Improving transcapillary transport by reducing interstitial fluid pressure

描述(由申请人提供)：这是一份R03申请的重新提交给国家生物医学成像和生物工程研究所(NIBIB)。我们最近开发了一种微创、基于生物传感器的诊断性外科手术程序，用于测量癌症患者的间质液体压力(IFP)。我们建议应用这一新的诊断技术来阐明收缩周细胞在IFP和肿瘤中纳米颗粒的跨毛细血管运输中的作用。与骨骼肌的等长收缩相似，新生血管周细胞不仅在血管壁上产生收缩力量，而且在细胞外纤维内的间质液体上产生收缩力量，称为组织凝胶。我们将测试是否可以通过干扰周细胞来降低肿瘤的间质液体压力，以改善基于纳米颗粒的抗癌药物的对流。我们将测试抑制周细胞是否会由于周细胞引起的压缩收缩力量的减少而导致间质流体压力的降低。我们将测试周细胞-NG2蛋白多糖抑制是否降低IFP并改善从血浆到间质空间的对流。我们将通过使用纳米颗粒作为示踪剂来量化跨毛细管的传输。我们预计，当周细胞受到抑制时，乳腺肿瘤中会发现更高的纳米颗粒(模拟高分子量抗癌药物)的跨毛细血管对流，以及更低的间质液体压力。通过结合生物工程、临床生理学和微血管科学的技能和学科，该项目将把我们基于生物传感器的诊断程序转变为癌症患者的有形诊断工具。根据美国国家生物医学成像和生物工程研究所生物传感器组合的新用途，使用超小型换能器尖端导管作为癌症间质流体压力生物传感器是一种创新。周细胞在乳腺癌间质中产生的压力的作用从未被研究过；这使得这一提议在揭示间质性高血压的病因方面具有创新性，从药物输送的角度来看，间质性高血压是乳腺癌治疗中的一个重大临床问题。

DESCRIPTION (provided by applicant): 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.