Computational Modeling

Computational modeling of multi-scale systems, frequently linking time-dependent effects at subcellular, cellular, tumor or organ, and systemic level, facilitates interrogation of these systems and allows estimation of parameters that cannot be measured directly. A project in this area that we have completed is as follows.

Metastatic tumors located in the peritoneal cavity are a significant source of morbidity and mortality. Intraperitoneal chemotherapy (IPC) has the potential to provide up to 1000-fold higher CXT to tumor cells when compared to systemic treatment. We evaluated IPC by development of a multiscale model to predict spatiotemporal changes in drug levels in peritoneal tumors in mice. A model comprising 4 anatomical scales (peritoneal cavity,
peritoneal tumor, cell/biomatrix, whole organism), plus space and time was developed and expressed in ordinary and partial differential equations that together account for (a) physical resistance due to ECM proteins and tumor cells, (b) drug interaction with biomatrices, (c)
reduction in diffusible drug due to binding to cells and ECM proteins, (d) tissue-specific properties (e.g., differences in lymphatic drainage of tumors and adjacent normal tissues), and (e) spatial-dependent and intratumoral heterogeneities (blood vessel distribution and blood
flow, cell density, P interstitial ). Heterogeneity was achieved by varying the model parameter values at different locations within the tumor, and computation of spatiotemporal changes in tumor drug levels by coupling the pharmacokinetics in peritoneal fluid and plasma with the macroscopic
and microscopic transport in tumors. This model was validated using paclitaxel micellar solution in mice and is in use to translate findings for IPC in mice to expectations in human patients.

References:

Tsai M, Lu Z, Wang J, Yeh TK, Wientjes MG, Au JL. Effects of carrier on disposition and antitumor activity of intraperitoneal paclitaxel. Pharm Res 2007; 24:1691-1701.

Lu Z, Tsai M, Lu D, Wang J, Wientjes MG, Au JL. Tumor penetrating microparticles for intraperitoneal therapy of ovarian cancer. J Pharmacol Exp Ther 2008; 327:673-682.

Au JL, Guo P, Gao Y, Lu Z, Wientjes MG, Tsai M, Wientjes MG. Multiscale tumor spatiokinetic model for intraperitoneal therapy. AAPS J 2014; 16:424-439. PMCID: PMC4012049.

Lu Z, Tsai M, Wang J, Cole DJ, Wientjes MG, Au JL. Activity of drug-loaded tumor-penetrating microparticles in peritoneal pancreatic tumors. Curr Cancer Drug Targets 2013; 14:70-78.

Tsai M, Lu Z, Wientjes MG, Au JL. Paclitaxel-loaded polymeric microparticles: Quantitative relationships between in vitro drug release rate and in vivo pharmacodynamics. J Control Release 2013; 172:737-744. PMCID: PMC3881265.

Wang J, Lu Z, Yeung BZ, Wientjes MG, Cole DJ, Au JL. Tumor priming enhances siRNA delivery and transfection in intraperitoneal tumors. J Control Release 2014; 178:79-85.

Lu Z, Wang J, Wientjes MG, Au JL. Intraperitoneal therapy for peritoneal cancer. Future Oncol 2010; 6:1625-1641.

Lu Z, Wientjes MG, Au JL. Development of drug-loaded particles for intraperitoneal therapy. In: P.Ceelen W, Levine E, editors. Intraperitoneal Cancer Therapy: Principles and Practice. CRC Press;  2015. p 331-344.