Albumin Nanoparticles Act As Carriers Of Hydrophobic And Hydrophilic Drugs

The nanoparticle drug delivery systems which are usually intravenously administrated have been one of the outcomes and focuses of nanotechnology. The commonly used carriers of nanoparticle include poly (lactic-co-glycolic acid) (PLGA), poly-caprolactone (PCL), poly lactic acid (PLA) and chitosan et al. Although these materials are biodegradable, their safety in intravenous administration still requires investigation, which limited its practical use. With the benefit of biodegradable, biocompatible, non-immunogenic, human serum albumin (HSA), a natural blood product, is a potentially ideal carrier for intravenous use. And the study of nanoparticle drug delivery system based on HSA is of great significance.The purpose of this thesis is to study the albumin nanoparticles system. The study deals with three aspects: the albumin nanoparticles loaded with water-insoluble drugs, the albumin nanoparticles for water-soluble drugs and the albumin nanoparticles for active drug targeting to brain.On the first hand, the antifungal drug, itraconazole, was selected as a model of water insoluble drugs. And the itraconazole-loaded albumin nanoparticles (ITZ-NPs) were developed by nanoparticle protein bound technology.The preparation craft and the influence factors of formulation including the concentration of HSA, the content of itraconazole and the fraction of organic phase were investigated. Then central composite design was used for further optimization. The optimized formulation was as follows: 1% of HSA, 50mg/mL of itraconazole and the faction of organic phase was 4%. The ITZ-NPs with particle size around 100nm were finally obtained, and the drug content was above 10%. Infrared spectrum (IR), Differential scanning calorimetry and X-ray powder diffractogram were measured to determine the existing station of itracoanzole in the ITZ-NPs, which indicated that itraconazole was at an amorphous state in the nanoparticles. The studies laid the foundation for the nanoparticle albumin bound technology which offers a good carrier for water insoluble agents.In antifungal activity test in Candida albicans in vitro, it was observed that the MIC50 of ITZ-NPs was only half of that of itraconazole (0.25μg/mL). In hemolytic test, the ITZ-NPs caused significantly milder hemolysis than the cyclodextrin formulation of itraconazole (ITZ-CD). Meanwhile, in safety test, the non-observed effect level for ITZ-NPs was 160 mg/kg, while 40 mg/kg for TZ-CD. The results suggested that the safety of ITZ-NPs was superior to the ITZ-CD for the substitution of cyclodextrin with HSA. In vivo evaluation test, it was indicated that ITZ-NPs did not alter the pharmacokinetics of itraconazole and OH-itraconaaole in rats. And the itraconazole’s biodistributions of ITZ-NPs in mice in liver, spleen and lung were higher than those of ITZ-CD. And the high distribution of itracoanzole in lung was of great significance for the lung was the main portal entry of fungal infection..On the second hand, the albumin nanoparticles active targeting of brain which were modified by 29 peptide of rabies virus glycoprotein (RVG) were developed and investigated. The modification of ITZ-NPs involved the avidin-biotin technology. The RVG-ITZ-NPs was of 90nm particle size and -33mV zeta potential. The obtained RVG-ITZ-NPs were evaluated in vitro, including particle size, zeta potential and release behavior et al.The brain targeting characteristics of RVG-ITZ-NPs were investigated both in vitro and in vivo. The uptake result demonstrated that the amount of RVG-ITZ-NPs uptaken by brain capillary endothelial cells (BCEC) was much 8-fold higher than that of non-modified ITZ-NPs. After 60min i.v. of fluoresce labeled RVG-ITZ-NPs and ITZ-NPs via caudal vein, the former brings much stronger fluorescence intensity in brain. In tissue distribution test, the itraconazole levels in brain, liver and lung of RVG-ITZ-NPs was significantly higher than ITZ-CD after 4h i.v. administration. Hence, the active targeting of RVG-ITZ-NPs was verified both in vivo and in vitro, indicating that RVG is a good active target ligand to brain and RVG-ITZ-NPs is a nolvle active drug delivery system for itraconazole targeting to brain for itraconazole was constructed.In the third aspect, to study the encapsulation of a model of water-soluble drug into the albumin nanoparticle system, gemcitabine-loaded albumin nanoparticles were developed by desolvation process. Gemcitabine was commonly used in pancreatic cancer chemotherapy. The influence factors of the craft and the formulation were investigated. The concentration of albumin, the amount of drug and the glutaraldehyde used was three main influence factors. Two kinds of gemcitabine-loaded nanoparticles were prepared: one of 110nm particle size, another 400nm. The pharmacokinetics, tissue distribution and antitumor activity of the two kinds of gemcitabine-loaded albumin nanoparticles were evaluated in vivo and in vitro. The results indicated that gemcitabine-loaded nanoparticles with particle size of 400nm could be a potentially promising nanoparticle drug delivery system in pancreatic tumor therapy for its significant increase of the gemcitabine distribution in pancrease and liver and higher antitumor effect compared with the 110nm-nanoparticles and gemcitabine solution.