Avaliação da biodistribuição e atividade antitumoral de carreadores lipídicos nanoestruturados carregados com doxorrubicina e ácido docosahexaenoico em modelo experimental

Abstract

Breast cancer is the most common type of tumor in women, representing about 20% of the new annual cases. The mortality rate is also high, reaching 19 deaths per 100 thousand women. Doxorubicin is one of the most widely used chemotherapeutic agent in the treatment of breast cancer. However, high toxicity, especially cardiotoxicity, and low penetration into solid tumors are the mainly limitations for its use. Therefore, combined therapy and nanoscaled drug delivery systems, such as nanostructured lipid carriers (NLC), are innovative options for improving the therapeutic index, decreasing systemic toxicity, and, thereby, increasing the effectiveness of the drug. Polyunsaturated fatty acids, such as docosahexanoic acid (DHA), play an important role in cancer inhibition and prevention. In this context, combining both, doxorubicin and DHA, into a single nanoparticle might be a promising alternative to increase the antitumor efficacy. As the blood flow is increased in the tumor and the vasculature is more permeable, NLC can be useful to passively deliver the drug inside the tumor site. For the development of a new medicine, pharmacokinetics and biodistribution studies are fundamental. The use of radioactive isotopes are an interesting technique for this purpose, due to high sensibility and possibility to acquire quantitative images. Technetium-99m (99mTc) is the most common radionuclide used for scintigraphic imaging, due to its physical and chemical properties suitable for a radiopharmaceutical. In this work, the NLC, loaded with doxorubicin and DHA, were labeled with 99mTc, in order to evaluate pharmacokinetics and biodistribution profile. In addition, the antitumoral activity was performed in an experimental model of murine breast cancer. The results showed an increase in blood circulation time and area under the curve for the radiolabeled NLC when compared to free drug. In biodistribution studies it was observed high uptake in the liver and spleen. Besides, tumor showed higher uptake compared to non-targeted tissues, i.e. muscle. Target-non target ratios showed that the formulation has higher affinity for tumor region than free doxorubicin. The NLC was able to inhibit primary tumor growth by 90%. The evaluation of animals weight variation, the survival analysis and renal and heart histology demonstrated that this system has less systemic toxicity than free drug. Thus, the NLC formulation loaded with doxorubicin and DHA constitutes a promising alternative to the combined treatment of breast cancer.