This is a resubmission of an R03 application to National Institute of Biomedical Imaging and Bioengineering (NIBIB). We have recently developed a minimally invasive, biosensor-based, diagnostic surgical procedure for measuring interstitial fluid pressure (IFP) in cancer. We propose to apply this new diagnostic technique to elucidate the role of contractile pericytes in IFP and transcapillary transport of nanoparticles in tumors. Similar to isometric contraction of skeletal muscle, neovascular pericytes generate contractile forces not only on the vessel walls but also on interstitial fluid entrapped within extracellular fibers, referred to as tissue gel. We will test whether interstitial fluid pressure in cancer can be reduced by interfering with pericytes to improve the convection of nanoparticle based anti-cancer drugs. We will test whether inhibition of pericytes results in a decrease in interstitial fluid pressure due to decreasing compressive contractile forces elicited by pericytes. We will test whether pericyte-NG2 proteoglycan inhibition lowers IFP and improves convection from the plasma to the interstitial space. We will quantify transcapillary transport by using nanoparticles as tracers. We anticipate finding a higher transcapillary convection of nanoparticles (simulating high molecular weight anti-cancer drugs) and lower interstitial fluid pressure in breast tumors when pericytes are inhibited. By combining skills and disciplines in bioengineering, clinical physiology and microvascular sciences this project will transform our biosensor-based diagnostic procedure into a tangible diagnostic tool for cancer patients. The use of ultraminiature transducer-tipped catheters as cancer interstitial fluid pressure biosensors is innovative in light of novel use of biosensors portfolio of National Institute of Biomedical Imaging and Bioengineering. The role of compressive forces generated by pericytes within breast cancer stroma has never been investigated;which makes this proposal innovative in shedding light on the etiology of interstitial hypertension, a significant clinical problem in breast cancer therapy in terms of drug delivery.
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