Tzafriri Abraham Rami, Lerner Elyakum Itzhak, Flashner-Barak Moshe, Hinchcliffe Michael, Ratner Eli, Parnas Hanna
The Otto Loewi Minerva Center for Cellular and Molecular Neurobiology, Department of Neurobiology, The Hebrew University, Jerusalem, Israel.
Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):826-34.
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.
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.
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.
紫杉醇是一种极具前景的时相敏感型抗肿瘤药物，理论上通过延长低剂量给药而非间歇性高剂量给药可能会有所改善。尽管已经实现了以不同载量和速率将紫杉醇瘤内递送至整个肿瘤，但确定用于根除肿瘤的紫杉醇最佳释放模式仍然困难。本研究旨在基于数学建模合理设计这样一种最佳微球释放模式。
使用一个计算反应扩散框架来模拟瘤内注射微球的药物释放、药物在肿瘤间质中的转运和结合，以及通过微血管的药物清除和细胞内摄取与结合。
数值模拟表明，间质药物浓度的特征是快速的空间不均匀上升阶段，在此期间间质和细胞内结合位点饱和，随后是由微球药物释放速率控制的缓慢空间均匀阶段。对于零级药物释放，缓慢阶段对应于一个平台药物浓度，该浓度与药物的血液清除速率与微球药物释放速率之比成正比。因此，增加瘤内药物释放持续时间会延长细胞暴露于药物的持续时间，但会降低平台药物浓度。这种权衡意味着可以设计瘤内药物释放以优化肿瘤细胞杀伤。将我们的建模预测与已发表的剂量反应数据相结合，我们提出了一种将载紫杉醇微球递送至小实体瘤的最佳方案。
