Design Of Nanoparticles With Biomemitic Surface For Tumor Targeting

Inorganic nanoparticles (NPs), because of their unique physicochemical properties and ability for surface functionalization, have shown great potential in biomedical applications, such as cancer diagnosis and therapy. The stability and antifouling ability of NPs in the complex biological condition are important prerequisites for their successful use in vivo. Based on the hydrophilicity and nonfouling properties of zwitterionic surface, in this dissertation, NPs were modified with either single-component zwitterionic ligand or mixture of two-component oppositely charged ligands. Focusing on the key requirements of NPs for tumor targeting, this dissertation explores how to utilize the strategy of zwitterionic surface modification to endow NPs with hydrophilicity, stability, antifouling ability and smart-responsive property. The details are given in the following parts:1. Cell membrane biomimetic modification of quantum dots with zwitterionic phosphorylcholine.Amphiphilic, zwitterionic11-mercaptoundecylphosphorylcholine (HS-PC) was used to convert hydrophobic CdSe/ZnS quantum dots (QDs) into water-soluble QDs, which possessed several advantages, such as small hydrodynamic diameter, good resistance to pH variations, excellent stabilities in biological media, and low protein adsorption. In addition, QDs with excellent cell penetration ability were prepared by modifying QDs with a mixture of HS-PC and Tat. Compared to the non-zwitterionic mercaptoundecanoic acid (MUA) modification, zwitterionic PC modification not only made the cell penetrating QDs more stable, but also provided the Tat-and PC-conjugated QDs with much lower nonspecific phagocytic uptake.2. The study of nanoparticles modified with mixed-charge monolayer surface and their properties.Gold nanoparticles (AuNPs) were surface modified by a mixture of sodium10-mercaptodecanesulfonic acid and (10-mercaptodecyl)-trimethyl-ammonium bromide in1:1molar feed ratio. The AuNPs protected by mixed-charge self-assembled monolayers (SAMs) showed much better stability than the single negatively or positively charged AuNPs in biological media. The mixed-charge SAMs can stabilize large AuNPs (50nm and100nm) better than the short-chain ligand monohydroxymercaptoundecyltetraethylene glycol (HS-C11-EG4). Compared with the long-chain mercaptopolyethylene glycol (Mw=2000, HS-PEG2000), they endowed AuNPs with smaller hydrodynamic diameters and better long-term stability. In vitro study demonstrated that16nm AuNPs modified by mixed-charge SAMs can effectively resist plasma adsorption and minimize the nonspecific cell uptake by either non-phagocytic or phagocytic cells, which is much better than these only positively or negatively charged AuNPs. They even showed stronger resistance to phagocytosis by macrophage than that of the HS-C11-EG4or HS-PEG2000modified AuNPs. In vivo study in mice model further demonstated that the mixed-charge AuNPs had a much longer blood half-life, lower capture by the liver and spleen, higher accumulation and longer retention in tumors than HS-PEG2000coated AuNPs did.3. The study of nanoparticles modified with weak electrolytic mixed-charge surface and their pH-responsive properties.A mixture of weak electrolytic11-mercaptoundecanoic acid and strong electrolytic (10-mercaptodecyl)-trimethylammonium bromide in1:1molar feed ratio was used to modified16nm AuNPs, which exhibited fast, ultrasensitive, and reversible response to the pH change from the pH7.4as in blood and normal tissues to pH6.5as in tumor microenvironment. The mixed-charge AuNPs well dispersed at pH7.4with excellent stealth ability to resist uptake by macrophages, while quickly aggregated at pH6.5, leading to greatly enhanced uptake by cancer cells. In vivo results demonstrated that the pH-sensitive mixed-charge AuNPs had a considerable blood half-life as nonsensitive PEGylated AuNPs, but they had lower capture by reticuloendothelial system, much higher accumulation, retention, and cellular internalization in tumors than the later did. Furthermore, the aggregation of AuNPs in tumors can be applied to cancer NIR photothermal therapy.