Development of a nanoparticle-mediated chemodynamic therapy for endometriosis.

Summary/Abstract Endometriosis is a debilitating disease in which tissue that resembles the uterine lining (the endometrium) forms lesions outside the uterus. It causes severe pelvic pain and infertility in ~176 million women worldwide, for which there is no cure. Despite recent advances in treating endometriosis-related pain, current clinical therapies cause infertility, prompting patients seeking to preserve fertility to pursue surgical lesion excision. Unfortunately, the recurrence rate after surgery is high, with 27% of patients requiring multiple surgical procedures. Moreover, physical surgery can fail to improve pain symptoms. The premise of this proposal is that chemodynamic therapy (CDT) can provide a non-surgical approach for removing endometriotic lesions that also improves endometriosis- associated pelvic pain. CDT is an emerging cancer treatment that uses nanomaterials containing iron or other transition metals to catalyze the conversion of the significantly elevated hydrogen peroxide (H2O2) levels found in cancer cells into toxic hydroxyl radicals through Fenton reactions. This targeted treatment selectively destroys malignant cells while minimizing damage to healthy tissue. Endometriosis cells, like cancer cells, also produce elevated levels of H2O2 and other reactive oxygen species (ROS). Moreover, endometriotic lesions contain high iron levels due to repeated bleeding cycles, which catalyze the production of hydroxyl radicals via the Fenton reaction, contributing to chronic oxidative stress. These conditions indicate that exogenously delivered CDT agents can also undergo Fenton chemistry within endometriotic tissue, elevating cytotoxic ROS beyond physiological levels, thereby achieving cytotoxic thresholds capable of selectively eradicating endometriotic tissue. Preliminary studies validated the feasibility of CDT treatment for endometriosis, showing that systemic administration of the CDT nanoagent Cu-TCPP to mice bearing endometriotic tissues leads to a two-fold reduction in lesion mass. To advance this therapy toward complete eradication of endometriosis lesions, the research team will capitalize on a recently invented Fe(II)-TCPP nanoagent, which generates hydroxyl radicals at a significantly higher rate than Cu-TCPP. Moreover, it also produces singlet oxygen, which can intensify oxidative damage to endometriosis cells and further promote lesion eradication. The multidisciplinary research team proposes in Specific Aim 1 to optimize the targeting efficiency of these Fe(II)-TCPP to human and macaque endometriosis by modifying it with the KDR peptide as a ligand to VEGF receptor 2 (KDR). This receptor is continuously overexpressed in endometriotic cells and minimally expressed or temporally restricted in other tissues. The proposed targeting approach will significantly increase Fe(II)-TCPP concentration within the lesions, enhance the therapeutic efficacy of CDT, and reduce the required therapeutic dose. The targeting, therapeutic efficacy, and safety of KDR-equipped Fe(II)-TCPP will be evaluated in mice with human and macaque endometriotic grafts (Aim 2) and in macaques with induced endometriosis (Aim 3). In sum, this CDT approach to treating endometriosis will provide the first non-surgical option to remove endometriotic lesions.