Folic acid magnetic nanotheranostics for delivering doxorubicin: Toxicological and biocompatibility studies on Zebrafish embryo and larvae

Abstract

Doxorubicin (DOXO) is a chemotherapeutic agent widely used for the treatment of solid tumors and hematologic malignancies in both adults and children. However, DOXO causes short- and long-term cardiotoxicity and others undesirable side effects, such as nephrotoxicity and neurotoxicity. Magnetic nanoparticles (MNPs) allow the delivery of drugs specifically to target place, employing an external magnet. Moreover, they may act as contrast agents in MRI providing information on the diagnostic of diverse pathologies. In this way, two functions may be combined in a unique nanosystem known as theranostic. Also, the MNPs can be modified with folic acid (MNPs@FA) to increase the uptake by cancer cells that overexpress the FA receptors. In previous works, our collaborators obtained and characterized MNPs, MNPs@FA, and MNPs@FA@DOXO. It is essential to study the biosafety of nanotheranostic, and there is no published study of FeO nanoparticles developmental toxicity. Because of that, this work aimed to study the in vivo toxicity and biocompatibility of DOXO, MNPs@FA, and MNPs@FA@DOXO using zebrafish embryo and larvae as an animal model. Viability, developmental toxicity, changes in spontaneous movement (neurotoxicity), changes in cardiac rhythm (cardiotoxicity), and efficiency of DOXO-uptake were studied. While the 48-h treatment with 50 μg/mL of DOXO resulted in a 30% larvae death and 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. Besides, the MNPs@FA@DOXO reduced the cardiotoxicity and promoted a more rapid and significant uptake of DOXO by zebrafish larvae.

R-α-Lipoic Acid Conjugated to d-α-Tocopherol Polyethylene Glycol 1000 Succinate: Synthesis, Characterization, and Effect on Antiseizure Activity

“…The end point includes coagulation of embryos; loss of heartbeat; delayed hatching; deformation in the tail, eyes, and head; and reduced pigmentation. 32 One distinctive aspect of zebrafish development is their sensitivity toward administered solutions in terms of timing and extent of hatching (which occurs around 2−3 dpf). Based on these aspects, survival, hatching rate, and overall embryonic development of larvae were monitored 33 (see the Supporting Information, Figures S1 and S2).…”

“…Therefore, the biocompatibility of synthesized TPGS-LA conjugate was assessed in zebrafish embryos, and any maltransformations/lethality was observed until 120 hpf. The end point includes coagulation of embryos; loss of heartbeat; delayed hatching; deformation in the tail, eyes, and head; and reduced pigmentation . One distinctive aspect of zebrafish development is their sensitivity toward administered solutions in terms of timing and extent of hatching (which occurs around 2–3 dpf).…”

Biological response and developmental toxicity of zebrafish embryo and larvae exposed to multi-walled carbon nanotubes with different dimension

“…Besides, teratogenicity of MWCNTs was studied through the analysis of sublethal parameters comprising abnormality of bent spine, tail, yolk, head, eyes or heart, reduction of pigmentation and delay of hatching. Embryos were designated as normal if none of the endpoints was observed, as malformed if one or more endpoints were observed, or as deceased if coagulation or no heartbeat was detected (Igartúa et al., 2018a; Martinez et al., 2018).…”

Toxicological Aspects and Bioanalysis of Nanoparticles: Zebrafish Model

“…Although one may assume that as it is a fish species, the literature review about zebrafish should largely include zoological studies, the review of studies from different disciplines in this study revealed that the most studies were indeed conducted in the field of toxicology (40.53%) and the least in the field of zoology (6.17%) (Figure 4). This shows that zebrafish is an important experimental animal in research and development studies such as toxicity studies [56], drug development [57], nanotheranostic studies [58], and medical-molecular methods [59].…”