Development of magnetic hyperthermia for the systemic treatment of endometriosis

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Summary/Abstract (30 lines) Thermal therapy is a clinical intervention to eradicate cancerous tissue by increasing the temperature of the tumors. Nanoparticle-mediated magnetic hyperthermia is a form of thermal therapy where magnetic nanoparticles delivered to cancer sites generate heat after exposure to an external alternating magnetic field (AMF). The goal of this project is to advance nanoparticle-mediated magnetic hyperthermia as a non-invasive treatment for endometriosis. Endometriosis is a disorder where endometrium-like tissue is present at “ectopic” sites outside of the uterus. The ectopic endometrium forms lesions that cause pelvic pain and infertility. Despite advances in therapies for endometriosis-related pelvic pain, there remains no medical cure for the disorder, and surgical removal of the lesions remains a treatment for many women. Unfortunately, the rate of disease recurrence exceeds 50% with many patients requiring three or more surgeries. The premise of this proposal is that magnetic hyperthermia can provide a non-surgical option to remove endometriotic lesions. Magnetic hyperthermia for cancer is currently restricted to the treatment of localized and accessible tumors because the required therapeutic temperatures (≥42 0C) can only be achieved by direct intratumoral injection of conventional magnetic nanoparticles. To address this limitation, this research team invented novel magnetic nanoclusters with high heating capacity. The nanoclusters consist of hexagonal-shaped magnetic nanoparticles encapsulated in polymeric vehicles. Animal studies validated that these nanoclusters are safe, efficiently accumulate in cancer tumors after intravenous (IV) injection, and elevate the intratumoral temperature to 44 0C in the presence of AMF. Preliminary studies revealed that following IV injection these nanoclusters also efficiently accumulated in the macaque endometriotic lesions grafted into severe combined immunodeficient (SCID) mice and exposure of these mice to external AMF after nanoclusters delivery increased the temperature inside of the grafts up to 43 0C. To advance this new therapy this multidisciplinary team of investigators with complementary expertise in nanomedicine, magnetic hyperthermia, and clinical endometriosis research proposes in Specific Aim 1, to optimize targeting efficiency of these nanoclusters to human and macaque endometriosis. Targeting will be optimized by modifying the surface of the nanoclusters with peptides that specifically bind to receptors (e.g., vascular endothelial growth factor (VEGF) receptor 2 (KDR)) overexpressed in primate endometriotic stromal cells. Binding specificity and therapeutic efficacy of these new nanoclusters will be assessed in primary endometrial and endometriosis (human and macaque) stromal cells in vitro. In Specific Aim 2, the effect of targeted versus non-targeted nanoclusters on the eradication of endometriosis lesions will be evaluated in SCID mice engrafted with human and macaque endometriotic grafts. In Specific Aim 3, safety and therapeutic efficacy of magnetic hyperthermia mediated by the optimized nanoclusters will be evaluated in macaques with induced endometriotic lesions.