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Nanoengineering of radioactive seeds for cancer therapy and diagnosis

Periodic Reporting for period 3 - NEST (Nanoengineering of radioactive seeds for cancer therapy and diagnosis)

Reporting period: 2020-10-01 to 2022-03-31

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 is to develop ultra-sensitive imaging and therapeutic nanometric platforms, by filling hot radionuclides in the interior of nanostructures (nanoseeds). This allows the protection of the radionuclides from the biological environment, and the in vivo fate becomes governed by the nanocarrier, being alien to the encaged compounds. Thus, the overall objective is the rational assembly of highly loaded and functionalized nanoseeds, controlling their size, shape or surface properties according to the desired pharmacokinetics and biodistribution. It is expected to allow an early diagnosis of the disease and a more personalised treatment of cancer, with less side effects to improve the living conditions of the patients.
Significant progress has been achieved since the beginning of the project. 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 compounds 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, completely sealed nanostructures containing the compounds inside their inner cavity have been obtained. 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, cytotoxicity of the synthetized platforms and different cancer cell lines has been evaluated, in order to determine the influence of these nanomaterials in the cell viability. The developed nanostructures have shown to be non-cytotoxic.
We have also already performed the first in-vivo study in healthy mice using a fluorescent marker 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. Therefore, the developed nanoseeds to date are good candidates to move forward to diagnostic and therapeutic studies with pre-clinical cancer models.
NEST research contributes to the development of new strategies for cancer diagnosis and therapy that allow the early diagnosis of the disease and a more personalized treatment, addressing some limitations of the current methodologies. At the end of the project, obtaining radioactive nanoplatforms with good biodistribution and that allow tumour diagnosis and eradication is expected. This approach might also minimize, as much as possible, the negative effects on the healthy cells. Thus, developing more specific treatments that reduce side effects is expected, thus improving the quality of life of cancer patients.
These nanoplatforms might not only contribute to the cancer radiodiagnosis and therapy but also can be useful for other approaches such as drug delivery or as contrast agent for different imaging modalities. 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 in-vitro. A priority patent application has been recently submitted with this proposed technology.
Cytotoxicity of the developed nanomaterials