RESUMEN
This study investigated toxicity of nanocarriers comprised of cationic polymer and lipid components often used in gene and drug delivery, formulated as cationic micelles and liposomes. Rats were injected intravenously with 10, 25 or 100 mg/kg and sacrificed after 24 or 48 h, or 24 h after the last of three intravenous injections of 100 mg/kg every other day. Histological evaluation of liver, lung and spleen, clinical chemistry parameters, and hematology indicated little effect of treatment. DNA strand breaks were increased in the lung and spleen. Further, in the dose response study we found unaltered expression levels of genes in the antioxidant response (HMOX1) and repair of oxidized nucleobases (OGG1), whereas expression levels of cytokines (IL6, CXCL2 and CCL2) were elevated in lung, spleen or liver. The results indicate that assessment of genotoxicity and gene expression add information on toxicity of nanocarriers, which is not obtained by histology and hematology. FROM THE CLINICAL EDITOR: This study investigates the toxicity of cationic micelles and liposomes utilized as nanocarriers in gene and drug delivery, demonstrating its effects on the lungs, spleen and liver.
Asunto(s)
Cationes/efectos adversos , Daño del ADN/efectos de los fármacos , Liposomas/efectos adversos , Micelas , Animales , Cationes/uso terapéutico , Quimiocina CCL2/biosíntesis , Quimiocina CXCL2/biosíntesis , ADN Glicosilasas/biosíntesis , Sistemas de Liberación de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Transferencia de Gen , Hemo Oxigenasa (Desciclizante)/biosíntesis , Liposomas/uso terapéutico , Hígado/efectos de los fármacos , Pulmón/efectos de los fármacos , Masculino , Ratas , Bazo/efectos de los fármacosRESUMEN
The aim of this study was to compare the effects of cationic micelle and liposome drug delivery systems on liver and lung cells in a toxicological in vitro screening model, with observations on cytotoxicity and genotoxicity. A screening battery was established for assessment of a broad range of parameters related to adverse effects. Clear concentration response effects were observed related to impairment of mitochondrial function, membrane integrity and oxidative stress markers, but no effect was observed on genotoxicity. The adverse effects were highest for the liposomes. The High Content Screening seems optimal for initial screening of adverse effects, and combined with standard cytotoxicity measurements initial screening can be performed for predictive toxicological screening.