Preparation And Characterition Of Rapamycin-Loaded Nanoparticles Via Nanoparticulate Drug Delivery Systems

Recent advances in nanotechnology have made a great contribution to Nanoparticulate Drug Delivery Systems(NDDSs)for clinical testing,diagnosis and therapy.Because of fast development of the lethal desease,atherosclerosis AS),many researchers are focusing on using different NDDSs to treat AS.Rapamycin(RAPA),poor water-soluble drug,was found to have the ability to control the development of AS.However,it cannot be used directly as oral drug or injective drug because of its low bioavailability.Therefore,in this thesis we developed two different NDDSs to encapsulate RAPA.Polymeric nanoparticles are increasingly proposed for the improvement of drug water solubility.The first NDDS loading RAPA into nanoparticles was prepared from PEG-PLGA(Polyethylene glycol-poly(lactic acid-co-glycolic acid))diblock copolymers by solvent displacement method.The preparation procedure of RAPA-loaded PEG-PLGA nanoparticles was optimized using Taguchi orthogonal array(TOA)and the effects of four parameters(PEG-PLGA/RAPA ratio,stirring time,dispersing agent and sonication power)on particle size were investigated.The optimized nanoparticles were characterized using particle size analyzer,transmission electronmicroscopy(TEM)and scanning electron microscopy(SEM).RAPA-loaded NPs were spherical with an average size of 150 nm and a drug loading of 12%.The particle size decreased significantly when the stirring time was increased and when the polymer to drug ratio was decreased.The in vitro release of RAPA from the optimized nanoparticles exhibited a sustained release pattern for several days with a cumulative release of 70%over 5 days.In vitro cytotoxicity study of RAPA-loaded nanoparticles on H9c2 cells showed a slight proliferation repression but no toxic effect.Cubosome was another NDDS for RAPA encapsulation by the liquid precursor or solvent dilution method.The preparation procedure of cubosomes was optimized using 23 full factors analysis and the effects of three parameters(ratios of CTAB,water and PBS)on particle size,PDI and Zeta potential were investigated.The optimized nanoparticles were characterized using particle size analyzer,Zeta potential analyzer and scanning electron microscopy(SEM).RAPA-loaded optimal cubosomes were spherical with an average size of 180 nm,polymer dispersity index(PDI)of 0.3 and an encapsulate efficiency of 92%.Different molecular weights of hyaluronic acid(HA)were added on the surface of RAPA-loaded cubosome using charge attraction effect.The modified cubosomes have different morphologies and drug release kinetic models,comparing four drug release systems in vitiro,including fiee drug from commercial Rapamune,drug from cubosomes,drug from 9kDa HA modified-cubosomes and drug from 38kDa HA modified-cubosomes.In vitro cytotoxicity study of RAPA-loaded cubosomes on H9c2 cells showed the half maximal inhibitory concentration(IC50)was about 4.5?g/ml of RAPA.The new developed water-soluble RAPA-loaded PEG-PLGA nanoparticles and RAPA-loaded cubosomes both showed a promising result as a drug delivery system and further in vivo studies may be conducted in the future.