Avaliação do uso de nanopartículas lipídicas que se ligam a receptores celulares como instrumento para a terapêutica do câncer

Abstract

Lipid-based nanoparticle systems have been used as vehicles for chemotherapeutic agents in experimental cancer treatments. More recently, those preparations have also been assayed in animal models of cardiovascular, rheumatic and other chronic inflammatory diseases. In general those systems reportedly attenuate the severe toxicities of chemotherapeutic agents. This study was aimed to investigate the effects of associating paclitaxel to a lipid-based nanoparticle system upon the organism of a non-human primate, Cebus apella, by extensively documenting the toxicity by serum biochemistry, hematological and detailed histopathological methods. The lipid nanoparticles (LDE) were constituted of cholesterol esters and esterified cholesterol, lecithin and triolin, with addition of paclitaxel. Eighteen Cebus apella were studied; three animals were treated with LDE only, without paclitaxel, as ministered intravenously every three weeks, during six treatment cycles; six animals were treated with paclitaxel associated to LDE at the same administration scheme, three with the lower (175mg/m2) and three with higher (250mg/m2) paclitaxel doses; six animals were treated with commercial paclitaxel, three with the lower and three with the higher doses levels. Three weeks after the treatment cycle the animals were euthanized by lethal anesthetic dose, and tissues fragments were collected for histopathological analysis. In three non-treated animals, the plasma kinetics of LDE’s labeled with radioactive cholesterol was determined after intravenous injection and blood sampling over 24 hours. The ethics committee in research with experimental animals UFPA (BIO008-11) approved the project. In the LDE-paclitaxel group, no clinical toxicity appeared, and the weight food consumption curve were similar to controls. Treatment was interrupted after the second cycle in four animals of commercial paclitaxel group for very high clinical toxicity but the remaining two complete the 6-cycle-treatment. Those two animals presented weight loss, nausea and vomiting, diarrhea, escame decamation, 70% fur loss and loss of physical activity. The 175mg/m2 paclitaxel dose is used in cancer chemoterapie with considerable toxicity, while the 250 mg/m2 dose shows intorable toxicity to the patients. The use of LDE as carrier in both those levels was almost complete neutralized the toxicity of the drug in this species more closed related to human subjects. This was observed not only by clinical, biochemical and hematological profiles but also by the histopathological analysis of stomach, small and large intestine, esophagus, pancreas, trachea and gallbladder. The current results support the assumption that lipid-based nanoparticles systems used was drug carriers can offer valuable tools decrease the toxicity and increase the safety of the chemotherapeutic agents, while extending the use to chronic diseases other than cancer.