Numerical simulation of solid tumor blood perfusion and drug delivery during the “vascular normalization window” with antiangiogenic therapy

This Article is provided by the Brunel Open Access Publishing Fund - Copyright @ 2011 Hindawi PublishingTo investigate the influence of vascular normalization on solid tumor blood perfusion and drug delivery, we used the generated blood vessel network for simulations. Considering the hemodynamic parameters changing after antiangiogenic therapies, the results show that the interstitial fluid pressure (IFP) in tumor tissue domain decreases while the pressure gradient increases during the normalization window. The decreased IFP results in more efficient delivery of conventional drugs to the targeted cancer cells. The outcome of therapies will improve if the antiangiogenic therapies and conventional therapies are carefully scheduled

Anti-angiogenic drug scheduling optimisation with application to colorectal cancer

Bevacizumab (bvz) is a first choice anti-angiogenic drug in oncology and is primarily administered in combination with chemotherapy. It has been hypothesized that anti-angiogenic drugs enhance efficacy of cytotoxic drugs by “normalizing” abnormal tumor vessels and improving drug penetration. Nevertheless, the clinical relevance of this phenomenon is still unclear with several studies over recent years suggesting an opposing relationship. Herein, we sought to develop a new computational tool to interrogate anti-angiogenic drug scheduling with particular application in the setting of colorectal cancer (CRC). Specifically, we have employed a mathematical model of vascular tumour growth which interrogates the impact of anti-angiogenic treatment and chemotherapeutic treatment on tumour volume. Model predictions were validated using CRC xenografts which underwent treatment with a clinically relevant combinatorial anti-angiogenic regimen. Bayesian model selection revealed the most appropriate term for capturing the effect of treatments on the tumour size, and provided insights into a switch-like dependence of FOLFOX delivery on the tumour vasculature. Our experimental data and mathematical model suggest that delivering chemotherapy prior to bvz may be optimal in the colorectal cancer setting

Tumor vasculature and microenvironment during progression and treatment : insights from optical microscopy

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, February 2010.Vita. Cataloged from PDF version of thesis.Includes bibliographical references.In addition to cancer cells, solid tumors consist of a variety of cell types and tissues defining a complex microenvironment that influences disease progression and response to therapy. To fully characterize and probe the tumor microenvironment, new tools are needed to quantitatively assess microanatomical and physiological changes during tumor growth and treatment. Particularly important, is the metabolic microenvironment defined in tumors by hypoxia (low p02) and acidity (low pH). These parameters have been shown to influence response to radiation therapy and chemotherapy. However, very little is known about spatio-temporal changes in p02 and pH during tumor progression and therapy. By modifying the technique of intravital multiphoton microscopy (MPM) to perform phosphorescence quenching microscopy, I developed a non-invasive method to quantify oxygen tension (p02) in living tissue at high three-dimensional resolution. To probe functional changes in the metabolic microenvironment, I measured in vivo P02 during tumor growth and antiangiogenic (vascular targeted) treatment in preclinical tumor models. Nanotechnology is rapidly emerging as an important source of biocompatible tools that may shape the future of medical practice. Fluorescent semiconductor nanocrystals (NCs), also known as quantum dots, are a powerful tool for biological imaging, cellular targeting and molecular sensing.(cont.) I adapted novel fluorescence resonance energy transfer (FRET) -based nanocrystal (NC) biosensors for use with MPM to qualitatively measure in vivo extracellular pH in tumors at high-resolution. While intravital multiphoton microscopy demonstrates utility and adaptability in the study of cancer and response to therapy, the requisite high numerical aperture and exogenous contrast agents result in a limited capacity to investigate substantial tissue volumes or probe dynamic changes repeatedly over prolonged periods. By applying optical frequency domain imaging (OFDI) as an intravital microscopic tool, the technical limitations of multiphoton microscopy can be circumvented providing unprecedented access to previously unexplored, critically important aspects of tumor biology. Using entirely intrinsic mechanisms of contrast within murine tumor models, OFDI is able to simultaneously, rapidly, and repeatedly probe the microvasculature, lymphatic vessels, and tissue microstructure and composition over large volumes. Using OFDI-based techniques, measurements of tumor angiogenesis, lymphangiogenesis, tissue viability and both vascular and cellular responses to therapy were demonstrated, thereby highlighting the potential of OFDI to facilitate the exploration of pathophysiological processes and the evaluation of treatment strategies.by Ryan M. Lanning.Ph.D