Transcatheter Intraarterial Delivery of Heparin, Protamine, and Ferumoxytol Nanocomplex-Labeled Natural Killer Lymphocytes to Hepatocellular Carcinoma

We aim to develop magnetic resonance imaging (MRI) techniques using US Food and Drug Administration (FDA)-approved drugs to optimize selective transcatheter intraarterial (IA) delivery of natural killer (NK) cells for the targeted treatment of hepatocellular carcinoma (HCC). We hypothesize that IA delivery of NK cells will significantly enhance NK localization to the targeted tumors compared to intravenous (IV) delivery. To monitor and confirm delivery of the NK cells to the tumors, we will label primary NK cells isolated from donor rats with an MRI-detectable heparin-protamine-ferumoxytol (HPF) nanocomplex. The relaxivity of HPF-labeled cells will be determined from quantitative MRI R2* measurements and known concentrations of the HPF-labeled NK in cell suspension phantoms; these measurements will be used for later in vivo quantification of NK cell delivery to the targeted tumors. In vivo studies will utilize the N1-S1 HCC rat model for preclinical validation of MRI-based HPF-labeled NK cell quantification. Quantitative MRI measurements following the delivery of a range of NK cell doses via systemic IV or transcatheter IA routes will be compared to histological measurements of NK cell concentrations. Our ultimate goal is to validate that the proposed approaches offer the potential to improve therapeutic outcomes; the ability to noninvasively confirm delivery will also permit patient-specific dose optimization and early prediction of treatment outcomes. Medical student (Alexander Sheu) will be directly responsible for performing procedures and scans and acquiring and interpreting all data; scientific advisor (Dr. Andrew Larson) will serve as Alexander’s mentor and will ensure that he has the tools, training, and collaborative learning environment necessary to successfully complete the proposed project.