Indomethacin-loaded Polymeric Micelles Based On Amphiphilic Polyphosphazenes: Preparation And Applications In Controlled Drug Delibery Systems

In this paper we report on drug containing polymeric nanocarriers were prepared by dialysis method and drug loading capacity of polymeric micelles to hydrophobic drug—indomethacin(IND),which were based on amphiphilic polyphosphazenes (PNIPAAm/EAB-PPPs) bearing poly(N-isopropylacrylamide)(PNIPAAm) and ethyl 4-aminobenzoate(EAB) as side groups.In addition,in vitro and in vivo indomethacin(IND) release dynamics,and intraartieular(IA) treatment of arthritis bearing rat through IND-loaded nanocarriers were also performed to observe the therapeutic effect.In vitro release profiles of IND-loaded micelles in various media suggested that drug was released from micelles through diffusion mechanism.After subcutaneous injection of IND-loaded micelles into SD rats,the in vivo pharmacokinetics study suggested that the higher the administered dosage of polymeric micelles,the more sustained effect may be achieved.Compared with the control group administered the same dosage of IND in PBS solution,more sustained behavior was found for micelles related group.In vivo pharrnaeodynamics was investigated through the carrageenan-induced paw edema,and the result indicated that higher dosage of IND-loaded polymeric micelles exhibit more significant therapeutic effect than that of control group.In the case of adjuvant arthritic study,after injection of complete Freund's adjuvant,IND-loaded micelles could significantly inhibit secondary inflammatory swelling,reduce the elevated PGE level located in ankle and pain scores in inflamed paws.Pathological change in ankle showed that hyperplastic synivium,inflammatory cells infiltration,and pannus formation were significantly reduced in AA after administration of IND-loaded micelles.Oral administration of IND resulted in significant formation of gastric ulceration,while no rats in mieelles related group was observed to exhibit ulceration.In vivo pharmacodynamic study based on both acute and adjuvant arthritis model indicated that sustained therapeutic efficacy could be achieved through intraarticular injection of IND-loaded micelles.Most importantly,local delivery of IND can avoid the severe gastrointestinal stimulation,which was associated with oral administration.As revealed by in vitro cytotoxicity study,the cytotoxic effect of these amphiphilic polyphophazenes against tumor cells(MG63) was strongly dependent on copolymer concentration.At lower copolymer concentration,no inhibition on cell growth and cell morphology changes were observed.In summary,these novel amphiphilic copolymers could be used as injectable drug carriers.However,further study should be carried out.