POWRE: Mathematical Models for Optimization of Anti-Cancer Chemotherapy

该项目的总体目标是将工程方法应用于质量传递建模，以优化几种常用抗癌药物向肿瘤细胞的输送问题。这些模型将为治疗方案的选择提供合理的依据。除了通过微血管和组织的运输外，还将考虑细胞内流的动力学。由于不同药物之间的转运性质差异很大，因此模型专门针对药物美法兰、甲氨蝶呤、顺铂、阿霉素和5-氟尿嘧啶，这些药物都被广泛使用。必要时，将考虑药物在隔室内的空间梯度。将开发诸如扩散和对流等过程的输运方程。所有输运参数的值均取自生物学文献中的数据。所得到的常微分方程组或偏微分方程组将用数值方法求解。三个具体目标是：(1)针对血管化良好和血管化不良的肿瘤，确定美法兰、甲氨蝶呤和5-氟尿嘧啶药物的最佳静脉输注方案；(2)研究自发性间歇性血流以及人工诱导肿瘤血流改变对美法兰、甲氨蝶呤、阿霉素和5-氟尿嘧啶给药的影响。将研究时变血流与药物捕获、药物长半衰期或药物滞留增强等现象之间的关系；(3)建立空间分布模型，比较顺铂在腹腔或静脉给药时对腹腔肿瘤（如卵巢或结直肠）的细胞递送情况。这些模型将用于检查腹膜内化疗背后的理论基础。PI的职业目标之一是应用理论原理和建模来改善癌症治疗。她强烈认为有必要更好地了解药物输送，理论研究落后于实验工作和新疗法的开发。她最近休了两次产假，中断了私家侦探在这方面的工作。在她的职业生涯中，这项power资助将帮助她重新获得作为该领域独立研究人员的动力，并在标准的联邦资助计划中具有竞争力。

The overall objective of the project is to apply engineering methods for modeling mass transport to the problem of optimizing delivery of several commonly used anti-cancer drugs to tumor cells. The models will provide a rational basis for selecting among treatment options. An important feature will be consideration of the kinetics of cellular influx in addition to transport across microvessels and through tissue. Because of the wide variation in transport properties between different drugs, the models are specialized to the drugs melphalan, methotrexate, cisplatin, doxorubicin and 5-fluorouracil, all of which are widely used. Where necessary, spatial gradients of the drug within the compartments will be accounted for. Transport equations for processes such as diffusion and convection within and between the body compartments will be developed. All values of transport parameters will be taken from data in the biological literature. The resulting systems of ordinary or partial differential equations will be solved numerically.The three specific objectives are: (1) to determine the optimal schedule of intravenous infusion for the drugs melphalan, methotrexate and 5-fluorouracil, for both well-vascularized and poorly vascularized tumors; (2) to study the effects of spontaneously occurring intermittent flow, as well as artificially induced alterations in tumor blood flow, on the delivery of melphalan, methotrexate, doxorubicin and5-fluorouracil. Connections between time-varying blood flow and such phenomena as drug trapping, long tumor half-life of drug, or enhanced retention will be investigated; (3) to develop spatially distributed models to compare cellular delivery of the drug cisplatin to abdominal tumors (such as ovarian or colorectal) when administered intra-peritoneally or intravenously. These models will be used to examine the theoreticalrationale behind intra-peritoneal chemotherapy.One of the PI's career objectives is to apply theoretical principles and modeling to improve cancer therapies. She feels strongly that there is a need for a better understanding of drug delivery, and that theoretical studies have lagged behind experimental work and development of new therapies. The PI's work in this area was interrupted when she recently took two maternity leave. This POWRE grant at this point in her career will help her to regain momentum as an independent researcher in this area and to become competitive for standrad federal grant programs.