Synthesis And Properties Of Drug-loaded Nanoparticles Based On Phytic Acid

Chemotherapy for bone tumors is not ideal due to factors such as myelosuppression,poor specific distribution,fast blood elimination rate,and blood barrier,etc.Nano-drug-loading systems have the advantages of small particle size,easy to penetrate cells,long blood circulation time in vivo,increased drug solubility,stability,and ability to deliver drugs to specific tissues and provide controlled-release therapy,nano-drug delivery systems have become a research hotspot.In addition,phytic acid is a naturally occurring polyphosphoric acid compound,which has the advantages of good biocompatibility,easy degradation,p H responsiveness,complexation with metal ions,and anti-tumor effect.So we use phytic acid as a nanotargeting material for drug delivery.The drug responsive release,bone affinity experiments and in vitro cell experiments were studied,and its performance was characterized by UV,FTIR,DLS,TEM,microplate reader,CLSM and flow cytometry.The main findings are as follows:(1)Phytic acid-cyclodextrin(PA-CD)nanoparticles are prepare by esterification and cross-linking with the phosphate group of phytic acid and the hydroxyl group of cyclodextrin,and DOX and CPT were loaded with it as a carrier to obtain PA-CD/DOX and PA-CD/CPT nano drug delivery system.The results shows that the particle size of PA-CD nanoparticles is 57.7 nm,and the particle sizes of PA-CD/DOX and PA-CD/CPT increase to 65 nm and 67.6 nm,respectively,after the nanoparticles are loaded.The prepared nano-drugs utilize the electrostatic force and inclusion effect between phosphate and cyclodextrin and drugs to achieve high-efficiency loading.The encapsulation efficiency of DOX and CPT reaches 98.2% and 81.2%,respectively,and the drug loading rate reaches 98.2% and 81.2% respectively.8.9% and 7.4%.In addition,both nanomedicines are p H-responsive and bone-targeted,with a faster release rate at p H=5.5 compared with p H=7.4,which can release 90%.Compared with free DOX and free CPT,the affinity of PA-CD/DOX and PA-CD/CPT drug-loaded nanoparticles to hydroxyapatite is higher than 90%;the affinity of mouse tibia is higher than 70%.In vitro cell experiments found that when the concentration of PA-CD reached 10 μg/m L,the cell viability is greater than 85%,indicating that PA-CD exhibits lower cytotoxicity,while PA-CD/DOX have obvious killing effect on cells;CLSM experiment it is found that PA-CD/DOX can be efficiently taken up by cells.(2)In order to control the nanoparticle size,Flash nanoprecipitation(FNP)method is used to prepare PA by using the electrostatic interaction and hydrophobic interaction between sodium phytate,chitosan and model drugs(DOX and β-carotene).PA-CS/DOX and PA-CS/β-carotene nanoparticles,the encapsulation efficiencies of DOX and β-carotene are 60% and 77.2%,respectively.It is found that the size of nanoparticles can be controlled by controlling the flow rate and different solvent ratios.When the flow rate is increased from 10 m L/min to 50 m L/min,the particle size of PA-CS/DOX nanoparticles decreases from 600 nm to134.3 nm,and that of PA-CD/β-carotene decreases from 120 nm.As small as 80 nm,the drug-loaded nanoparticles can exist stably within 72 h.The drug-loaded nanoparticles are also p H-responsive and have good affinity for bone.PA-CS/DOX can release 95% under acidic conditions,only 50% under neutral conditions,and 50% of PA-CS/β-carotene under acidic conditions,and The release amount is 31%.The bone affinities of the drug-loaded nanoparticles are higher than that of the free drug.MTT experiment shows that the cytotoxicity of PA-CS is low,and PA-CS/DOX can effectively kill tumor cells;CLSM experiments found that PA-CS/DOX could enter cells smoothly to release drugs,so that DOX can be effectively enriched in the nucleus.(3)In order to promote the proliferation and differentiation of osteoblasts,we use the complexation of phytic acid and calcium ions to prepare PA-Ca/DOX and calcium chloride by Flash nanocomplexation(FNC)with sodium phytate and calcium chloride.The PA-Ca/β-carotene drug-loaded nanoparticles have 66% and71.5% encapsulation efficiencies for DOX and β-carotene,respectively.It is found that the particle size can be controlled by adjusting the flow rate and solvent ratio when calcium phytate is loaded with drugs.When the flow rate is increased from 10 m L/min to 50 m L/min,the size of PA-Ca/DOX nanoparticles decrease from 420 nm to 193 nm,and the size of PA-Ca/β-carotene nanoparticles decrease from 60 nm.as small as 45 nm.Exploring p H-responsive release and affinity experiments found that the release of the two drug-loaded nanoparticles reached 60% at p H=5.7.The release amount at p H=7.4 is only 30%;the affinity of drug-loaded nanoparticles to hydroxyapatite and mouse tibia is higher than that of free drug.The results of in vitro cell experiments show that the cytotoxicity of PA-Ca is low,and PA-Ca/DOX have good performance of killing tumor cells;PA-Ca/DOX could penetrate the cell membrane smoothly and reach the nucleus.