Abstract B67: In silico study of drug active transport via macrophages in tumor chemotherapy
Authors: Wu Min , Frieboes Hermann B. , Lowengrub John 
Published: June 2012

Abstract
This work focuses on the study of active transport of nanoparticles loaded with drug in cancer chemotherapy to achieve a more homogeneous distribution of chemotherapeutics in the tumor inner regions. These regions are known for insufficient functional lymphatic vessels as well as blood vessels with enhanced permeability contributing to near zero interstitial fluid velocity. Moreover, due to the hypertension caused by elevated interstitial pressure in the tumor inner regions and the functional lymphatic vessels near the exterior margin of the tumor, the interstitial fluid velocity directs towards the outside of the tumor. On the other hand, the effective diffusion distance of nanoparticles may be decreased by binding with the extracellular matrix. As a result, the delivery of nanoparticles by convection and diffusion is hindered. However, it is known that inner tumor regions have lower oxygen levels compared to the tissues near the vasculature. Current experimental research is focusing on the idea to deliver nanoparticles by conjugating them to macrophages, which are known to heavily infiltrate tumor hypoxic regions. This may achieve higher drug concentrations since macrophages can travel into tumor inner regions by chemotaxis.
We launched our in silico experiment on a two-dimensional 4 mm square area of tissue incorporating a tumor angiogenesis model describing the distribution of vessel permeability and radius, blood flow rate, and hematocrit levels along the vessel system. The model calculates the corresponding oxygen levels, extracellular matrix density, interstitial pressure and tumor cell pressure fields by simulating viable and necrotic tumor tissue, diffusion of small molecules (cell nutrients, oxygen, and drug), and conservation of mass. Mass conservation equations describe growth (proliferation as a function of total cycling cells) and death from drug cytotoxicity (apoptosis as a function of cell sensitivity and cycling cells). These are combined with diffusion of small molecules to a reaction-diffusion equation. Rate constants for proliferation and apoptosis are modified by functions that represent their dependence on cell nutrients and oxygen (proliferation) and drug concentration (death), along with a dependence on spatial diffusion of these substances.
We fully simulate the extravasation of macrophages from the vasculature into the tissue, the movement of macrophages competing with the interstitial fluid velocity, the release of nanoparticles into the tissue, and the effect on tumor apoptosis. The macrophages-particle treatment protects the nanoparticles from binding to the extracellular matrix and is thus able to overcome the biophysical barriers in traditional nanoparticle delivery, with the macrophages moving into the tumor with elevated cell mobility. At the start, we observe that the macrophages form a ring around the tumor margin by balancing the interstitial pressure and oxygen gradients. Inside the tumor, the macrophages are more likely to cluster in the hypoxic region. However, tumor apoptosis due to the nanomedicine may lead to drastic changes in tumor size and oxygen levels, as well as an elevation of the interstitial pressure gradient which may convect the macrophages away from the tumor boundary (active region) or push the macrophages away from the hypoxic / necrotic area before fully unloading the drug. This finding predicts a physical resistance to the treatment.
We conclude that to reduce the potential resistance of macrophage-nanoparticle treatments, the strength of the nanomedicine needs to be in an optimal range to shrink the tumor while maintaining a steady environment for the macrophages lodged in the hypoxic regions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B67.