The long-term goal of this project is to use nanoparticles containing a therapeutic radionuclide to treat metastatic ovarian cancer and to translate the research findings from animal models to ovarian cancer in humans. The overall hypothesis of the proposed work is that a stable isotope contained within tumor-targeted nanoparticles can be activated to a radioisotope by a neutron-capture process. The resulting radiotherapeutic nanoparticles can be subsequently administered intraperitoneally to deliver efficacious absorbed radiation doses to metastatic ovarian tumors. This is expected to improve therapeutic responses while lowering toxicity. The proposed radiotherapeutic nanoparticles will be produced by the neutron activation of stable Holmium atoms (165Ho) that are contained with the matrix of mesoporous silica nanoparticles (MSNs), a durable carrier that withstand long neutron-irradiation times. The radionuclide produced by neutron irradiation of these nanoparticles, 166Ho, decays by the emission of high-energy beta particles that have a radiation tissue diffusion range capable of delivering absorbed radiation doses to the tumors sufficient to result in their death. Furthermore, the surface of these MSNs will be functionalized with folate, a targeting ligand for ovarian tumors. Making the MSNs radioactive after they have been prepared provides maximum safety for the medical staff and patients, and allows compliance with current Good Manufacturing Practices (cGMP) and detailed characterization of the stable nanoparticles prior to irradiation. Preliminary studies demonstrated predominant tumor accumulation of non-targeted 166Ho-MSNs and significant improvement in survival in ovarian tumor- bearing mice. The current project is focused on the delivery of targeted-radiotherapeutic nanoparticles after intraperitoneal administration to metastatic ovarian tumors and the core of tumor tissues.
The specific aims are to optimize targeting ligands associated with the MSNs and to assess the penetration of nanoparticles in tumors. We hypothesize that targeted 166Ho-MSNs will avidly bind to the surface of the tumors due to their specific affinity, and that the radiation will promote the penetration of the 166Ho-MSNs deep within the tumor by inducing apoptosis of the surface tumor. In vitro cell models will be employed to confirm the targeting effect and surface interaction between MSNs and tumor cells. The results will be supported by measurements of targeted nanoparticle accumulation and penetration into tumors in animals and human tumor tissues. These measurements will be used for dosimetry calculations for determination of optimal doses of 166Ho-MSNs. The data generated by this work will bridge the gaps in translating the results of animal studies to humans. This approach also offers flexibility in the design of treatment regimens. By paying attention to these clinicall relevant factors as well as to manufacturing and validation processes, these innovations will make it easier for this targeted radionuclide therapy to reach the clinical investigation stage and more rapidly translate this work into clinical practice.
The work described in this proposal involves administering small particles that contain a radioactive material to the abdominal cavity of patients suffering from metastatic ovarian cancer. A novel process of making the nanoparticles radioactive after they have been prepared is expected to increase access of this new internal radionuclide therapy agent to ovarian cancer patients. A number of development activities will be conducted to rapidly advance the translation of this treatment from the work in animals to use in the clinic for the benefit of real patients.
|Fu, Qiang; Hargrove, Derek; Lu, Xiuling (2016) Improving paclitaxel pharmacokinetics by using tumor-specific mesoporous silica nanoparticles with intraperitoneal delivery. Nanomedicine 12:1951-1959|