Sorafenib tosylate is a multi-kinase inhibitor recently approved for the treatment of patients with hepatocellular carcinoma (HCC). Systemic exposures and a lack of tumor specificity leads to side-effects including severe skin rashes, hand and foot syndrome, diarrhea, and hypertension. These side effects might be overcome by use of nanoparticles for tumor delivery and controlled release of sorafenib. Targeted drug delivery platforms should offer the potential to significantly increase the efficacy of sorafenib therapy for HCC while reducing systemic exposures via catheter-directed delivery. Drug delivery platforms permitting repeated controllable sorafenib release periods will ultimately be necessary to avoid repeated catheterization and drug infusion procedures. For this purpose, we propose development of a magneto-thermal sensitive magnetic nano-micelle sorafenib delivery platform permitting image-guided transcatheter infusion and magneto-heating stimulated sorafenib release. Quantitative approaches for imaging nano-micelle delivery to liver tumors will be critical to permit early prediction of longitudinal response thus prompting adjustments to individual treatment regimens as needed. Through a collaborative project building upon our strengths in nanotechnology and interventional oncology, we seek to develop a powerful new approach for image-guided catheter-directed delivery of sorafenib to liver tumors. This pre-clinical project will address the following Specific Aims in a well-established rat model of liver cancer:
Specific Aim 1 : Determine the relationship between magnetic nano-micelle synthesis protocols and resulting sorafenib loading, magneto-thermal stimulated drug release kinetics and MR imaging properties.
Specific Aim 2 : Validate that sorafenib loaded magnetic nano-micelle drug-carriers with magneto-thermal stimulation inhibit angiogenesis and tumor growth and compare MRI measurements of transcatheter delivery to elicited tumor responses.
We propose the development of magnetic nanomicelles for catheter-directed sorafenib delivery to liver tumors. A selectively targeted stimuli 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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