RESUMO
BACKGROUND: Poly(hydroxyalkanoates) (PHA) have recently attracted increasing attention due to their biodegradability and high biocompatibility, which makes them suitable for the development of new prolong drug formulations. OBJECTIVE: This study was conducted to develop new prolong paclitaxel (PTX) formulation based on poly(3- hydroxybutyrate) (PHB) microparticles. METHOD: PHB microparticles loaded with antitumor cytostatic drug PTX were obtained by spray-drying method using Nano Spray Dryer B-90. The PTX release kinetics in vitro from PHB microparticles and their cytotoxity on murine hepatoma cell line MH-22a were studied. Microparticles antitumor activity in vivo was studied using intraperitoneally (i.p.) transplanted tumor models: murine Lewis lung carcinoma and xenografts of human breast cancer RMG1. RESULTS: Uniform PTX release from PHB-microparticles during 2 months was observed. PTX-loaded PHB microparticles have demonstrated a significant antitumor activity versus pure drug both in vitro in murine hepatoma cells and in vivo when administered i.p. to mice with murine Lewis lung carcinoma and xenografts of human breast cancer RMG1. CONCLUSION: The developed technique of PTX sustained delivery from PHB-microparticles has therapeutic potential as prolong anticancer drug formulation.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Hidroxibutiratos/farmacologia , Paclitaxel/farmacologia , Poliésteres/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Neoplasias da Mama/patologia , Carcinoma Pulmonar de Lewis/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidroxibutiratos/administração & dosagem , Hidroxibutiratos/química , Injeções Intraperitoneais , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Estrutura Molecular , Paclitaxel/administração & dosagem , Paclitaxel/química , Tamanho da Partícula , Poliésteres/administração & dosagem , Poliésteres/química , Proibitinas , Relação Estrutura-Atividade , Propriedades de Superfície , Células Tumorais CultivadasRESUMO
BACKGROUND: Poly(hydroxyalkanoates) (PHA) have recently attracted increasing attention due to their biodegradability and high biocompatibility, which makes them suitable for the development of new prolong drug formulations. OBJECTIVE: A preclinical toxicology study of paclitaxel biopolymer formulation (PBF) (paclitaxel-loaded poly(3- hydroxybutyrate) (PHB) microparticles) was done in order to assess its safety and to forecast side and toxic effects in a clinical study on patients. METHOD: PHB microparticles loaded with antitumor cytostatic drug PTX were obtained by spray-drying method using Nano Spray Dryer B-90. The comprehensive study of cytotoxicity (on bone marrow stem cells), acute and chronic toxicity, allergenic and pyrogenic properties, histological investigation (in mice, rats and rabbits) of obtained PBF was carried out. RESULTS: The acute toxicity study showed that PBF is much less toxic in equivalent PTX-content doses than PTX in conventional formulation when administered intraperitoneally to mice and rats. However, the chronic toxicity study showed that at intraperitoneal administration PBF has distinct cumulative properties and toxic effects that prevent PBF from clinical testing in current composition. CONCLUSION: Thus, the PBF as a prolong drug needs to correct its parameters for further drug formulation development.
