Coordination Bonding Based Ph-Responsive Albumin Nanoparticles For Drug Delivery

Stimuli-responsive drug delivery systems have attracted much attention in recent years, as the use of"smart"carriers offers an interesting opportunity to improve the bioavailability and reduce side effect. Of these stimuli–responsive systems, the pH–sensitive system is of special interest. The extracellular pH of tumors is more acidic (pH 5.7–6.8) than that of blood and normal tissue, and the pH values in endosomes and lysosomes reach values as low as 5.5 and 5.0, respectively. The low immunogenicity, nontoxicity, biodegradability and preferential uptake in tumor make serum albumin an ideal candidate carrier for anticancer drug delivery. In this thesis, coordination bonding based pH responsive system was combined with the excellent anticancer drug carrier-albumin, to develop pH responsive albumin nanoparticles for anticancer drug delivery.In chapter 1, the research background including the current treatment of cancer, the targeting and responsive research of nanoparticles, the approaches to realize pH responsive and the albumin based anticancer drug delivery systems was reviewed.In chapter 2, Zn loaded albumin nanoparticles ("BSA-Zn") were prepared via two pot method. BSA nanoparticles were prepared by desolvation, then zinc was introduced into this system to load anticancer drug ("BSA-Zn-drug"). The obtained nanoparticles were spherical with diameter of 50-60 nm with narrow size distribution. Mitoxantrone (MX) was chosen as the model drug to study its release behavior and the inhibitory efficacy against tumor cells. In vitro release behavior of MX loaded BSA-Zn nanoparticles ("BSA-Zn-MX") showed a fine pH-responsiveness. At pH 4.0, the release amount exceeded 80%; while at pH 7.4, the cumulative release amount was less than 6% within 24 h. The blank"BSA-Zn"nanoparticles were of low cytotoxicity, while a high cytotoxic activity of"BSA-Zn-MX"nanoparticles against breast cancer cells (MCF-7) was demonstrated by in vitro cell assays.In chapter 3, BSA-Zn nanoparticles were prepared in different kinds of salt solution via one pot method. The influence of the type and ion concentration of salt solution to the nanoparticles morphology was investigated. The release behaviors of the samples prepared in different solution were tested as well. The nanoparticles synthesized in PBS with moderate ion concentration were spherical with unique diameter. Besides in vitro release study showed excellent pH responsiveness, the release percentage exceeded 90% at pH 4.0, while the cumulative release percentage was less than 10% within 24 h at pH 7.4. The diameter of the nanoparticles prepared in NaCl solution of low ion concentration was uniform. But the coordination bonding between Zn and MX was influenced by chloride ions which resulted in the imperfect pH-responsiveness of this sample. The cumulative release percentage was over 20% within 24 h at pH 7.4.In chapter 4, X-ray Photoelectron Spectroscopy (XPS), Inductively Coupled Plasma (ICP) and UV-vis were introduced to study the adsorption and release mechanism of BSA-Zn nanoparticles. BSA-Zn nanoparticles prepared via two pot method were chosen as the model to study the adsorption and release mechanism for its unique diameter and excellent pH-responsiveness.?The release at pH 6.5 was mainly caused by the cleavage of the bonding between BSA and Zn, and the cleavage of the bonding of Zn-BSA and Zn-MX resulted in the release in medium of pH 5.0 and 4.0.Chapter 5 sums up the work and proposes the outlook.