Porous Hydroxyapatite Micro/nanoparticles As Controllable Drug Delivery Carrier

Hydroxyapatite[Ca10(PO4)6(OH)2,HAp],the important inorganic component of biological hard tissues,has attracted much attention as an excellent candidate for biomedical applicationns,owing to its outstanding biocompatibility.Many efforts have been made towards fabricating HAp-based nanostructures because of their promising applications in drug deliveries,bone substitute filler,catalysts,sensors,photoelectric materials,chemical and environmental engineering.The performance of HAp in above applications depends greatly on its crystallite size,chemical compositions,three-dimensional(3D)architectures and morphologies.To build more effective HAp and composite systems,the particle synthesis processes,chemistry,and toxicity have to be thoroughly investigated.In addition,many researches have been focused on the possibility of combining HAp with various drugs,proteins,and genes for multipurpose applications.In order to achieve successful drug-delivery systems,numerous efforts have been devoted to generate HAp materials with porous 3D hierarchical structures in use of templates and surfactants.Template-based synthesis has been demonstrated as a versatile approach to falbricate porous structures.Plenty of templates have been extensively employed to prepare porous structures.Although template-based synthesis is very effective in fabricating porous structures,the reaction procedures are a little tedious,including surface modification,precursor attachment,and template removal.Thus,the exploration for template-free,simple,mild,high-yield,and environmentally friendly methods to synthesize HAp micro-particles or nanoparticles with porous structures stil remains a tremendous challenge.Initially,3D hierarchical microspheric hydroxyapatite(HAp)composed of two porous hemispherulites was hydrothermally fabricated at low temperature in the absence of any surfactant,organic solvents and templae-directing reagents.The Ca(NO3)2·4H2O andNH4H2PO4 were used as Ca and P sources,respectively,NaNO3,Mg(NO3)2,KNO3,NH4Cl,NH4F were utilized as substituted ion sources,and(CH2)6N4 was applied as the homogeneous precipitation reagent and CO32-source.Through tuning the reaction time,reaction temperature and additives,a potential growth mechanism of structural evolution of the HAp prodtucts from dumbbell-like particles to microspheres was proposed.Meanwhile,reaction condition to obtain the optimal morphology was determined,which is 80 ? for 8 h.As regulating agents,the substitutions play a key role in the formation of hierarchically nanostructured HAp.The X-ray diffraction(XRD),Fourier transform infrared spectroscopy(FTIR),scanning electron microscope(SEM),UV-Vis absorption spectroscope were used to study the morphology and size of the aggregates and their pH-responsive drug delivery behavior.The as-obtained hierarchical microspheric HAp composed of two hemispherulites were assembled from nanorods as building blocks with diameters of about 40 nm and the nanorods were parallel to each other along the long axis,exhibiting porous loose structure.The degradation,drug loading and release property of the synthetic materials were further investigated.Ibuprofen(IBU),a nonsteroidal anti-inflammotory drug,was loaded in sHAp and rHAp for in-vitro pH-responsive drug delivery system Compared to rHAp having a low drug-loading efficacy(56.98%),sHAp exhibited an excellent drug-loading efficacy(74.35%).In addition,the cumulative release amount of IBU:from sHAp reached a maximum value of 24.5wt%in PBS during 72 h,while rHAp reached 76.9wt%.In addition,the drug release rate increased apparently with the decrease of the pH value of the solution medium.Next,3D hierarchical porous flower-like hydroxyapatite microspheres with co-substituted essential trace elements(Na+,Mg2+,K+,F-,Cl-and CO32-)were hydrothermally fabricated with the aid of(CH2)6N4 and NaNO3,Mg(N03)2,KNO3,NH4Cl and NH4F as the homogeneous precipitation reagent and substituted ion sources.As regulating agents,the substitutions play a key role in the formation of hierarchically nanostructured HAp.The micro-orphology,crystal structure and texture feature were characterized using SEM,TEM,FTIR and XRD,respectively.The synthesized porous hydroxyapatite microspheres(sHAp)have several advantages over rod-like hydroxyapatite nanoparticles(rHAp),where the porous structure enhances drug-loading capacity and reduces burst release of drug and provides pH-responsive release.Ibuprofen was loaded in sHAp and rHAp for in-vitro pH-responsive drug delivery system.Compared to rHAp having a low drug-loading efficacy(56.98%),sHAp exhibited an excellent drug-loading efficacy(70.21%).In addition,the cumulative release amount ofIBU from sHAp reached a maximum value of 26.7 wt%in PBS during 72 h,while rHAp reached 76.9 wt%.Finally,mesoporous hydroxyapatite(HAp)rhombs were successfully synthesized by transforming CaCO3 into HAp via an ion-exchange reaction without any surfactants.Through tuning the concentration of H3PO4 and reaction time,different proportions of CaCCO3/hydroxyapatite compositions were obtained.The micro-orphology,crystal structure and texture feature of samples were characterized using SEM,TEM,FTIR and XRD,respectively.It is found that the concentration of H3PO4 has a great influence on the phase and morphology of calcium phosphate converted from calcium carbonate.With the concentration of H3PO4 solutions increasing,the content of calcium phosphate increased while the calcium carbonate content decreased,and the surfaces and inner parts of the CaCO3/HAp composites were full of nanoparticles.Eventually,CaCO3 microparticles were transformed to HAp completely when the concentration of H3PO4 solutions was 0.2M after reaction for 72 h.The aggregates of the nanoparticles in the fabricated HAp rhombs induced the formation of mesopores,which were further confirmed by the nitrogen adsorption desorption isotherm(BET).The final product displayed a rhombic micro-particle with a meso-porous structure,the pore size was distributed in a range of about 10-30 nm.Given the unique micro morphology structure of the porous hydroxyapatite square,the nonsteroidal anti-inflammatory ibuprofen(IBU)was used as the drug model to conpare the loading and release capabilities of mrHAps.The drug loading capacity of the fabricated mrHAps was 75.78%,while that of rHAp was 19.4%.In addition,the cumulative release amount of IBU from sHAp reached a maximum value of 22.2 wt%in PBS during 72 h,while rHAp reached 76.9 wt%.