The broad, long-term objective of this proposal is to improve the prognosis of patients with unresectable hepatocellular carcinoma (HCC). For these patients, transarterial chemoembolization (TACE) is the most widely accepted local treatment because of its proven survival benefit in patients with preserved liver function. However, benefit to patients with advanced disease or poor liver function is still limited. The optimal dose for TACE also remains unknown. To address the need to expand patient eligibility and optimize dosing protocols for TACE, the investigators propose: a) developing the next generation of TACE by using nanoparticles (NP) as drug delivery vehicles for doxorubicin (DOX) and b) devising a new magnetic resonance imaging (MRI) system to predict and monitor dosimetry for this locally delivered therapy. The proposed improvement to TACE employs therapeutic nanoparticles (NP) in a new procedure termed nanoembolization (NE). NE is local delivery of therapeutic NPs, together with embolic agents, into the tumor blood supply to increase intratumoral drug uptake. The investigators'NP platform employs a central superparamagnetic oxide (SPIO) core that can be imaged with MRI, enclosed within a gold (Au) shell that is attached to DOX as the therapeutic agent. The proposal will test the utility of an MRI-monitoring system for delivery of Au-SPIOs in the VX2 rabbit model of HCC. This system will enable prediction of dosimetry prior to drug delivery, real-time monitoring during drug delivery, and feedback after delivery to verify that desired intratumoral drug concentrations have been reached.
Specific Aim 1 will develop a model that predicts tissue concentrations of Au-SPIOs before delivery and provides imaging parameters for dosimetry. It is hypothesized that quantitative MRI parameters can be used to predict the biodistribution of injected Au-SPIOs before delivery and to provide dosimetry for NE. The health relevance will be to personalize liver tumor therapies for patients based upon local tumor perfusion.
Specific Aim 2 will develop a real-time projection MRI fluoroscopy technique that can monitor Au-SPIO delivery in real- time during NE. It is hypothesized that Au-SPIO delivery during NE can be monitored in real-time with dynamic projection MRI. The health relevance is to develop a real-time imaging method that ensures injected NPs reach their intended tumor target.
Specific Aim 3 will use MRI to quantify tissue concentrations of Au-SPIOs after NE. It is hypothesized that MRI R2* mapping accurately quantifies tissue concentrations of Au-SPIOs after NE. The health relevance is to provide quantitative intra-procedural feedback during drug delivery, with the goal of maximizing intratumoral drug concentrations, while minimizing toxicity to adjacent liver tissue.
To improve the treatment of liver cancer, this proposal devises a new system for magnetic resonance imaging (MRI)-guided delivery of therapeutic nanoparticles. In animal studies, we will show that the method can be used to quantify dosing, delivery, and uptake of this proposed therapy. This new MRI-based drug dosimetry system may be translated in the future to patients undergoing local treatments for a variety of solid organ tumors.
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