Estudos sobre o antineoplasico CPT-11 : I. Interação com albumina de soro humano (HSA) ; II. Encapsulação e caracterização de CPT-11 em lipossomas estericamente estabilizados

AUTOR(ES)
DATA DE PUBLICAÇÃO

2002

RESUMO

This project was motivated by the prospects of both an improvement in the efficacy of anticancer drugs and a reduction in their side effects as a result of being encapsulated in liposomes. The first part of this work consisted in the study of the interaction between the antineoplasic drug CPT-11 and Human Serum Albumin (HSA), in order to evaluate the stability of the lactone form in the presence of HSA, through the kinetic behavior of CPT - 11 hydrolysis. Our study also aimed at verifying whether modifications in the secondary structure of the protein would occur due to its interaction with CPT-11. Both type of experiments were carried out by monitoring the fluorescence spectra of CPT-11 in the presence of different HSA concentrations. A chemometric approach showed that, in a physiological HSA concentration (30mg/mL), a new species is formed, due to the rapid interaction between HSA and CPT-11 lactone form, which has a different spectrum compared to the free lactone one. Based on these results, we proposed a mechanism of reaction between CPT-11 and HSA. The understanding of this mechanism was only possible by using chemometrics, indicating the benefits of this technique. Moreover , chemometrics evidenced that using 1:1 stoichiometry, HSA does not interact with lactone form of CPT-11, contradicting the researches in the literature. The second part involved the preparation and characterization of LUV sterically stabilized liposomes, with DSPC, DSPE-PEG2000, DSPG and cholesterol, including CPT-11. The kinetic behavior of the hydrolysis of included CPT-11, combined with the study of proton migration through lipid bilayer, according to fluorescence spectra of 9-aminoacridine in different pH buffers, showed that our liposomal system can maintain CPT-11 in a stable form, avoiding its hydrolysis in physiological pH, for a long period of time.

ASSUNTO(S)

fluorescencia albumina lipossomos agentes antineoplasicos

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