimization of Drug Delivery from Intratumorally Injected Microspheres
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, deter...
Gespeichert in:
Veröffentlicht in: | Clinical cancer research 2005-01, Vol.11 (2), p.826-834 |
---|---|
Hauptverfasser: | , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | 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. |
---|---|
ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.826.11.2 |