Human Serum Albumin-Inorganic Hybrid Nano-materials For Delivery Of Metal-based Anticancer Drugs

More than ten millions of people develop cancers every year in the world. Cancer has been seriously imperiled human’s health and life. In chemotherapy, metal-based drugs play an important role in cancer therapy, such as cisplatin, carboplatin, oxaliplatin, arsenic trioxide, which have been used widely in clinic. Other metal-based drugs as ruthenium complexes (KP1019, NAMI-A) and gold complexes are in clinical assessment. However, these drugs show severe side effects, drug resistance, short circulation time in treatment, which limits their use and reduces the drug efficacy in clinic. In this work, the main works are summarized. (1) A carrier based on calcium phosphate nanoparticles and human serum albumin is used for delivering cisplatin prodrug. The drug delivery system will release the cisplatin in acid and reducing environment. (2) The HSA coated up-conversion nanoparticles are used to deliver photoactive polypyridyl ruthenium complexes. The carrier has two kinds of fluorescence, which can be applied in bioimaging. The delivery system can release toxic species with light irradiation. (3) An aspirin conjugated Pt(IV) complex (asplatin) is designed. The asplatin will be reduced in cellular and release cisplatin and aspirin, which produces synergistic effects of the two drugs and improves anticancer efficacy. A cholesterol is conjugated to the axial of asplatin which result in a hydropholic Pt(IV) complex. The cholesterol-asplatin can be loaded effectively in PEG-PLGA nanoparticles.In chapter 1, we give a brief review about metal-based anticancer drugs and drug delivery systems. It mainly includes the development and anticancer mechanism of platinum-based and ruthenium-based anticancer drugs, the development and anticancer mechanism of nano-delivery system. The development and anticancer mechanism of HSA based drug delivery system.In chapter 2, we design and synthesize a Pt(IV) complex-HSA/calcium phosphate nano-system. The Pt(IV) prodrug is linked to HSA to form a Pt-HSA complex. Then the Pt-HSA complex is conjugated to calcium phosphate (CaP). The Pt-HSA/CaP system is a highly biocompatible, pH and redox dual-responsive delivery system. The hybrid system is stable in the extracellular environment; however, upon cellular uptake by endocytosis, the CaP nanoparticles decompose in the weakly acidic environment of endosomes/lysosomes and the HSA protein is then released. The prodrug loaded on HSA can be reduced by cellular reductants, such as AsA, and the active form of cisplatin will be generated. The Pt(Ⅳ) prodrug loaded on HSA react with the target DNA only in the presence of reductant. The formation of HSA/CaP nanoparticle protect the Pt(Ⅳ) prodrug from premature reduction in the extracellular environment; hence, it is an ideal platform for controlled drug delivery. Moreover, the Pt-HSA/CaP hybrid inhibits the proliferation of various cancer cells more efficiently than cisplatin, but less cytotoxicity to normal cells. Different cell cycle arrests of Pt-HSA/CaP, relative to Pt-HSA and cisplatin, suggests a different cellular response of the Pt(Ⅳ) prodrug in the CaP nanocarrier. All materials used in the preparation are highly biocompatible and the mild preparation process lead to unaffected protein folding. Therefore, this method can have potential utility for the preparation of delivery systems for proteins and drugs.In charpter 3, we synthesize three polypyridyl ruthenium complexes and chose the best photoactive complex ([Ru(bpy)2(6,6’-dimethyl-2,2’-bipyridine)]Cl2) by comparing the photoactivity and phototoxicity. The [Ru(bpy)2(6,6’-dimethyl-2,2’-bipyridine)]Cl2 (Ru-1) complex will be loaded in drug delivery system. Three surface modification methods as mesoporous silica shell, PAA coating, HSA coating to modifying up-conversion nanoparticles (UCNPs) are prepared to investigate the stability of nanoparticle and Ru-1 complex loading efficacy in nanoparticles. The results show the HSA coated UCNPs (HSA-UCNPs) have excellent stability and high Ru-1 complex loading efficacy. The HSA coated layer makes UCNPs highly biocompatible and well dispersed in aqueous solution. Meanwhile, HSA-UCNPs are endowed two fluorescence characters separately from HSA and UCNPs. The core UCNPs (NaYF4:20 mol%Yb,0.5 mol%Tm) convert 980 nm near infrared light to blue light (451 nm and 474 nm). In addition, the HSA protein acquires green fluorescence after forming the coating layer by polymerization. This dual-fluorescence property makes the material well applicable in bio-imaging and provides more choices of excitation and detection wavelengths. The cellular internalization can be observed via either upconversion fluorescence or regular 450 nm excitation. With the loading of a photo-sensitive ruthenium complex (Ru-1) the conjugates (Ru-HSA-UCNPs) show photo-induced cytotoxicity. Ru-HSA-UCNPs show very low inhibitory effect to cell proliferation in the dark, while light irradiation significantly enhances the cytotoxicity to cancer cells. Further investigations indicate that Ru-1 is inactive in dark, and it turns quickly into an active species under the light irradiation and become highly reactive to DNA. The activated ruthenium complex is much more reactive than cisplatin in the reaction with DNA. This result suggests the potential application of this conjugate in the controlled release of active anticancer agents in tumor sites.In charpter 4, we design and synthesize a new Pt(Ⅳ) complex, an aspirin conjugated Pt(IV) complex (asplatin). The asplatin will be reduced in cellular and release cisplatin and aspirin, which produces synergistic effects of the two drugs and improves anticancer efficacy. In order to deliver asplatin efficiently by polymers as PEG-PLGA, A cholesterol is conjugated to the axial of asplatin which result in a hydropholic Pt(IV) complex. The cholesterol-asplatin can be loaded effectively in the hydropholic core of PEG-PLGA nanoparticles.