Primary liver cancer is the third leading cause of cancer-related death in the world. Most patients are offered only non-surgical palliative treatments, due to advanced stage of disease at presentation. Image-guided intra- arterial embolization therapy with chemotherapy, or chemoembolization, is a non-surgical palliative treatment that comprises local intra-arterial delivery of chemotherapy to the tumor, followed by arterial embolization. Chemoembolization only modestly improves patient survival and the need for improved treatment strategies remains unmet. Hyperthermia sensitizes cancer cells to chemotherapy. We hypothesize that the enhancement of chemoembolization with hyperthermia produced by magnetic nanoparticles (thermo-chemoembolization) will improve therapeutic outcomes and provide multimodal [magnetic resonance (MR) and computed tomography (CT)] non-invasive imaging validation of treatment delivery and cancer targeting. The objectives of this proposal are to: 1) demonstrate the cytotoxicity of the proposed therapy in translational models of liver cancer and, 2) develop a multimodal (MR and CT) imaging methodology for assessing tumor targeting and delivery of thermo-chemoembolization (T-C) formulation. For the proposed T-C combination, a multifunctional formulation will be intra-arterially injected, comprising bionized nanoferrite (BNF) particles and common chemoembolization drugs. Specifically, the BNF particles provide the heat when exposed to an alternating magnetic field (AMF) and simultaneously provide contrast for magnetic resonance (MR) and x-ray computed tomography (CT). These will be mixed with the most commonly used chemoembolization drugs lipiodol, a liquid microembolic drug carrier that provides x-ray contrast, and doxorubicin, a first line chemotherapeutic agent that is standard of care for cancer. In order to achieve the proposed aims, we will first characterize the heating properties of the proposed formulation in both in vitro and in vivo models. The tumoricidal efficacy of the proposed therapy will be tested using the VX2 rabbit liver tumor model, the "gold-standard" interventional radiology animal model of liver cancer, by comparing tumor viability against chemoembolization only and hyperthermia only controls. In order to validate the imaging capabilities of the proposed formulation, we will customize and evaluate MR and CT imaging techniques appropriate for assessing targeted and non-targeted distribution of the formulation in vivo by co-registering images with histology and iron quantification. The long- term objective of this effort is to provid a new image-guided strategy to counter primary liver cancer.

Public Health Relevance

Primary liver cancer is the third leading cause of cancer-related death in the world, with most patients being offered only non-surgical palliative treatments, which show modest therapeutic benefits. We hypothesize that the addition of hyperthermia, produced by magnetic nanoparticles, to chemoembolization (a commonly used image-guided, non-surgical chemotherapy) will enhance therapeutic outcomes and provide imaging confirmation of cancer targeting. If successful, results from this project will demonstrate feasibility in a clinical setting for treatment of patients with unresectable primary liver cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Radiation Therapeutics and Biology Study Section (RTB)
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Zhang, Yantian
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Johns Hopkins University
Schools of Medicine
United States
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