From Modeling To In Vivo Tracking: A New Platform For The Design Of Delivery Vectors That Exploit Tumor Microfluidics

Within the field of oncology, a new perspective has recently emerged, where cancer treatment is viewed as a transport problem that can be addressed with nanomedicine. In fact, because of the unique local conditions of transport and microfluidics in the tumor environment, microparticles and nanoparticles that exhibit specific geometries have proven advantageous to enhance preferential delivery of drugs to tumor tissue. However, the theoretical and modeling backbone required to describe, understand, and manipulate such flow-specific design advantages is currently limited to semi-analytical methods. These methods have proven successful in explaining the power and efficacy of geometrical targeting. Nevertheless, since such approaches have limited predictive power, they are not ideal tools for the systematic development of a new class of efficient and customizable delivery vectors. In this work, we propose an innovative and rational approach for understanding the delivery of micro- and nanotherapeutics to cancer tissue by modeling transport in tumor microvessels. Specifically, we focus on the differences between healthy and tumor vasculature that affect fluid mechanics. We tackle this problem with a combined experimental and modeling approach. Our model is based on a Navier-Stokes solver for complex fluids based on dissipative particle dynamics (DPD) simulations, where blood constituents (i.e. red blood cells, neutrophils, platelets) and microparticles/nanoparticles interact through forces or collisions of different nature. The model is calibrated and validated with real-time flow chamber experiments. With this modeling approach, complex geometrical structures and interactions can be implemented with high computational efficiency. We use our innovative platform to analyze the differences in margination of micro- and nanostructures in tumor versus healthy microvasculature. We address the fundamental structural differences between tumor vessels and healthy vessels by systematically reconstructing the characteristic patterns of endothelial fenestrations, radius variability, and blood flow. Our parametric analysis is then compared with in vivo tracking studies in animal models. Our approach and results open the way to the understanding and rational design of a new class of nanoparticle and microparticle-based delivery strategies that exploit tumor-specific microfluidics. Citation Format: Sara Nizzero, Sergey Litvinov, Dmitry Alexeev, Athena Economides, Enrica De Rosa, Joy Wolfram, Petros Koumoutsakos, Mauro Ferrari. From modeling to in vivo tracking: a new platform for the design of delivery vectors that exploit tumor microfluidics. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B04.