Zebrafish as a model organism for the study of toxicity and effectiveness of new antitumor therapies

Resumo

The zebrafish have many advantages that led to be a model organism with a great potential in translational research. Today, there are many techniques that have been described for the study of different diseases in zebrafish embryos. In fact, the zebrafish embryos are an ideal platforman to evaluate novel cancer therapies. For this reason, the main goal of this thesis has been evaluating the therapeutic potential of different anticancer therapies, including innovative nanomedicines in zebrafish embryos. To accomplish this, we evaluated the toxicity in vitro and in vivo of some commonly used anticancer drugs (Carboplatin, Irinotecan, Doxorubicin, and Paclitaxel), and a recently discovered drug with anticancer properties (Chloroquine) in order to determinate specific toxicity parameters and toxicological profiles crucial for zebrafish xenograft studies. The toxicity in zebrafish embryos was carried out by the fish embryo test (FET) during 96 h starting at 0 hpf and 72 hpf and we compare the results with the citotoxicity data obtained using the tumor cell lines: A549 (human lung carcinoma cell line), MCF7 cells (human breast adenocarcinoma cell line) and Panc185 (pancreatic ductal adenocarcinoma patient derived xenografts-PDX cancer cells). Additionally, we developed a newly nanoemulsion based on the anticancer drug edelfosine (E-NEs) which let us to study parameters such as toxicity, biodistribution and efficacy in xenografted zebrafish models. In conclusion, the results obtained in this thesis show that the toxicity values obtained for the antitumor drugs in vitro cannot be extrapolated to in vivo models such as zebrafish because they do not form a complete system. On the other hand, we formulated and characterized E-NEs by the ethanol injection method with adequate physicochemical, biopharmaceutical and functional properties. The E-NEs demonstrated the efficacy on zebrafish embryos xenotransplanted with triple negative breast adenocarcinoma cells (MDA-MB-231). In general, zebrafish embryos serve as a promising tool in preclinical studies in which the stability, toxicity, and efficacy of therapeutic anticancer drugs and new nanosystems against various types of cancer can be evaluated.