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Novel polymer-based system for intrauterine delivery of everolimus for anti-cancer applications.

ABSTRACT: Non-surgical treatment options for low-grade endometrial cancer and precancerous lesions are a critical unmet need for women who wish to preserve fertility or are unable to undergo hysterectomy. The PI3K/AKT/mTOR pathway is frequently activated in endometrial cancers and has been associated with resistance to endocrine therapy, making it a compelling target for early stage disease. Oral everolimus, an inhibitor against mTORC1, has shown clinical benefit in advanced or recurrent disease but has severe adverse effects that may lead to treatment interruption or dose reduction. To overcome this, we developed a polymer-based intrauterine delivery system to achieve persistent, local delivery of everolimus without systemic exposure. In vivo studies, using a rat model, showed that a poly(propylene fumarate)-based rod loaded with everolimus achieved everolimus delivery to the endometrium with levels similar to oral administration, but with limited systemic exposure and up to 84 days of release. Biological activity of everolimus delivered with this system was confirmed, measured by reduced lumen epithelial cell height and PI3K pathway biomarkers. This study shows a promising new delivery approach for anti-cancer drugs for non-surgical treatment of low-grade endometrial cancer.

SUBMITTER: Melendez B

PROVIDER: S-EPMC8650567 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Novel polymer-based system for intrauterine delivery of everolimus for anti-cancer applications.

Melendez Brenda B Shah Sarita S Jiang Yunyun Y Dottino Joseph J Watson Emma E Pearce Hannah H Borthwick Mikayla M Schmandt Rosemarie E RE Zhang Qian Q Cumpian Kayleah K Celestino Joseph J Fellman Bryan B Yuan Ying Y Lu Karen H KH Mikos Antonios G AG Yates Melinda S MS

Journal of controlled release : official journal of the Controlled Release Society 20211012

Non-surgical treatment options for low-grade endometrial cancer and precancerous lesions are a critical unmet need for women who wish to preserve fertility or are unable to undergo hysterectomy. The PI3K/AKT/mTOR pathway is frequently activated in endometrial cancers and has been associated with resistance to endocrine therapy, making it a compelling target for early stage disease. Oral everolimus, an inhibitor against mTORC1, has shown clinical benefit in advanced or recurrent disease but has s ...[more]

PMID: 34648891

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Dataset Information

Novel polymer-based system for intrauterine delivery of everolimus for anti-cancer applications.

Publications

Novel polymer-based system for intrauterine delivery of everolimus for anti-cancer applications.

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