University of Pittsburgh scientists have developed novel Glucose Oxidase (GOD) iron oxide bioconjugates to destroy cancer cells (GOD-therapy). These compounds, containing superparamagnetic iron oxide (SPIO) nanoparticles, GOD enzyme, and tumor specific monoclonal antibodies (mAb) are designed to dramatically increase the levels of reactive oxygen species (ROS) in cells, resulting in cell death. Additionally, the SPIO nanoparticles can act as an MRI imaging core and could allow clinicians to better understand biodistribution of the therapeutic agent, consequently facilitating patient screening.
Superparamagnetic iron oxide (SPIO) nanoparticles connected to GOx enzymes and a tumor specific mAb have been developed. Using a novel therapeutic mechanism ROS are produced in tumor cells leading to cell death.
Description
Increased ROS in cells can induce cell death through both apoptosis and necrosis. Developing a tumor cell-specific method to increase ROS could be a novel therapeutic approach. GOD is an enzyme that catalyzes the oxidation of glucose to gluconic acid and H2O2. When iron oxides react with H2O2 in the Fenton reaction, hydroxyl radicals (OH•) are produced. GOD-therapy harnesses the Fenton reaction to increase ROS in cells as a novel anti-cancer therapeutic modality.
Applications
• Cancer therapy
• Cell specific therapy
Advantages
While radiotherapy and photodynamic therapy (PDT) are ROS-induced anti-neoplastic therapies, they have limitations and can result in off-target effects. Radiotherapy can damage healthy tissue, and its use is limited by safety concerns. PDT is limited by the ability of light of the required wavelength to penetrate tissue and by the sensitivity of molecules to photodynamic reactions.
This novel GOD-therapy overcomes the shortcomings of existing ROS-based therapies. Firstly, a tumor-specific targeting probe (e.g., antibody) ensures the GOD-therapy only targets tumor cells, reducing the risk of off-target effects. Secondly, the iron oxide nanoparticle has several roles including an MRI imaging core, drug delivery vehicle, and catalyst for the Fenton reaction resulting in ROS generation. Thirdly, the GOD enzyme, central to the structure, catalyzes the oxidation of glucose glucose from the blood producing H2O2 which, following the Fenton reaction, generates ROS leading to cell death. Additionally, these compounds have a long half-life and could reduce treatment frequency and costs. Overall, this approach of using GOD therapy to induce ROS selectively in tumor cells is completely new and could lead to more targeted therapy with reduced off-target effects.
Invention Readiness
A cetuximab-GOD-SPION bioconjugate containing cetuximab, an anti-epidermal growth factor receptor mAb was synthesized. In vitro testing in A431 cells demonstrated similar cytotoxity to doxorubicin, a commonly used chemotherapy drug after 24 hours. Cytotoxicity was observed even at concentrations as low as 100 ng/mL. Further testing with the fluorescent dye Cy3 attached, confirmed highly specific tumor uptake. Ex vivo biodistribution studies confirmed uptake of these novel compounds was primarily in the tumor followed by liver, kidney and spleen.
IP Status
https://patents.google.com/patent/US11931423B2
