Green Synthesis, Anti-tumor And Anti-metastasis Activity Of Targeted Nanoparticles

Tumor metastasis is the major cause of cancer morbidity and mortality. In the past few years, the survival rate of cancer has been greatly improved due to the progress made in the treatment of cancer. However, there exist various serious adverse effects in the applications of these treatment strategies, and the drug resistance, relapse, and metastasis are still unresolved problems. There are many different molecules involved in tumor metastasis that perform a specific yet critical role. Thus designing specifically key targets for intervention in tumor metastasis has become the focus of research on anticancer.Methods for the synthesis of nanoparticles(NPs) for biomedical applications ideally involve the use of nontoxic reducing and capping agents, and more importantly, enable control over the shape and size of the particles. Thus, based on molecular level understanding of cancer metastasis, three kinds of NPs using plant polyphenols with important biological activities have been designed and synthesized. Furthermore, we studied anti-tumor activities of NPs systematically, and clarified their probable mechanism.This thesis consists of four chapters:Chapter 1: Firstly, the mechanism of cancer metastasis was briefly described. Secondly, methods for the synthesis of nanoparticles and physicochemical properties of them suitable for biomedical application were clarified. Finally, the research progress of nanomedicine in treating cancer cell invasion was summarized.Chapter 2: It is more important to select suitable morphology of Se NPs for biomedical application. So spherical, Spindle and flower TA-Se NPs were synthesized using Tannic Acid(TA) as reducing and capping agents. TA-Se NPs(spherical) exhibited higher efficient cellular uptake and cytotoxicity against cancer cells compared to spindle and flower TA-Se NPs. Thus, spherical NPs continued to be studied in further experiments. Furthermore, our results indicate that TA-Se NPs can inhibits b FGF- induced angiogenesis in vivo and in vitro. We investigated the mechanism of anti-angiogenesis mediated by TA-Se NPs. We found that TA-Se NPs can bind to and stabilize b FGF, which affected the binding affinity of b FGF for FGFR. TA-Se NPs can inhibit b FGF-induced angiogenesis by suppressing the AKT and Erk signaling pathways and reduce the expression of b FGF.Chapter 3: We used gallic acid(GA) as both a reducing and a capping agent in a simple and “green” synthesis of stable Se/Ru alloy NPs(GA-Se/Ru NPs). The diameter and morphology of the Se/Ru alloy NPs were regulated by GA concentration, and the presence of Ru was found to be a key factor in regulating and controlling the size of GA-Se/Ru NPs. Moreover, GA-Se/Ru NPs suppressed He La cell proliferation through the induction of apoptosis at concentrations that were nontoxic in normal cells. Furthermore, GA-Se/Ru NPs effectively inhibited migration and invasion in He La cells via the inhibition of MMP-2 and MMP-9 proteins. Our findings confirm that bimetallic(Se/Ru) NPs prepared via GA-mediated synthesis exhibit enhanced anticancer effects.Chapter 4: Functionalization can promote the uptake of nanoparticles into cancer cells via receptor-mediated endocytosis, enabling them to exert their therapeutic effects. In this paper, epigallocatechin gallate(EGCG), which has a high binding affinity to 67-k Da laminin receptor overexpressed in HCC cells, was employed in the present study to functionalized ruthenium nanoparticles(Ru NPs) loaded with luminescent ruthenium complexes to achieve anti-liver cancer efficacy. Ru BB-loaded EGCG-Ru NPs showed small particle size with narrow distribution, better stability, and high selectivity between liver cancer and normal cells. The internalization of Ru BB-loaded EGCG-Ru NPs was inhibited by 67LR-blocking antibody or laminin, suggesting that 67LR-mediated endocytosis played an important role in the uptake into HCC cells. Moreover, TEM and confocal microscopic images showed that Ru BB-loaded EGCG-Ru NPs accumulated in the cytoplasm of SMMC-7721 cells. Furthermore, our results indicated that the EGCG-functionalized nanoparticles displayed enhanced anti-cancer effects on a target specific manner. Concentrations of Ru BB-loaded EGCG-Ru NPs, nontoxic in normal L-02 cells, showed direct reactive oxygen species-dependent cytotoxic, pro-apoptotic, and anti-invasive effects in SMMC-7721 cells. Furthermore, in vivo animal study demonstrated that Ru BB-loaded EGCG-Ru NPs possessed high anti-tumor efficacy on tumor-bearing nude mice.