Carrageenan and chitosan nanoparticles: production, characterization and preliminary evaluation as controlled release system of 5-fluorouracil

A liberaÃÃo controlada de fÃrmacos atravÃs de sistemas nanoparticulados à uma estratÃgia promissora para contornar os efeitos adversos da quimioterapia convencional do cÃncer. Nesse trabalho, nanopartÃculas produzidas por complexaÃÃo polieletrolÃtica da quitosana e carragenanas (kappa, iota e lambda) foram avaliadas como sistema de liberaÃÃo de 5-Fluorouracil. Inicialmente, os complexos polieletrolÃticos foram produzidos a partir de diversas condiÃÃes experimentais como concentraÃÃo inicial de polieletrÃlitos (0,5, 0,25 e 0,1 mg/mL), razÃo de cargas (10, 1 e 0,1) e ordem de adiÃÃo das soluÃÃes de polieletrÃlitos. Os complexos apresentaram diÃmetro hidrodinÃmico (Dh) entre 217 e 1555 nm, com Ãndices de polidispersÃo (IPD) inferiores a 0,6 e potenciais zeta acima de 30 mV para partÃculas catiÃnicas e abaixo de -30 mV para partÃculas aniÃnicas, indicando que os complexos possuem alta estabilidade coloidal. As nanopartÃculas apresentaram pouca variaÃÃo de tamanho, Ãndice de polidispersÃo e potencial zeta durante 30 dias de armazenamento. A espectroscopia na regiÃo do infravermelho por transformada de Fourrier (FTIR) comprovou a interaÃÃo dos grupos amina da quitosana e sulfato da carragenana na formaÃÃo das nanopartÃculas, bem como a incorporaÃÃo do 5-FU na matriz polimerica. A presenÃa do 5-FU promoveu alteraÃÃes discretas no tamanho, Ãndice de polidispersÃo e potencial zeta das partÃculas. A eficiÃncia de encapsulaÃÃo variou entre 3,5  1,1 a 15,4  0,6% e a capacidade de carga se manteve entre 8,2  0,4 e 38  2,4% e ambos foram influenciados pela concentraÃÃo inicial de 5-FU. Os ensaios de liberaÃÃo in vitro do 5-FU encapsulado apresentaram efeito burst, com parte do fÃrmaco sendo liberado nas primeiras horas, seguido de uma liberaÃÃo lenta e incompleta ao longo de 8 horas do experimento. Os complexos nanopartÃcula/5-FU apresentaram baixo efeito citotÃxico em linhagens de cÃlulas tumorais HL-60 e HCT-116, provavelmente devido ao pH fisiolÃgico do meio de cultura, resultado que viabiliza estudo das nanopartÃculas de quitosana/carragenanas/5-FU em modelos in vivo como sistema de liberaÃÃo sÃtio dirigida sensÃvel ao pH do microambiente tumoral.The nanoparticle drug delivery systems are a promising strategy to avoid the adverse conventional effects of cancer chemotherapy. In this work, nanoparticles produced by polyelectrolytic complexation of chitosan and κ, ι, λ-carrageenan were evalueted as a release system of 5-Fluorouracil. At first, the polyelectrolyte complexes were produced from several experimental conditions such as initial polyelectrolytes concentration (0.5, 0.25 and 0.1), charge ratio (10, 1 and 0.1) and mixing order of the polyelectrolytes solutions. The complexes presented hydrodynamic diameter (Dh) between 217 and 1,555 nm, with polydispersity indexes (PDI) below 0.6. The complexes showed zeta potential above 30 mV for cationic particles and below -30 mV for anionic particles, indicating that the complexes have high stability. The nanoparticles showed soft size, polydispersity index and zeta potential variation during 30 days of storage. The Fourier transform infrared spectroscopy (FTIR) proved the interaction of the amine groups of chitosan and sulfate groups of carrageenan in the nanoparticles formation. The 5-FU entrapment in the nanoparticles was also confirmed by FTIR and promoted soft changes on characteristics of the complexes. The encapsulation efficiency ranged from 3.5  1.1 to 15.4  0.6%, the load capacity was maintained between 8.2  0.4 and 38  2.4%, and both were affected by 5-FU initial concentration. The in vitro drug release assay showed a burst effect with much of the drug being released within the first hours, followed by a slow and incomplete release over 8 hours of the experiment. The nanoparticles/5-FU complex showed low cytotoxic effect on tumor cell lines HL-60 and HCT-116, probably due to slightly alkaline pH of the culture medium. This result indicates the need for evaluating in vivo models to study the chitosan/carrageenan/5-FU nanoparticles as a promising tumor targeting delivery system