Y. Park, A. Demessie, A. Luo, O.R. Taratula, A.S. Moses, P. Do, L. Campos, Y. Jahangiri, C.R. Wyatt, H.A. Albarqi, K. Farsad, O.D. Slayden, O. Taratula
Oregon State University,
Keywords: endometriosis, nanoparticles, MRI, magnetic hyperthermia
Summary:Endometriosis is a debilitating systemic disease in which tissue that resembles the uterine lining (the endometrium) grows outside the uterus. It causes infertility and severe pelvic pain in approximately 176 million women worldwide, and there is currently no cure for the disease. To address this issue, we present a novel nanoplatform that can advance magnetic hyperthermia as the first targeted non-surgical therapy to eradicate endometriotic lesions. Magnetic hyperthermia is an emerging cancer therapy based on the concept that magnetic nanoparticles delivered to cancer tumors can generate intratumoral temperatures when exposed to an external magnetic field (AMF). It was not previously considered a modality for the ablation of endometriosis lesions because currently available magnetic nanoparticles have relatively low heating efficiency and can only provide the therapeutic temperature (> 42 °C) after direct injection into the diseased tissue. As a result, this therapy is not yet feasible for deep-seated lesions, which are difficult to access for direct injection. Therefore, we invented biocompatible magnetic nanoparticles capable of efficient accumulation in endometriotic xenografts after one intravenous administration at a clinically relevant dose (3 mg per kg) and generation of the required ablation temperatures (>50 °C) in these lesions upon exposure to AMF. To achieve this goal, an advanced thermal decomposition method for the preparation of magnetic nanoparticles with ultrahigh heating capacity was developed. Our results suggest that the low nitrogen flow rate of 10 mL min-1 during the thermal decomposition reaction results in cobalt-doped nanoparticles with a magnetite (Fe3O4) core and a maghemite (γ-Fe2O3) shell that exhibit the highest intrinsic loss power reported to date of 48.0 nH m2 kg-1. The heating efficiency of these nanoparticles correlates positively with increasing shell thickness, which can be controlled by the flow rate of nitrogen. To provide efficient delivery of the developed magnetic nanoparticles to endometriosis lesions after intravenous injection, their surface was modified with both polyethylene glycol (PEG) and a peptide as a targeting moiety to vascular endothelial growth factor receptor 2 (also known as KDR) overexpressed in endometriotic cells and minimally expressed or temporally restricted in other tissues. In vivo studies in mice bearing transplants of macaque endometriotic tissue revealed that the newly developed nanoparticles accumulate with high efficiency in the endometriotic grafts following intravenous injection at a low dose, selectively elevating the temperature inside of grafts above 50 °C in the presence of external AMF and completely eradicate the grafted tissue after one session of magnetic hyperthermia. Animal studies further revealed that these nanoparticles could be used as MRI contrast agents to detect lesions before ablation with AMF.