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Doxil® — The First FDA-Approved Nano-Drug: From an Idea to a Product
Published in Dan Peer, Handbook of Harnessing Biomaterials in Nanomedicine, 2021
We studied the toxicity of a few liposomal doxorubicin formulations of different lipid compositions in small rodents as a part of the selection process of the optimal formulation. Here we will summarize our comparison of the leading formulation of EPC/EPG/Cholesterol/TCS 7:3:4:0.2 OLV-DOX with free drug (F-DOX). The comparison included a few studies that included single-dose and multi-dose experiments (Gabizon et al., 1986b). We demonstrated that OLV-DOX is much less toxic than F-DOX; LD50 value of OLV-DOX is twofold higher than the LD50 value of F-DOX. The lower toxicity of OLV-DOX was also demonstrated by higher, close to normal, body weight and organ weights and almost no histopathological damage to the kidney and myocardium. The low level of cardiotoxicity observed was fully reversible. It is also very important that despite the fact that i.v. administration of OLV-DOX resulted in high accumulation of doxorubicin in the liver, hepatotoxicity was minimal and limited to some megalonucleosis, with slight changes in liver function observed at the end of a six-month-long experiment in rodents. The much lower toxicity of OLV-DOX than of F-DOX is related first to the fact the encapsulation in the OLV affected dramatically the drug biodistribution, with much less drug reaching the heart and the kidneys (Gabizon et al., 1982, 1983). However, this is not the only effect of the encapsulation. Not less important is the effect on subcellular distribution, which results in the diminishing interaction of the intracellular doxorubicin with the mitochondria. The latter may explain part of the chronic free drug toxicity (related to the high affinity of the drug to the mitochondrial lipid DPG. The bottom line of the toxicity studies is that our OLV-DOX is significantly less toxic than F-DOX.
Effects of Chloramine T on zebrafish embryos malformations associated with cardiotoxicity and neurotoxicity
Published in Journal of Toxicology and Environmental Health, Part A, 2023
Carla Letícia Gediel Rivero-Wendt, Luana Garcia Fernandes, Andreza Negreli dos Santos, Igor Leal Brito, Jeandre Augusto dos Santos Jaques, Edson dos Santos dos Anjos, Carlos Eurico Fernandes
Among the set of abnormalities, those associated with cardiotoxicity were relevant. The cardiac edemas commenced to become evident from 16 mg/L, and were markedly different at the 128 mg/L (Table 1; Figure 1c,d,f,g). The reduction in heartbeat noted at 48 hpf was significant at the 128 mg/L concentration (Figure 1b), demonstrating the cardiotoxicity attributed to chemical treatment. Cardiotoxicity is characterized by swelling and altered heartbeat in response to disrupted myocardial electrophysiology, thereby affecting the circulatory system (Cross et al. 2015). Thus, evidence indicates that at 128 mg/L. concentrations, CL-T produced cardiotoxicity.