Periodic Reporting for period 5 - NEST (Nanoengineering of radioactive seeds for cancer therapy and diagnosis)
Berichtszeitraum: 2023-07-01 bis 2024-09-30
Due to its high incidence and unfavourable prognoses, cancer is one of the most common causes of death worldwide (only overcome by heart disease). Cancer includes a wide number of diseases, characterized by the uncontrollable growth of abnormal cells that, in some cases, are able to disseminate along the body, causing severe multi-organ failure. The high cell differentiation of tumoral cells, among other factors, is responsible of the low success in the treatment and eradication of the disease, with a survival rate of ca. 40 %.Thus, cancer is a public health problem throughout the world and countless efforts are currently being made for the development of new drugs that help its early diagnosis and treatment.
Nanotechnology has emerged as one of the most promising approaches in the fight against cancer. Research in the nanomaterials field has allowed the development of new strategies to overcome the current therapeutic limitations that include the late stage diagnosis, cancer cell plasticity, lack of specificity and multi-drug resistance. Some of them being already approved for clinically use in humans. However, additional research is necessary to obtain novel and efficient nanocarriers for the detection and treatment of cancer, in order to improve the survival rate and reduce the incidence of the disease.
The purpose of the NEST project has been to develop ultra-sensitive imaging and therapeutic nanometric platforms. This has been achieved by filling compounds of intertest for imaging and radiation therapy in the interior of nanoparticles (nanoseeds). This allows the protection of the active element from the biological environment, and the in vivo fate becomes governed by the nanocarrier, being alien to the encaged compounds. Thus, the overall objective has been the rational assembly of highly loaded and functionalized nanoseeds, controlling their size, shape or surface properties according to the desired pharmacokinetics and biodistribution.
Nanotechnology has emerged as one of the most promising approaches in the fight against cancer. Research in the nanomaterials field has allowed the development of new strategies to overcome the current therapeutic limitations that include the late stage diagnosis, cancer cell plasticity, lack of specificity and multi-drug resistance. Some of them being already approved for clinically use in humans. However, additional research is necessary to obtain novel and efficient nanocarriers for the detection and treatment of cancer, in order to improve the survival rate and reduce the incidence of the disease.
The purpose of the NEST project has been to develop ultra-sensitive imaging and therapeutic nanometric platforms. This has been achieved by filling compounds of intertest for imaging and radiation therapy in the interior of nanoparticles (nanoseeds). This allows the protection of the active element from the biological environment, and the in vivo fate becomes governed by the nanocarrier, being alien to the encaged compounds. Thus, the overall objective has been the rational assembly of highly loaded and functionalized nanoseeds, controlling their size, shape or surface properties according to the desired pharmacokinetics and biodistribution.
Major scientific progress has been achieved during the execution of NEST. First efforts have been focused on the synthesis of the selected nanoplatform. Different protocols have been used, studying in each case the effect of the parameters of synthesis on the characteristics of the final particles. Nanoparticles with specific sizes, shapes and inner structures have been selected according to the proposed administration routes or the targeted tumour. Then, several radionuclides have been loaded and sealed inside the nanoparticles, testing their capability to be encaged and retained. Major efforts have been carried out to optimize the loading amount and the time of the process, as this is a limiting factor due to the short half-life of the radioactive payloads. Thus, nanostructures containing the radioisotopes inside their inner cavity have been obtained.
We have determined the parameters that have a key role in the successful containment of radionuclides and performed stability studies. The external surface has been functionalized with different biomolecules and targeting agents. Attachment of specific groups to the particles surface, has been explored in order to improve their circulation time and enhance tumor accumulation once the nanomaterials are introduced inside the organism.
Finally, the synthetized platforms have been tested in-vitro using different cancer cell lines, in order to determine the influence of these nanomaterials in the cell viability and proliferation. The developed nanostructures have shown to be non-cytotoxic.
We have also performed in-vivo studies and have confirmed lack of toxicity, normal behaviour of the animals and the ex vivo analysis of clinically relevant organs revealed a good biodistribution profile of the nanoseeds, with normal organs at necropsy and normal tissue architecture. A successful reduction in tumour growth has been observed when using the nanoparticles designed within NEST.
We have determined the parameters that have a key role in the successful containment of radionuclides and performed stability studies. The external surface has been functionalized with different biomolecules and targeting agents. Attachment of specific groups to the particles surface, has been explored in order to improve their circulation time and enhance tumor accumulation once the nanomaterials are introduced inside the organism.
Finally, the synthetized platforms have been tested in-vitro using different cancer cell lines, in order to determine the influence of these nanomaterials in the cell viability and proliferation. The developed nanostructures have shown to be non-cytotoxic.
We have also performed in-vivo studies and have confirmed lack of toxicity, normal behaviour of the animals and the ex vivo analysis of clinically relevant organs revealed a good biodistribution profile of the nanoseeds, with normal organs at necropsy and normal tissue architecture. A successful reduction in tumour growth has been observed when using the nanoparticles designed within NEST.
NEST research has contributed to the development of new strategies for cancer diagnosis and therapy towards a more personalized treatment, addressing some limitations of the current methodologies.
The most important achievement has been the successful design and synthesis of highly versatile, biocompatible nanoparticles, capable of bearing high amounts of diverse therapeutic or imaging agents, while preventing their leakage in non-target organs. Not only they are efficiently uptaken by tumor cells in vitro, but they have also been successfully tracked by in vivo imaging, altering the natural biological fate of the employed agents and demonstrating no adverse effects themselves (in the absence of cytotoxic agent). In healthy mice, they successfully altered the biodistribution of for instance the imaging radionuclide 89-Zr, which naturally accumulates in bone tissue, and the biodistribution pattern was merely governed by the nanoparticle. Therapeutic experiments were carried out in prostate cancer mice models. When loaded with therapeutic radionuclide 90-Y at high activity, they shown a dramatic therapeutic effect, with low collateral damage.
The developed nanoparticles present a high versatility. In fact, the versatility of NEST has already been explored for the delivery of neutron capture agents, which have proven to be effective for tumor cancer cell eradication. A patent has been filed with this proposed technology.
The most important achievement has been the successful design and synthesis of highly versatile, biocompatible nanoparticles, capable of bearing high amounts of diverse therapeutic or imaging agents, while preventing their leakage in non-target organs. Not only they are efficiently uptaken by tumor cells in vitro, but they have also been successfully tracked by in vivo imaging, altering the natural biological fate of the employed agents and demonstrating no adverse effects themselves (in the absence of cytotoxic agent). In healthy mice, they successfully altered the biodistribution of for instance the imaging radionuclide 89-Zr, which naturally accumulates in bone tissue, and the biodistribution pattern was merely governed by the nanoparticle. Therapeutic experiments were carried out in prostate cancer mice models. When loaded with therapeutic radionuclide 90-Y at high activity, they shown a dramatic therapeutic effect, with low collateral damage.
The developed nanoparticles present a high versatility. In fact, the versatility of NEST has already been explored for the delivery of neutron capture agents, which have proven to be effective for tumor cancer cell eradication. A patent has been filed with this proposed technology.