Improving transcapillary transport by reducing interstitial fluid pressure

通过降低间质液压力改善跨毛细血管运输

• 批准号: 7387153
• 负责人: UGUR OZERDEM
• 金额: $ 9.47万
• 依托单位: LA JOLLA BIOENGINEERING INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-05 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7387153
• 关键词: Adhesions; Antineoplastic Agents; Area; Basement membrane; Biological Assay; Biomedical Engineering; Biosensor; Blood; Blood Vessels; Blood capillaries; Bone Marrow; C57BL/6 Mouse; CSPG4 gene; Caliber; Cancer Patient; Catheters; Cells; Clinical; Collagen; Condition; Contracts; Convection; Cutaneous Melanoma; Development; Diagnostic; Diagnostic Procedure; Diffusion; Discipline; Drug Delivery Systems; Drug Transport; Elements; Endothelial Cells; Endothelium; Etiology; Exhibits; Extracellular Matrix; Face; Fiber; Gel; Generations; Ground Substance; Hypertension; In Vitro; Institutes; Intercellular Fluid; Invasive; Investigation; Investments; Isometric Contraction; Isometric Exercise; Isotonic Contraction; Isotonic Exercise; Kidney; Knock-out; Knockout Mice; Label; Lead; Length; Lifting; Light; Liquid substance; Lymphangiogenesis; Malignant Neoplasms; Mammary Neoplasms; Measures; Mechanics; Methods; Modeling; Molecular Weight; Monoclonal Antibodies; Mus; Muscle Fibers; Myocardium; NG2 antigen; Normal tissue morphology; Numbers; Operative Surgical Procedures; Pathologic Neovascularization; Peptides; Pericytes; Phage Display; Pharmaceutical Preparations; Phase; Physiology; Plasma; Principal Investigator; Property; Relative (related person); Role; Rubber; Science; Simulate; Site; Skeletal Muscle; Smooth Muscle; Stream; Surface; Testing; Therapeutic; Therapeutic Agents; Tissues; Tracer; Transducers; Transgenic Organisms; Treatment outcome; Tumor-Associated Vasculature; Water; Week; Weight; Wild Type Mouse; angiogenesis; base; bioimaging; cancer therapy; capillary; density; enhanced green fluorescent protein; extracellular; fluid flow; human tissue; improved; innovation; interstitial; malignant breast neoplasm; nanoparticle; neovascular; neovascularization; novel; novel diagnostics; pressure; progenitor; programs; reconstitution; sensor; skills; stem; subcutaneous; tool; tumor; vasculogenesis

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.

描述（由申请人提供）：这是向美国国家生物医学成像和生物工程研究所（NIBIB）重新提交的R 03申请。我们最近开发了一种微创的、基于生物传感器的诊断外科手术，用于测量癌症的间质液压力（IFP）。我们建议应用这种新的诊断技术来阐明收缩性周细胞在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类似，新生血管周细胞不仅在血管壁上产生收缩力，而且在细胞外纤维内捕获的间质液（称为组织凝胶）上产生收缩力。我们将测试是否可以通过干扰周细胞来降低癌症中的间质液压力，以改善基于纳米颗粒的抗癌药物的对流。我们将测试周细胞的抑制是否会导致由于周细胞引起的压缩收缩力降低而导致间质液压力降低。我们将测试周细胞-NG 2蛋白聚糖抑制是否降低IFP并改善从血浆到间隙空间的对流。我们将通过使用纳米颗粒作为示踪剂来量化跨毛细血管转运。我们预期发现当周细胞被抑制时，纳米颗粒（模拟高分子量抗癌药物）的跨毛细血管对流更高，乳腺肿瘤的间质液压力更低。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液压力生物传感器是创新的。乳腺癌间质内周细胞产生的压缩力的作用从未被研究过;这使得该提议在阐明间质性高血压的病因学方面具有创新性，间质性高血压是乳腺癌治疗中药物递送方面的重要临床问题。