Design,Preparation And Drug-loading Properties Of Water-soluble Carrier Materials

Some effective drugs,such as vitamins,amitriol and doxorubicin,have been widely used in clinical practice because of their good therapeutic effects.However,the disadvantages of poor solubility in water and the large side effects of solvent toxicity limit their efficacy and application.Therefore,in order to effectively improve and improve the efficacy of the active ingredients of liposoluble drugs,directional delivery and targeted therapy are realized,with the help of biocompatible water-soluble drug loading materials,which can be formed by self assembly in aqueous solution.The effective dispersion of liposoluble drugs in aqueous solution system is one of the hotspots in the current research and development of the nano micelles,particles or vesicles of the inside water（"O/W"）type.Amphiphilic polymers have a good solubilization effect on liposoluble drugs because of their hydrophilic chain segments and lipophilic groups on the molecular chains.The surface charged groups of the amphiphilic polymers modified by the terminal group and the drugs can be targeted by the electrostatic attraction.The targeted delivery of components to target organs or target sites can maximize the efficacy of drugs and reduce the side-effect of non-therapeutic sites.In this paper,organosilicon polymers with good flexibility and biocompatibility and polyhexyl ester with low toxic as water-soluble polymers were covalently grafted on the hydrophobic chain by silico hydrogenation,ring opening polymerization and click reaction.Cationic and pH responsive amphiphilic polymers were prepared.The drug loaded micelles of vitamin E（VE）were prepared by dialysis,and their drug loading performance and drug release behavior under physiological conditions were studied.The specific contents are as follows:1、Preparation and drug loading properties of cationic silicone polymers.The polymethyl siloxane polyethylene glycol（PEG-PDMS-PEG）was prepared by the addition reaction of hydrogen siloxane macromolecular prepolymer and allyl polyethylene glycol,and the polyether chain end of the copolymer was modified with quaternary ammonium salt by chlorination and quaternation,and the cationic silicone polymers were obtained(QAC-PEG₂₂-PDMSm-PEG₂₂-QAC m=20,40and 60).The reaction intermediates and target product polymers were characterized by FTIR and NMR spectroscopy.Particle size potential analysis showed that the Zeta potentials of 3 products in aqueous solution were 43.6mV,41.5mV and 43.3mV,showing positive electricity.The results of pyrene probe,dynamic light scattering（DLS）and transmission electron microscopy（TEM）show that the critical micelle concentration（CMC）of the 3 products in aqueous solution was 3.17x10^-2 g/L,2.25x10^-2g/L and 8.27x10^-3g/L,and the spherical structure of DLS particle size between 75nm to 190 nm was formed in aqueous solution,with a narrow particle size distribution and less than 0.26 of the particle size distribution.The results showed that the 3 polymers could form spherical micelles with vitamin E（VE）.The size of DLS particles was between 90nm and 280nm,and PDI was less than 0.27.The encapsulation efficiency of the drug loaded micelles（DLE）were 64%,84.2%and 85.8%respectively.The amount of drug loading（DLC,the amount of drug/polymer in the drug loaded micelles,unit g/1g）was 0.126g/1g,0.162g/1g and 0172g/1g respectively.In vitro release experiments of drug loaded micelles showed that the cumulative release rate of VE was 44%,35%and 33%within 78 hours,respectively.The toxicity test of normal human hepatocytes（L-O2）showed that when the concentration of QAC-PEG₂₂-PDMS₄₀-PEG₂₂-QAC was 125μg/mL,the cell survival rate was88.1%,which was suitable for drug loading material.In addition,the change of DLS monitored drug micelles showed that the size of the particle size was maintained between100nm and 110 nm during the 70 days observation period,and the particle size distribution coefficient（PDI）was maintained between 0.20 and 0.25.2、The preparation and drug loading properties of PEG polycaprolactone copolymer.2 kinds of pH responsive and degradable poly（ethylene glycol）poly（ethylene glycol）copolymer（Me₂N-PEG-b-PCL-1 and Me₂N-PEG-b-PCL-2）and 1 nonionic poly（ethylene glycol）polyhexyl ester copolymer（MeO-PEG-b-PCL）were prepared by ring opening polymerization and clicking chemistry,using infrared spectroscopy and nuclear magnetic resonance to characterize the structure of target polymer.The CMC values of the 3copolymers were 6.44x10^-4g/L,2.30x10^-3g/L and 7.46x10^-4g/L,respectively.Among them,in the micro environment of Me₂N-PEG-b-PCL-1（pH=6.0⁷.0）Zeta potential value between2.20 mV⁸.85mV,with pH response.The results of DLS and TEM show that the 3 kinds of polymers can form spherical nano micelles in aqueous solution,with a particle size of 50 nm to 90 nm,and the size of the particles decreases with the increase of the length of the hydrophobic chain PCL.The size of the micelles after the encapsulated model drug VE increases 30nm to 40nm,The DLE of Me₂N-PEG-b-PCL-1,Me2N-PEG-b-PCL-2 and MeO-PEG-b-PCL was 86.3%,71.3%and 90.3%respectively,and DLC was 0.173g/1g,0.150g/1g and 0.181g/1g respectively.In vitro release of drug loaded micelles showed that the release amount of Me₂N-PEG-b-PCL-1 in pH=5.0⁷.0 PBS buffer solution increased with the decrease of pH value,and the release amount in 78h in vitro was 47%.The MTT cytotoxicity test of Me₂N-PEG-b-PCL-1 showed that when the concentration was 125μg/mL,the cell survival rate was 89.1%,which was suitable for the carrier of drug loading material.In addition,DLS monitored the changes in drug loaded micelles,indicating that the particle size was maintained at 80nm to 90nm during the 70 days observation period,and PDI remained between 0.16 and 0.20.