FOLIC ACID MAGNETIC NANOTHERANOSTICS REDUCED THE TOXICITY CAUSED BY DOXORUBICIN IN ZEBRAFISH LARVAE MODEL

PAMELA AZCONA; VERÓNICA LASSALLE; DANIELA IGARTÚA; SILVIA DEL VALLE ALONSO; CAROLINA MARTINEZ; MARÍA JIMENA PRIETO

Cuernavaca

Congreso; V Latin American Zebrafish Network Course and Symposium; 2018

Latin American Society for Developmental Biology

Magnetic nanoparticles (MNPs) allow drug targeting to a specific tissue or organ by the influence of an external magnetic field. The modification of the surface with both biological and drug molecules, in addition to their ability to act as contrast agents in MRI, turn these nanosystems as theranostics. The functionalization of MNPs surface with folic acid (MNPs@FA) improves specific targeting, ensuring the uptake by cancer cells that overexpress the FA receptor. Doxorubicin (DOXO) is a chemotherapeutic agent widely used for the treatment of solid tumors and hematologic malignancies in both adults and children. However, it causes short- and long-term cardiotoxicity and others undesirable side effects, as nephrotoxicity and neurotoxicity. In this way, the incorporation of DOXO to MNPs@FA would ensure therapeutic targeting and lead to a decrease in its side effects (MNPs@FA@DOXO).Since the physicochemical properties of the compounds vary when they are at nanoscale, it is not possible to predict the hazards to human and ecosystem health. Nanomaterial toxicity studies based on cell cultures are often inconsistent and might underestimate their effects, so biosafety of nanomaterials needs to be analyzed in whole animal systems. Over the last few years, zebrafish were frequently employed for evaluation of nanoparticles. Objectives.The aim of this work was to study the in vivo biocompatibility of DOXO, MNPs@FA, and MNPs@FA@DOXOusingZebrafish larvae (Danio rerio) as a high-throughput model. Methods and Results.At 5 days post-fecundation, the larvae were exposed to DOXO (3.125-50 µg/mL), MNPs@FA@DOXO (3.125-50 µg/mL of DOXO ? 70.75-1132 µg/mL of MNPs@FA), or MNPs@FA (70.75-1132 µg/mL of MNPs@FA). Viability, changes in spontaneous movement (neurotoxicity), cardiac rhythm (cardiotoxicity), morphology and efficiency of DOXO-uptake (by optical and fluorescence microscopy) were studied after 4-, 24- and 48-h treatment. While the 48-h treatment with 50 µg/mL of DOXO resulted in the death of 30% of the larvae and in the development of significant morphological abnormalities, the treatment with MNPs@FA@DOXO and MNPs@FA did not reduce the viability and did not cause developmental abnormalities. In addition, the MNPs@FA@DOXO reduced the cardiotoxicity caused by DOXO and promoted a more rapid and significant uptake of the drugby zebrafish larvae. Conclusions. MNPs@FA@DOXOpresenteda reduced toxicity in comparison to free DOXO and promoted the drug-uptake. This work highlights that the MNPs@FA@DOXO could be applied to a targeted therapy without toxicity.Supported by PUNQ 1388/15, PUNQ 1076/15, Alonso-PIP/14, and PICT CABBIO 0511/14.