Periodic Reporting for period 3 - ICARO (Colloidal Inorganic Nanostructures for Radiotherapy and Chemotherapy)
Période du rapport: 2019-03-01 au 2020-12-31
Radio and chemotherapy are the major clinical treatments for cancer. However, these treatments lack cell specificity and can have severe side effects against healthy cells, especially when used in combination. Icaro's goal was to develop a nanocrystal (NC) platform to merge radio and chemotherapy into a single entity that is more specific towards tumor cells.
During the lifetime of ICARO project, the ICARO’s team has managed to fully achieve the goals of the project. ICARO project was correctly implemented towards the three objectives set in the description of work.
First, we have set synthesis of magnetic nanoparticles, semiconductors and novel magnetic-semiconductor heterostructures accordingly to WP1 and needed throughout the project. For the first objective, we have successfully managed to set one-step and simple cation exchange (CE) reactions or intercalation (INT) reactions with Cu-64 radioisotope of clinical use on water soluble and aqueous stabilized semiconductor nanocrystals (NCs), including CuS, ZnS, ZnSe and CuFeS2 NCs (Avellini et al., Advanced Functional Materials, 202030 (28), 2002362). We have demonstrated that on these semiconductor NCs is possible to establish CE/INT reactions that occur in aqueous media, also when they are pre-functionalized with specific recognition molecules (i.e. folate receptors). Moreover, by exploiting the complete CE reaction (rather than the partial exchange of CE of cations), the dose of Cu-64 accumulated into a tiny dose (microgram dose)of semiconductor NCs is enough to perform radiotherapy. Worth to note, we have also worked on a different NCs platform, such as sodium fluoride-based upconverting NCs, to perform CE reactions with clinically used Y-90 and Lu-177 radionuclides (paper in preparation).
As a second objective, we have also demonstrated the possibility to perform CE reactions with Cu-64 radioisotope on semiconductor NCs entrapped within a matrix. This condition simulates the tumor mass and the CE reaction parameters (such as the exchange time as well as the reaction temperature and the amount of 64Cu radioisotope needed) for the CE reactions on matrix did not differ from that performed on NCs in solution.
For the third objective that was related to the development of heterostructures to combine radiotherapy and heat-mediated drug-delivery in magnetic hyperthermia (MHT), we have managed to develop and to test two main heterostructures, both made of three-component materials. The first one is a heterostructure composed of iron oxide-gold-Cu2-xS heterostructure with the Cu2-xS NC exploitable for the Cu-64 radiolabeling (paper in preparation). The second heterostructures is a nanoplatform based on chains of nanocubes of iron oxide nanoparticles coated by mesoporous silica structure having pore size of less than 2 nm in which we have nucleated and grown ZnS NCs, the latter exploitable for Cu-64 radio-insertion (paper in preparation). Remarkable, on both heterostructures we have proved the feasibility to perform radiolabeling protocols with Cu-64 following post-synthesis CE protocols on the heterostructures stabilized in water. Moreover, both heterostructures produced significant heat in MHT for hyperthermia or drug delivery purposes and both have proven to be excellent photothermal agents. Therefore, multimodal delivery tools for combining magnetic hyperthermia, heat-mediated drug delivery and radiotherapy have been provided.
First, we have set synthesis of magnetic nanoparticles, semiconductors and novel magnetic-semiconductor heterostructures accordingly to WP1 and needed throughout the project. For the first objective, we have successfully managed to set one-step and simple cation exchange (CE) reactions or intercalation (INT) reactions with Cu-64 radioisotope of clinical use on water soluble and aqueous stabilized semiconductor nanocrystals (NCs), including CuS, ZnS, ZnSe and CuFeS2 NCs (Avellini et al., Advanced Functional Materials, 202030 (28), 2002362). We have demonstrated that on these semiconductor NCs is possible to establish CE/INT reactions that occur in aqueous media, also when they are pre-functionalized with specific recognition molecules (i.e. folate receptors). Moreover, by exploiting the complete CE reaction (rather than the partial exchange of CE of cations), the dose of Cu-64 accumulated into a tiny dose (microgram dose)of semiconductor NCs is enough to perform radiotherapy. Worth to note, we have also worked on a different NCs platform, such as sodium fluoride-based upconverting NCs, to perform CE reactions with clinically used Y-90 and Lu-177 radionuclides (paper in preparation).
As a second objective, we have also demonstrated the possibility to perform CE reactions with Cu-64 radioisotope on semiconductor NCs entrapped within a matrix. This condition simulates the tumor mass and the CE reaction parameters (such as the exchange time as well as the reaction temperature and the amount of 64Cu radioisotope needed) for the CE reactions on matrix did not differ from that performed on NCs in solution.
For the third objective that was related to the development of heterostructures to combine radiotherapy and heat-mediated drug-delivery in magnetic hyperthermia (MHT), we have managed to develop and to test two main heterostructures, both made of three-component materials. The first one is a heterostructure composed of iron oxide-gold-Cu2-xS heterostructure with the Cu2-xS NC exploitable for the Cu-64 radiolabeling (paper in preparation). The second heterostructures is a nanoplatform based on chains of nanocubes of iron oxide nanoparticles coated by mesoporous silica structure having pore size of less than 2 nm in which we have nucleated and grown ZnS NCs, the latter exploitable for Cu-64 radio-insertion (paper in preparation). Remarkable, on both heterostructures we have proved the feasibility to perform radiolabeling protocols with Cu-64 following post-synthesis CE protocols on the heterostructures stabilized in water. Moreover, both heterostructures produced significant heat in MHT for hyperthermia or drug delivery purposes and both have proven to be excellent photothermal agents. Therefore, multimodal delivery tools for combining magnetic hyperthermia, heat-mediated drug delivery and radiotherapy have been provided.
The development of magnetic, semiconductor and magnetic-semiconductor nanomaterials for radiotherapy, magnetic hyperthermia and chemotherapy are of high relevance for the treatment of cancer malignancies. In particular, with ICARO we have tested our nanomaterials in vitro on cancer cells and in some cases in vivo, on murine model of adenocarcinoma, ovarian cancer, colorectal, breast cancer and glioblastoma. This research will certainly have an impact in the field of cancer nanomedicine and therefore on a more long-term perspective of patient life affected by these pathologies.