Preparation And Preliminary Study Of Targeting Of Cyclodextrin Coated PLGA Nanoparticles

The nanoscale of single materials are susceptible to the limitations of the material itself and the pathophysiological conditions of human body,resulting in poor targeting therapy.Hydrophilic substances in polymer coated layer can protect the drug molecules from the inside of the micelles to be absorbed or degraded,help drugs escape the uptake of the reticuloendothelial system,prolong the time of drug circulation,and ultimately control the release of drugs to achieve better therapeutic effects.The nanoparticle carrier coated with two affinity polymer is self assembled to form a thermodynamically stable system with core-shell structure in solution.The hydrophobic core can be loaded with insoluble drugs to improve the solubility of drugs.In this study,the surface of PLGA nanoparticles was coated with hydrophilic 2-HP-beta-cyclodextrin(2-HP-β-CD),in order to improve the stability and biocompatibility of the nano system,enhance the surface hydrophilic effect,explore the new recognition function of the system in tumor targeting therapy and to find out the regularity of increasing the targeting of anticancer drugs by constructing a variety of carrier materials,and to solve common key problems affecting the stability of single carrier material system.The main contents and results are as follows:1.Paclitaxel PLGA nanoparticles were prepared by a modified emulsification solvent evaporation method,and the effects of glycolide / lactide copolymer ratio of PLGA,molecular weight and the coated of 2-HP-β-CD on the particle size,potential and appearance of nanoparticles were investigated.The both nanoparticles were spherical.There is a large number of holes were observed in the surface of uncoated nanoparticles under the transmission electron microscope.While the surface of the 2-HP-β-CD coateded nanoparticles is coated with a layer of semitransparent material,and the hole is not observed.The both particle size were range around 140~210nm,and the coated nanoparticle potential is significantly reduced.The results of differential scanning calorimetry(DSC),infrared spectroscopy and X-ray diffraction showed that paclitaxel was self assembled with carrier in amorphous state by hydrogen bonds and other interactions.The part of paclitaxel can be encapsulated through the hydrophobic cavity of 2-HP-β-CD after coated,which is beneficial to the drug loading and increases the encapsulation efficiency of the nanoparticles.2.Dialysis bag method was used to simulate the biological environment in vivo.The results showed that pH had no significant effect on the drug release rate,and the uncoated nanoparticles were obviously released,and the coated nanoparticles all reached the release balance at 480 h.There was a burst release of unmodified nanoparticles in initial release and all the modified nanoparticles reached the release balance at 480 h.The result showed the decreases drug release with the increase of the molecular weight of the carrier of pre-and post-coated nanoparticles.Except for the copolymerization ratio of 50/50,the other two copolymerization ratios have little effect on the release rate.Therefore,nanoparticles coated with 2-HP-β-CD can help slow release of drugs and prevent the brust release,which is beneficial to prevent excessive blood concentration in vivo for a short time.3.The preliminary safety evaluation of paclitaxel PLGA nanoparticles was carried out in pre-and post-coated nanoparticles by abnormal toxicity evaluation and hemolytic test.The results of the abnormal toxicity test of pre-and post-coated PTX-PLGA nanoparticles were qualified,so there was no abnormal toxicity was produced during the preparation process.The results of blood compatibility showed the high safety of the preand post-coated nanoparticles although differences in existence.4.The near-infrared imaging technique was used to observe the distribution of nanoparticles in mice by using rhodamine as a fluorescent probe.The fluorescence of drug delivery groups distributed in all parts of the body at the early stage of administration.The fluorescence intensity of PLGA nanofluorescence probe decreased obviously with the extension of time.The fluorescence signals of each group with molecular weight of 10000 decreased significantly.The fluorescence signals of PLGA nanofluorescence probe indicated that the liver / kidney was enriched after 30 min.And it is mainly concentrated in the kidney and bladder excretion after 4h.The fluorescence signals of 2-HP-β-CD/PLGA nanofluorescence probe were concentrated in the liver,and lung after 30 min.The degradation rate of carrier in vivo slowed down and the metabolic time prolonged with the increase of molecular weight.The pharmacokinetics of commercially available injection and 2-HP-β-CD/PLGA nanoparticles in the rats were investigated.The results showed that 2-HP-β-CD/PLGA nanoparticles significantly prolonged the time of systemic circulation and increased the concentration of plasma.By studying the preparation,characterization,safety,pharmacokinetics and tissue targeting of paclitaxel PLGA nanoparticles,the results showed that PLGA nanoparticles modified with 2-HP-β-CD have the following advantages.PLGA nanoparticles coated with 2-HP-β-CD could improve the entrapment efficiency and solubility of the hydrophobic drugs.The preparation is safe and can be used for intravenous administration by using biodegradable and compatible excipients.The release curve shows that the drug can be released slowly and reducing the sudden release of nanoparticles,so that the drug can reach the target site to maintain effective concentration.It can change the drug distribution in the dynamic characteristics and the tissue of the body,avoid the recognition and phagocytosis of reticuloendothelial system effectively,prolong circulation time and improve the bioavailability.