Abstract
We describe here new technology that enables noninvasive imaging of therapeutic functional normalization of tumor blood vessels by antiangiogenic agents. Noninvasive variable-magnification in vivo-fluorescence imaging as well as fluorescence tomography was used to visualize functional vessel normalization. Changes in the same vessel before and after drug treatment were imaged with high resolution in real time. Differences in vascular responses to the mTOR inhibitor rapamycin and to an anti-VEGF antibody were functionally imaged. Tumor vessel normalization was shown by significantly reduced leakiness and subsequent improved tumor delivery of Paclitaxel-BODPY as well as by normalized morphology. The tumor vascular pool agent, AngioSense(750), was retained only in tumors after either anti-VEGF antibody or rapamycin treatment, as visualized by noninvasive fluorescence tomography. The antiangiogenic therapy normalized vessels, which significantly enhanced the antitumor efficacy of paclitaxel because of increased drug penetration throughout the tumor. The optical imaging technology described here is thus a powerful, noninvasive, time-course imaging tool of functional tumor vessel normalization and its therapeutic consequences.
Highlights
Tumor vessel normalization has been proposed as the main mechanism of antitumor efficacy of vascular targeting agents [1, 2]
VEGF production was negligible in MCF-7 and SK-BR3 luminal breast cancer cells, basal MDA-MD-231 cells produced a high level of VEGF
The combined imaging technologies used in this study have provided a more complete understanding of mechanisms of functional vascular response to antiangiogenesis agents and how to maximize their antitumor efficacy
Summary
Tumor vessel normalization has been proposed as the main mechanism of antitumor efficacy of vascular targeting agents [1, 2]. Vascular normalization in the tumor can allow increased drug delivery to the tumor. Normal tumor vasculature may inhibit the shedding of cancer cells into the circulation, a critical step for metastasis [1]. VEGF promotes the survival and proliferation of endothelial cells [1]. VEGF is overexpressed in the majority of solid tumors, and it was thought that blocking VEGF might revert abnormal tumor vascularity to a more normal state of function [1, 3]. Jain [1] initially showed that blockage of VEGF eliminated the immature and leaky vessels of transplanted tumors in mice and remodeled the remaining vasculature.
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