Construction Of Nano Reserveriors Drug Delivery Systems Based On Mesoporous Apatite Nanoparticles And Their Biological Evaluations

Cancer is one of the leading diseases to threat human health,and chemotherapy remains the major treatment modality.However,conventional chemotherapy suffers the disadvantages of strong side effect,low drug bioavailability,and lack of specific recognition,which results in treatment failure in cancer.Nano-biomedicine can effectively solve the disadvantages of conventional chemotherapy by using nanomaterials as carriers to load drugs with intelligent controlled release behavior,which plays an important role in improving human health.Mesoporous hydroapatite nanoparticles(MHAPNs)have been developed to be novel drug nanocarriers owing to their unique mesoporous structure,large surface area,tunable pore size,good biocompatibility and biodegradability,which show promising application in the field of intelligent controlled drug release system.Based on these mentioned advantages,in this study,we empoloyed MHAPNs as substrates to construct redox-responsive MHAPNs with end-capped collagen nanocomposite system for targeted drug delivery,pH-responsive MHAPNs with end-capped bovine serum albumin nanocomposite system for targeted drug delivery,and high drug loading pH-responsive MHAPNs with grafted polyacrylic acid nanocomposite system.Moreover,the responsive release and endocytosis mechanism of MHAPNs nanocomposite systems were studied,which paved the way for the future clinical applcations.MHAPNs with high specific surface area and uniform pore distribution were prepared by template method using calcium pantothenate monohydrate as calcium ion source,dipotassium hydrogen phosphate as phosphate ion source and triblock copolymer F127 as template.Redox-responsive nanoreservoirs based on MHAPNs(LA-Col-S-S-MHAPNs)end-capped with collagen were fabricated by using MHAPNs as nanoreserviors,disulfide bonds as internmediate linkers and lactobionic acid conjugated collagens(LA-Col)as caps.The results of SEM,TEM,BET,BJH,FTIR,fluorescamine and zeta potential measurements confirmed the successful preparation of LA-Col-S-S-MHAPNs nanocomposite system.The LA molecules acted as special ligands endow the system targeting ability through the special interaction with galactose receptors ASGP-R on the membrane of Hep G2 cell.The nanocopmposite system show redox-responsive drug release behavior triggered by glutathione by the rupture of disulfide bonds.Confocal laser scanning microscope(CLSM)images and flow cytometry assay demonstrated that LA-Col-S-S-MHAPNs nanocomposite system could be endocytosed and located in the cytoplasm of cells.pH-responsive nanoreservoirs based on MHAPNs(LA-BSA-CBA-MHAPNs)end-capped with bovine serum albumin were fabricated by using MHAPNs as nanoreserviors,4-carboxyphenylboronic(CBA)as internmediate linkers and lactobionic acid conjugated bovine serum albumin(LA-BSA)as caps.The results of SEM,TEM,BET,BJH,FTIR,XRD and zeta potential measurements confirmed the successful preparation of LA-BSA-CBA-MHAPNs nanocomposite system.The LA molecules acted as ligands endow the system targeting ability through the special interaction with galactose receptors of Hep G2 cells.Cumulative release profiles of drug from LA-BSA-CBA-MHAPNs in response to pH change confirmed the property of pH-responsive controlled drug delivery.CLSM images and flow cytometry assay demonstrated that LA-BSA-CBA-MHAPNs nanocomposite system were specifically endocytosed and located in the cytoplasm of cells.The organic-inorganic composite nanoparticles polyacrylic acid modified MHAPNs(PAA-MHAPNs)were prepared by grafting polyacrylic acid(PAA)onto the surface of MHAPNs.The results of SEM,TEM,FTIR,1H-NMR,BET,BJH,TGA and zeta potential measurements confirmed the successful preparation of PAA-MHAPNs.The DOX could be loaded to both the surface of PAA-MHAPNs and the mesoporos of MHAPNs by the electrostatic interaction at neutral conditions.The DOX loading efficiency can reach to 3.3%.Cumulative release profiles of DOX from PAA-MHAPNs in response to pH change confirmed property of pH-responsive controlled drug delivery.CLSM images demonstrated that DOX@PAA-MHAPNs nanocomposite system were endocytosed and released DOX in the cytoplasm of cells.