6-methoxyethylamino numonafide (MEAN) is an innovative new anti-cancer drug with potent efficacy for the treatment of hepatocellular carcinoma (HCC). However, even though MEAN offers to importantly reduce systemic toxicity compared to prior generation amonafides, systemic administration may still lead to potentially serious adverse events. Previously developed catheter-directed techniques for treatment of HCC include radioembolization with Y-90 microspheres or chemoembolization with drug-eluting beads selectively infused into the tumor vascular beds. For these approaches, local delivery affords significant reductions in systemic toxicity due to selective catheter-directed delivery. We propose the development of MEAN-eluting magnetic nanocomposites (MEAN-MNCs) consisting of embedded porous USPIO nano-clusters in a biodegradable polymer matrix to permit controlled drug release and selective transcatheter delivery to HCC. These nanocomposite drug delivery platforms offer the potential to significantly increase the efficacy of MEAN for the treatment of HCC while reducing systemic exposures via catheter-directed delivery. Through a collaborative project building upon our strengths in materials science, nanotechnology, biomedical engineering and interventional oncology, we seek to develop a powerful new approach for image-guided catheter-directed delivery of MEAN to liver tumors. This pre-clinical project will address the following Specific Aims in a well-established rat model of liver cancer:
Aim 1 : To determine the relationship between micro-fluidic MEAN-MNC synthesis protocols and resulting MEAN loading, release kinetics, and magnetic resonance imaging (MRI) properties.
Aim 2 : To compare a) tumor responses following transcatheter infusion of MEAN-MNCs and IV administration of MEAN and b) MRI measurements of MEAN-MNC delivery to the elicited response.
We propose the development of MEAN-eluting magnetic nanocomposite (MEAN-MNC) for catheter-directed drug delivery to HCC. A selectively targeted drug delivery system will offer importantly benefits, prolonging exposure of tumor tissues to the drug and localizing exposure to the targeted tumor tissues (rather than tissues throughout the body) thus significantly reducing side effects.
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