The Comparison Of Preparing Two Polylactide Nanoparticles Loaded Lipophilic Anti-cancer Herb Drug By Nanoprecipitation Method And The Study On Its Distribution In Vivo

Nanoparticles have been widely used in biomedical science and biomedical engineering,especially in targeted drug delivery systems.It can deliver anti-cancer drugs to liver passively,so it has good curative effects in the treatment of hepatitises and liver cancer.Though there have been many artificial or natural polymers which can be used to prepare nanoparticles.only a few can be used in human. Polylactide(PLA) is an ideal carrier because of its excellent biocompatibility and biodegradation.Cucurbitacins (Cu)and Curcuminoids(Cur) are lipophilic anti-cancer herb drugs which are both insoluble in water.In this research, polylactide nanoparticle loaded Cucurbitacin (Cu-PLA-NP) and polylactide nanoparticle loaded Curcuminoids(Cur-PLA-NP) were prepared by nanoprecipitation method which is suitable for lipophilic drugs at present. The entrapping effects and drug loading process were compared. Cur-PLA-NP which had good entrapping effect was selected to prepare lyophilization injection. The property, stability, in vitro release characteristics of lyophilization injection were studied.The in vivo drug distribution of Cur-PLA-NP lyophilization injection and Cur injection in mice were also investigated.The appearance and physical stability.particle size and distribution.SEM of Cu-PLA-NP system before/after filtering through 0.8 um micropore filter membrane were observed.The results demonstrated that there were drug microcrystals besides Cu-PLA-NP during the preparation of Cu-PLA-NP by nanoprecipitation method. These drug microcrystals must be f.ltered. Uniform design was used to optimize the formula and technology for preparing Cu-PLA-NP based on simple factor investigation. An optimal condition was established.At last the average drug entrapping ration of Cu-PLA-NP was 38.53%, the average drug loading was 2.21%, the average drug recovery was 27.02%,the average diameter of quantity distribution was 151 nm and the average diameter of volume distribution was 149 nm.There were no drug microcrystals when Cur-PLA-NP was prepared by nanoprecipitation method. The effects of F^ concentration, PH of water phase, volume of acetone and water, amount of Cur and PLA on the quality of Cur-PLA-NP were investigated. The quality of Cur-PLA-NP finally got was significantly different from Cu-PLA-NP:the mean drug entrapping ration was 94.36%, i:he mean drug loading was 14.35%, the mean drug recovery was 91.23%,the mean diameter of quantity distribution was 113.1 run and the mean diameter of volume distribution was 171.6 nm. The study on drug stability which was relative to the preparation of Cur-PLA-NP showed that nanoprecipitation method had few effect on the stablility of Cur.The enormous difference between Cu-PLA-NP and Cur-PLA-NP resulted in the study on the drug loading process.By comparing the solvent evaporation rate,the residual quantity of acetone,the precipitation rate of drug and PLA ,the drug distribution in system and the entrapping ration at different time of preparation, the main reason was discovered. It was the difference of drug precipitation rate when the organic phase was injected into water.On the other hand, the affinity between drug and PLA also had great effect on entrapping effect.The stability of Cur-PLA-NP colloidal solution was poor, so Cur-PLA-NP lyophilization injection were prepared by using 8% Lactose as freezing protective agent. There were no differences between the colloidal solution and the lyophilization injection in the morphology, particle size ,pH and entrapping ration. The lyophilization injection was stable.The CRH of Cur-PLA-NP lyophilization injection was 69.86%. The in vitro release characteristics were well in accord with Weibull and Higuchi model.RP-HPLC method was used lo compare the distribution in vivo of Cur-PLA-NP to that of Cur at different time after i.v. administration. The results showed that the fate of Cur-PLA-NP was different from that of free Cur.Compared with Cur injection, Cur-PLA-NP showed higher distribution in liverthe absolute concentration increased 23.15 times, ALJC increased 5.26 times and relative distribution was raised to 92.68% from 70.45% at 10 minutes after i.v. administration. To Cur-PLA-NP, the targeting efficiency of liver to heart,spleen,lung and kidney were 2.15~25.26,which were 0.69~4.24 times more than Cur ingection? All these data demonstrated that Cur-PLA-NP had selective targeting to liver tissue.All these studies above-mentioned were not yet reported, so this research is quite innovative and has very important value. Through analyzing and comparing the drug loading process of two polylactide nanoparticles loaded lipophilic anti-cancer herb drug, the mechanism and affecting factors of nanoprecipitation method were discovered.The study results hint that besides solubility of drug, the interaction among drug,solvent and carrier also should be considered when nanoprecipitation method is selected.This can offer reference and experience for rational application of nanoprecipitation method. This research enriches the study contents of PLA-XP and establishes a good theoretical foundation for producing PLA-NP on a large scale and using PLA-NP in clinic.