Desenvolvimento de implantes poliméricos intraoculares contendo etoposídeo destinados ao tratamento do retinoblastoma

Abstract

Retinoblastoma is an intraocular most common childhood malignancy and its treatment by systemic chemotherapy has some devantagens: limited penetration of the drug to the posterior segment of the eyeball and systemic toxicity. The intraocular implants rpresentam a promising alternative for the treatment of retinoblastoma. Moreover, these systems are able to protect labile drugs in physiological conditions, such as etoposide, commonly employed anti-tumor systemic chemotherapy retinoblastoma, slightly soluble in water and unstable in acid and alkaline media. The poly (-caprolactone) (PCL) and poly-lactic-co-glycolic acid (PLGA) are biodegradable and biocompatible polymer widely used in drug delivery systems. In this work, two cylindrical polymer systems were developed: implants made of PCL and etoposide; PLGA implants embedded and etoposide. Both systems were analyzed by techniques of spectrophotometry in the infrared Fourier transform, X-ray diffraction, thermogravimetry, differential scanning calorie and scanning electron microscopy. Furthermore, the implants were submitted to the sterility test, the content uniformity test and the evaluation of stability to ultraviolet radiation for thirty minutes. Also determined the profile of the in vitro drug release from implants and ocular tolerance assessed by means of the test-chorion allantois of embryonated chicken egg membrane (HET-CAM test). Additionally, the implants made of PLGA and etoposide were submitted to the study of in vivo release of the drug. For quantitation in the different samples etoposide (PCL implants, PLGA implants and vitreous humor), methods by liquid chromatography of high efficiency have been developed and validated. The results show that it was possible to prepare cylindrical biodegradable implants. The various characterization techniques showed that the drug has maintained its chemical integrity upon incorporation into the polymer matrix and after sterilization. Polymeric systems enabled the in vitro release of etoposide over a prolonged period (150 days for PCL implants and 50 days for the devices PLGA). In the in vivo study, the PLGA implants led to the release of approximately 63% of the antitumor for 42 days and kept intravitreal concentrations ranging from 1.1 to 2.5 g / ml. The implants were classified as non-irritant according to the HET-CAM test, suggesting that these systems will be well tolerated after insertion into the vitreous cavity of the eye. The developed analytical methods showed selectivity, linearity, accuracy, precision and robustness adequate for quantification of etoposide in the vitreous humor and in the polymeric implants. The results suggest that the polymeric implants containing etoposide represent a potential delivery system for drugs for the treatment of retinoblastoma.