POWRE: Mathematical Models for Optimization of Anti-Cancer Chemotherapy

该项目的总体目标是将模拟质量传输的工程方法应用于优化几种常用抗癌药物向肿瘤细胞的输送问题。该模型将为治疗方案的选择提供合理的依据。一个重要的特点是除了通过微血管和组织运输外，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，模型专门针对马法兰、甲氨蝶呤、顺铂、阿霉素和5-氟尿嘧啶等药物，所有这些药物都得到了广泛的应用。如有需要，将考虑隔室内药物的空间梯度。将建立人体舱室内部和之间的扩散和对流等过程的传输方程。传输参数的所有值都将从生物学文献中的数据中获取。三个具体目标是：(1)确定药物马法兰、甲氨蝶呤和5-氟尿嘧啶的最佳静脉输注方案；(2)研究自发的间歇性血流以及人为诱导的肿瘤血流改变对马法兰、甲氨蝶呤、阿霉素和5-氟尿嘧啶的输送的影响。将研究时变血流与药物捕获、长肿瘤半衰期或增强滞留等现象之间的联系；(3)开发空间分布的模型，以比较顺铂的细胞给药与腹部肿瘤(如卵巢或结直肠)在腹膜内或静脉给药时的差异。这些模型将被用来检验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模型来改进癌症治疗。她强烈地认为，有必要更好地了解药物输送，而理论研究已经落后于实验工作和新疗法的开发。当她最近休了两次产假时，私家侦探在这方面的工作被中断了。在她职业生涯的这个时候，这笔POWRE拨款将帮助她在这一领域重新获得作为独立研究员的势头，并在标准的联邦拨款项目中变得有竞争力。

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.