Nanomaterials are promising carriers in the field of nanomedicine and represent a very intriguing approach in drug delivery applications, due to their small size, easy surface functionalization and tunable solubility. Among others, metal nanoparticles (MNPs, with M = Au, Ag) are considered ideal materials and nanomedicine applications have greatly increased, especially with respect to drug delivery. Many surface ligands are currently used, ranging from short molecules to polymeric shells in order to limit aggregation phenomena and produce water-dispersible colloids. The possibility to join the MNPs properties with nanomedicine requests, has driven our interest in the field of nuclear medicine. Thanks to an interdisciplinary approach, also based on previous strong collaboration within the Share-Science research group of the Faculty of Science, this project aims to improve basic knowledge on nanomaterials and nuclear medicine. The idea is to synthetize hydrophilic MNPs and to load onto the surface a source of Yttrium-89, a ¿cold¿ isotope as a model for Yttrium-90 a ß- emitting radioisotope. This strategy can be used in applications such as radio-guided surgery (RGS) and it represents an innovative approach where the chemistry of nanoparticles can be joined with physics of radioisotopes. The ¿cold¿ nanomaterial can be prepared by combining an appropriate linker and chelator for Y3+ with the MNPs. The new material will be tested in vitro and the feasibility of an ¿hot¿ preparation with radionuclide 90Y3+ will be investigated in collaboration with the Nuclear Medicine Institute of Policlinico Gemelli. A part of the project will be dedicated to the development of a detector of ß-radiation to better study the in vitro and in vivo compounds labeled with 90Y3+.
The innovation represented by this project is on the preparation of noble metal nanoparticles (AuNPs, AgNPs) as carriers of radionuclides. The chemical properties of nanoparticles can be tailored to obtain a surface functionalization according to the purpose. Compared to the conventional approach, MNPs promise safe and controllable transport of radionuclides in the blood stream, as well as offer a passive vectoring mechanism for targeting tumors based on their selective size accumulation. Despite the presence of several classes of highly biocompatible nanomaterials, MNPs stabilized with hydrophilic charge thiols seem to be the most appropriate for carrying and delivering therapeutic radioisotopes. In addition, noble metal nanoparticles provide a large surface area and various types of functional groups that allow for chemical reactions taking place on the nanoparticle surface and to load bioactive agents via linker.
One of the major obstacles in the delivery of therapeutic agents, especially small molecular agents such as radioisotope chelates, is rapid elimination of the agents and their widespread distributions into normal organs and tissues. To overcome these issues, the administration of the agent in a large quantity, which is not cost-effective and often results in undesirable toxicity is required. Nanoparticles with proper surface characteristics potentially provide better platforms for carrying and delivering purposes. There are several advantages of using nanoparticles-radioisotope to deliver therapeutic radioisotopes:
1) Prolonged blood retention time: from 30 minutes to 24 hours, depending on the morphology and size of the particle, coating materials, and compositions of nanoparticle conjugate. Longer blood circulation time than radioisotopes alone.
2) Loading of more radioisotopes on a single particle: dose reduction with fewer side effects.
3) Enhancing local accumulation of the therapeutic agent.
4) Peculiar physico-chemical properties provide additional capabilities and functions to monitor the response.
Conjugating radioisotope chelates for Yttrium-89 as active agent to surface functionalized nanoparticles represents an innovative perspective that can be achieved thanks to a bottom up approach and different synthetic strategies. Of importance are loading, stability and release studies that will influence the choice of nanoparticles surface functionalities.
The design and study of new nanomaterials for nanomedicine applications requires a multidisciplinary approach, with team members committed to overcome issues related to the synthesis and detection methods of loaded radionuclides. The development of the proposed project takes approximately 36 months. In a preliminary phase synthesis and characterizations of MNPs will be carried out. In the same time, selected and well-defined colloidal systems will be used for fine characterizations and applicative tests by loading yttrium containing salts. In parallel, the development of instruments capable of detecting MNPs emission is needed. In particular, particle detectors for Radio Guided Surgery will be optimized on the developing MNP, but also instruments dedicated to preclinical mice studies will have to be developed. Lastly, detector for dosimetry in radio metabolic therapy (TRT) will also be investigated. After these steps in vitro studies will be carried out in collaboration with external partners.
The main element for the evaluation of the quality of the results lies in their dissemination and publication in international scientific journals with high impact factors. The participants in this research project therefore intend to submit their results to the scientific community through conferences and scientific journals. The participants are also involved in national and international research project applications.