The intra-cardiac autonomic nervous system has long be known to a play a key role in the initiation and perpetuation of cardiac arrhythmias. However currently available technologies do not allow for selective mapping and denervation while sparing adjacent tissues. This project is a collaboration between Dr. Jrme Kalifa's and Drs. Kopelman and David Raffel's groups in the Department of Internal Medicine, Radiology and Chemistry, respectively. Dr. Kalifa's group has expertise in animal models of cardiac arrhythmias and in photodynamic therapy (PDT) for cardiac cells. During the PDT treatment, the photosensitizer excited by illumination from an appropriate wavelength light source (e.g. laser) produces cytotoxic reactive oxygen species, resulting in tissue damage. Dr David Raffel has extensive expertise in implementing radiotracers for imaging cardiac sympathetic neurons, such as [123I]-meta-iodobenzylguanidine (MIBG) and [11C]metahydroxyephedrine (HED). Here, we will conjugate MIBG to a PDT-enabling nanoplatform, the 8-arm PEG-Ce6, to enable selective sympathetic nerve terminal photo-ablation. Thus, this project's overarching goal is to conduct a preliminary in vitro and in vivo evaluation of a nanoplatform-enabled PDT approach that selectively ablates cardiac sympathetic nerve terminals. Our Aim 1 is to generate a modified MIBG moiety (MIBGm) amenable towards conjugation to an 8-arm-PEG-Ce6 nanoplatform. MIBGm is designed to conserve its affinity to the norepinephrine transporter expressed at the surface of sympathetic nerve terminals. The efficacy of the new MIBGm-8-arm PEG-Ce6 nanoplatform to achieve selective PDT ablation will be tested in vitro. Then, our Aim 2 is to evaluate the feasibility of sympathetic nerve-specific mapping and photo-ablation in vivo. In an open chest rat preparation and after MIBGm-8-arm PEG-Ce6 intra-venous injection, illumination with a 671 nm low-power laser light beam will allow for regional photo-ablation of ventricular sympathetic nerve terminals. Before and after photo-ablation, the regional sympathetic nerve density will be evaluated with [11C]HED micro-positron emission tomography imaging.
|Effective start/end date||01/01/2017 → 12/31/2018|