Sunday, November 24, 2024
11/24/2024
Project Summary This R03 application is focused on creation of an innovative microneedle patch (MNP) composed entirely of a polymerized 17β-estradiol (E2), the major female sex hormone. The macromolecular pro-drug materials are cured thermosets in which every repeating unit in the polyester chains contains an equivalent of E2. These crosslinked polyester resins undergo slow hydrolytic degradation to release low doses of estrogen, locally at the site of implantation, for exceptionally long time periods (up to many years). Transdermal microneedle patches offer minimally invasive, painless administration of estrogen. These delivery methods enhance patient compliance relative to repeated injections with hypodermic needles and they require lower doses than oral administration due by avoiding first-pass hepatic clearance. Of all the many advanced MNP technologies, there are still no examples of MNPs composed entirely of poly(pro-drug). Our lab has developed a new class of polymerizable estrogen pro-drugs containing pendant alkene groups. In this proposal, we will polymerize the pro-E2 monomers in a microneedle mold. A key innovation is that we plan to tune the glass transition of the polymer network such that the needles are hard and glassy at room temperature for skin penetration, but then they transition into a soft/rubbery material upon equilibration to physiological temperature. This project is likely to make significant contributions by developing new poly(pro-drug) based microneedle patches capable of releasing low doses of E2 transdermally for exceptionally prolonged timescales. The chemistry and engineering approaches used here will be broadly generalizable in two key ways: 1) our polymerization scheme is easily modified to accommodate nearly any drug molecule with two or more reactive functional group handles, and 2) the MNP of poly(pro-E2) can be applied to a broad range of clinical applications where prolonged low-dose E2 is desired. Our goal for future work is to apply these E2-releasing MNPs in a preclinical rodent model to first assess safety and skin irritation and later to explore the impact of the patch on functional recovery from contusive spinal cord injury.
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