Sunday, November 24, 2024
11/24/2024
DESCRIPTION (provided by applicant): Detection and treatment of cancer can be greatly facilitated by noninvasive in vivo imaging techniques. In vivo imaging methods are most effective if they can be seamlessly tied to therapies. We propose to develop a novel imaging system using allosteric aptamers that can be used alternately to concentrate either an imaging agent or a drug around a cancer cell. Our aptamer-based design is referred to as a CLAMP (cis-/inked aptamers for medical or microanalytical procedures). CLAMPs provide the basic structure for developing allosteric aptamers in which the binding of one aptamer target to the CLAMP results in activation of another aptamer that is located in another part of the CLAMP molecule. The second, activated aptamer can then bind an imaging agent or a therapeutic agent. Because of HER2, a member of the epidermal growth factor receptor family, is highly expressed in many cancers, it will be the target for evolving a new aptamer by SELEX. The selected and optimized HER2 aptamer will be used as the allosteric aptamer in the CLAMP. Thus, binding of HER2 to the cell surface will activate the second aptamer that binds the imaging agent which is attached to a polymer such as inulin. The allosteric CLAMPs are expected to provide the following advantages for imaging: 1) relatively rapid renal clearance due to the small size of the DNA and 2) slow release rates from the target cells. Release rates are an inverse function of the valency. The availability of more than one closely located CLAMP on the cell surface will create multivalent regions for binding to the targeted imaging agent, resulting in slow release rates. Because the CLAMP will link the cancer cell surface to another molecule, the CLAMP imaging technology can be seamlessly interfaced with peptide prodrug therapies in which the peptide substrates of proteases are degraded to release a toxic drug. The high concentration of proteases that surround metastatic cancer cells, combined with the ability of the CLAMP to concentrate the prodrug around the cells, will result in more effective therapies that are seamless with imaging.
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