Ischemic heart disease is the leading cause of death in the U.S.A., and stem cell therapy can improve the ejection fraction of damaged cardiac tissue by over 10%. Unfortunately, many stem cells days after implantation and those that do survive are often located in hypoxic or fibrotic tissue that are unreceptive to tissue regeneration-my near term goal is to improve the efficacy of cardiac stem cells therapy. Exciting preliminary data suggests that silica nanoparticles can be used to both study stem cells and ensure their survival after transplant. These nanoparticles have ultrasound contrast for image-guided delivery away from fibrosis as opposed to the existing paradigm of imaging only after injection. The multifunctional nanoparticle also has MRI contrast for high resolution follow-up. Finally, the same nanoparticle offers sustained release of growth factors to encourage cell proliferation. This nanoparticle is the ideal vehicle to facilitate my long-term objective of improving heart function with stem cell therapy, but this approach requires the additional refinement and validation proposed here. The workflow is divided into three main components to test my hypothesis that combining a sustained release delivery vehicle for prosurvival agents with a real time imaging agent can overcome challenges with both cell delivery and poor cell survival. 1) I will improve the biodegradation and porosity (for loading prosurvival agents) of the nanoparticle with materials chemistry. The nanoparticle will then be evaluated with cell and animal toxicity studies and refined if needed. 2) Prosurvival agents will be loaded into nanoparticles and used to treat stem cells under challenging growth conditions ex vivo. The agents will be iteratively optimized to improve therapy. 3) Finally, I will use animal models of ischemic disease and imaging to determine the efficacy of nanoparticle-enabled stem cell therapy. The innovation lies in real-time, quantitative imaging, which allows a transition to intra-cardiac injection rather tha intra-coronary delivery and thus implantation into the most receptive tissue in the heart. Sustained release of prosurvival agents from the sponge-like nanoparticle will combat the cell death that plagues this field. This proposal advances a fundamentally new tool and approach to stem cell therapy, which will have broad applications well beyond cardiovascular medicine. Finally, the research and professional training facilitated by this grant comprise an ideal stepping-stone to my career goal of an independent career with guidance and mentoring from Stanford Profs. Sanjiv Sam Gambhir and Joseph Wu-internationally renowned experts in cell imaging and cardiovascular research.

Public Health Relevance

Regenerative medicine has the potential to transform the treatment of heart disease by implanting potent replacement cardiac tissue derived from stem cells. Despite the tremendous promise of these approaches, many of these new cells die after they have been implanted into damaged areas. Innovative visualization tools and novel strategies for ensuring cell survival will be required to effectively understand and overcome this limitation. Here I propose to use a new material that can both image cells in real time via ultrasound and release a constant supply of growth factors to encourage cell growth ultimately leading to new functional tissue.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Career Transition Award (K99)
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Special Emphasis Panel (ZHL1-CSR-P (O1))
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Carlson, Drew E
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Stanford University
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Ho, I-Ting; Sessler, Jonathan L; Gambhir, Sanjiv Sam et al. (2015) Parts per billion detection of uranium with a porphyrinoid-containing nanoparticle and in vivo photoacoustic imaging. Analyst 140:3731-7
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