Preparation,Physicochemical Properties And Applications Of Catanionic Mixtures As Drug Carriers

Amphiphilic molecules with opposite charges can form a variety of aggregates different forms, such as, vesicles, micelles, icosahedron, nanodisc and nanotubes. Catanionic mixtures can serve as drug carriers because of their advantages as avoiding the drug inactivation, reducing side effects of drugs, overcoming multidrug resistance index and improving the bioavailability of the therapeutic agent. The catanionic mixures composed of surfactants with opposite charge have been the hot area because their spontaneously formation, high stability and the adjustability stucture and properties by controlling the molar ratio, chain length, temperature, ionic strength.In order to reduce the toxicity of carrier material of the catanionic mixtures and increase the drug loading, our group proposed to substitute one or two surfactants in catanionic mixtures with charged amphiphilic drug molecules, so that drug molecules could form catanionic mixtures with oppositely charged surfactants or drug derivative. The drug-derivative catanionic mixtures formed by the drug and its oppositely charged derivative could further avoid the use of a carrier material to achieve a carrier-free drug delivery.In this paper, we invesgied two catanionic mixture systems composed respectively with positively charged drug molecules and negatively charged surfactant molecules and positively charged drug molecules and negatively charged drug derivative molecules. This paper is divided into three parts. In the first section, drug diphenhydramine hydrochloride (diphenhydramine hydro chloride, DH) was selected as model drug and food additive Sodium bis (2-ethylhexyl) sulfosuccinate (AOT) was selected as negatively charged surfactant. The aggregation behavior, physical and chemical properties and in vivo release behavior of the prepared catanionic aggregates. In the second and the third part, the anticancer drug chlorambucil (CLB) was selected as the model drug. After modification, positively charged derivative CLBM·HCl and derivative CLBM were formed and CLBM/AOT and CLB/CLBM catanionic mixtures were prepared. The physical and chemical properties, in vitro nature of the drug release kinetics behavior and cell toxicity were investigated, study its Subject research methods, content and results are as follows:1. Preparation and properties of catanionic DH-AOT mixtures and their application in prolonged drug release.In this part, catanionic DH-AOT mixtures were prepared with the amphiphilic drug diphenhydramine hydrochloride (DH) serving as the cationic molecule model and double-stranded sodium bis (2-ethylhexyl) sulfosuccinate serving as the anionic surfactant. The physical and chemical properties, and their aggregation behavior and application as controlled-release drug delivery carrier of the as prepared catanionic mixtures were studied. Pyrene probe method, dynamic light scattering, transmission electron microscopy, conductivity, turbidity and other technology were used in the investigation of the as prepared catanionic mixtures. Under certain conditions, DH and AOT couled spontaneously form drug/surfactant catanionic aggregates with different structure such as micelles and vesicles. The structure, diameter size, zeta potential properties could change with the molar ratio of the two composition. Results of in vitro drug release test showed that in the neutral medium, DH-AOT aggregates have significant sustained drug release effect. The hemolytic toxicity study gave a preliminary evaluation of the security of the selected catanionic vesicles. The results showed that the involving of DH molecules in the catanionic vesicle, to some extent, reduced the hemolytic toxicity of pure surfactant vesicles at the certain concentration. Using New Zealand rabbits as experimental animal models, we studied the plasmaconcentration of DH after intramuscular injection of DH solution and catanionic DH-AOT vesicles. Compared with the drug solutions, the average residence time in vivo and AUC were increased. The above research, especially research of in vivo release properties the catanionic DH-AOT mixtures builded the theoretical foundation of thre applications as drug carriers of drug-participating catanionic mixtures.2. Preparation and properties of catanionic CLBM-AOT aggregate.We selected alkylating antineoplastic chlorambucil (CLB) as a model drug in this part. Firstly CLB was modified and its derivative hydrochloride (N-(2-Amino-ethyl)-4-{4-[bis-(2-chloro-ethyl-amino]-phenyl}-butyramide, CLBM·HCl) was used as the cationic molecule of the catanionic mixture with double-stranded sodium bis (2-ethylhexyl) sulfosuccinate serving as the anionic surfactant. The physical and chemical properties, release behavior, cytotoxicity and cellular uptake properties of the as-prepared catanionic CLBM-AOT mixtures were invesgated. CLBM and AOT could spontaneously form drug/surfactant catanionic aggregates under certain conditions. The structure, particle size, zeta potential and other properties of the aggregates would change with the adding of the CLBM·HCl molecules. Results of in vitro drug release test showed that in the neutral medium, DH-AOT aggregates have significant sustained drug release effect. The cytotoxicity to K562 cells and MCF-7 cells of CLB, CLBM·HCl and the catanionic CLBM-AOT aggregates were measured by WTT method. The results show that after the formation of catanionic CLBM-AOT aggregates, the vitro antitumor activity of CLBM·HCl was significantly enhanced. Amphiphilic fluorescent molecule D109 was used to investigate the cellur uptake of MCF-7 cells to the as-prepared catanionic aggregates. Results show that thecellur of D109 was significantly enhanced after being loaded in catanionic CLBM-AOT aggregates. Studies have shown that the as-prepared catanionic mixtures have potential applications in delivery of anticancer drugs.3. Construction and Evaluation of carrier-free catanionic CLB-CLBM mixtures.Based on the researches on catanionic drug-surfactant mixtures, in this paper we further carried out the study on the catanionic drugs-derivatives mixtures using CLB as the model drug molecules. CLB-CLBM ionic pairs were synthesized by the proton exchange and the structure was confirmed with FTIR chromatography. The properties of the as-prepared catanionic CLB-CLBM mixtures were invesgated with the conductivity, transmission electron microscopy, dynamic light scattering technique. The results show that the critical aggregate concentration of the CLB-CLBM ionic pairs is about 9 ×10"5 mol·L1. In the solution of catanionic CLB-CLBM mixtures there were spherical nano-aggregates with an average particle diameter of 100-200 nm at certain range of concentrations. Through the establishment of the catanionic drugs-derivatives mixtures system, self-drug delivery could be achieved, avoiding the use of toxical carrier material. The establishment of as-prepared catanionic CLB-CLBM mixtures slowed the release of drug molecules and increased the cytotoxicity to HL-60 cell line.In this paper we systematically studied the preparetion of catanionic drug-surfactant mixtures composed with DH and derivatives of chlorambucil and invesgated the application of catanionic drug-surfactant mixtures as drug delivery system. Also catanionic drugs-derivatives aggregates were innovatively developed. And their aggregation behavior, in vitro release properties and cytotoxicity were studied. This paper enriched the study of catanionic mixtures, and provided experimental basis to their application as a drug carrier.