One in 10 American adults, more than 20 million people, has some level of chronic kidney disease (CKD). This problem is especially severe in the elder population. For example, the incidence of recognized CKD in people ages 65 and older more than doubled between 2000 and 2008, and the prevalence in people ages 60 and older is now nearly 25%. At the end of 2009, more than 871,000 people were being treated for end-stage renal disease (ESRD) at an annual cost of $40B in public and private funds. Among the ESRD population, nearly 400,000 were being treated with some form of dialysis. Vascular access is a key component of dialysis systems and complications with both arterio-venous (AV) grafts and fistulas limit long-term survival rates. Frequent thrombosis is well described in prosthetic AV grafts and, to a lesser extent, fistulas. Current declot strategies often use a pharmacomechanical approach with initial thrombolysis and subsequent use of mechanical thrombectomy and/or balloon angioplasty. However, occasionally thrombolysis can be a lengthy and costly procedure with inherent risk. This is particularly the case if infusion thrombolysis is used. We have developed a targetable nanoagent containing nanoemulsion beads (NEB) with gold nanoshperes (GNS) decorating the surface (NEB-GNS) and combined it with a system delivering integrated photo-sono therapy and ultrasound(US)/photacoustic(PA) imaging to produce a tool for molecular theranostics using non-ionizing radiation. We hypothesize that this system can enable rapid, site-localized clot breakage with greatly reduced complications to manage thrombus in AV grafts and fistulas. To test this hypothesis, a research plan with four specific aims has been developed.
In Aim 1, we will extend the capabilities of NEB-GNS nanoagents and explore new formulations to optimize both non-linear PA imaging and photo-sono activated therapies.
Aim 2 will focus on PA imaging using non-linear processing to enhance both the sensitivity and specificity of molecular imaging with NEB-GNS nanoagents. Therapeutic methods based on site-localized cavitation using simultaneous photo/sono activation will be optimized in Aim 3 with a wide range of studies identifying optimal laser and US parameters for highly controlled cavitation. These studies will be validated on an in vitro clot model. Finally, in Aim 4 the overall approach to non-invasive molecular theranostics using NEB-GNS will be tested in vivo using a well-defined porcine model of vascular clotting.
The incidence of recognized chronic kidney disease in people ages 65 and older more than doubled between 2000 and 2008, and the prevalence in people ages 60 and older is now nearly 25% with about 400,000 people in the USA being treated for end-stage renal disease (ESRD) with some form of dialysis. Vascular access is a key component of dialysis systems and complications with both arterio-venous (AV) grafts and fistulas limit long-term survival rates. This project will develop a molecular theranostics system combining targeted nanoemulsions with integrated photo/sono therapy and photoacoustic/ultrasonic (PA/US) imaging to address the clinically significant problem of non-invasively treating thrombosed/occluded dialysis grafts/fistulas.
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