The broad, long-term objective of this proposal is to improve the prognosis of patients with unresectable hepatocellular carcinoma (HCC). Current therapies are palliative and relatively ineffective for improving prognosis. There exists a critica need for improved methods for effective treatment. Our recent studies have demonstrated the exciting potential of an innovative new therapeutic option for solid tumors;our proposed approach involves using magnetic vortex disks that apply magneto-mechanical forces at the surface of targeted cell membranes to induce apoptotic cell death. We propose the first in vivo study to validate the anti-cancer efficacy of magneto-mechanical therapy for the treatment of HCC. Magnetic nanodisks will be fabricated and characterized for magneto-mechanical cell destruction. We will use transcatheter infusions to deliver the magnetic disks directly into the blood supply of the targeted hepatic tumors. In vivo targeting efficiency via transcatheter hepatic artery injection will be studied with MRI quantification and histological measurements in an HCC rat model. Finally, we will evaluate in vivo therapeutic responses of targeted transcatheter magneto-mechanical cancer therapy;we will validate the ability to induce apoptotic HCC cell death using anti-CD44 conjugated magnetic nanodisks in the rodent model. Through a collaborative project building upon our strengths in biomedical engineering, radiology, and cancer biology, we seek to develop a powerful new magneto-mechanical therapeutic method for the treatment of HCC. Our proposed project will address the following Specific Aims:
Aim 1 : To determine targeting efficiency and imaging characteristics of our nano magnetic disks Task 1.1: To fabricate various nano-sized magnetic spin-vortex disks (Au coated Fe disk) at a specific geometrical ratio for magneto-mechanical motion upon cell membrane. Task 1.2: Biofunctionalization of magnetic disks and validation of in vitro magneto-mechanical destruction of hepatocellular carcinoma cells. Task 1.3: To characterize relationship between magnetic nanodisks concentration and T2/T2* relaxations rates for magnetic resonance imaging (MRI).
Aim 2 : To validate that transcatheter magneto-mechanical cancer therapy leads to tumor regression in HCC rat models. Task 2.1: To determine in vivo targeting efficiency of magnetic nanodisks using both in vivo quantitative MRI measurements and invasive histological measurements at necropsy. Task 2.2. To demonstrate in vivo therapeutic responses to targeted transcatheter magneto-mechanical therapy with both functional MRI technique and pathological analysis of tumor cell death.
Recently we developed a new type of magnetic particle permitting selective destruction of cancer cells upon targeted binding to cell membranes. Our proposed approach involves fabrication of magnetic nanodisks and transcatheter infusion to deliver the magnetic disks directly into the blood supply of the targeted hepatic tumors that apply magneto-mechanical forces at the surface of targeted cell membranes to induce apoptotic cell death. We propose the first in vivo study to validate the anti-cancer efficacy of magneto-mechanical therapy for the treatment of HCC.
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