Anticancer Activitives Of Cancer-targeted Selecompounds Nanosystems And Metal Complexes Sensitize Chemotherapeutic Drugs

Cancer incidence and mortality have been increasing and become a major public health problem in China and many other parts of the world. It is becoming the first leading cause of death in the world. Cancer is when abnormal cells divide in an uncontrolled way due to all kinds of factors that happen over a person’s lifetime. The malignant tumor is those abnormal extra cells which can divide without stopping and may form growths eventually to spread into other tissues. So the malignant tumor is called cancer. The most common way to cure cancer are surgery, chemotherapy and radiotherapy, and chemotherapy remains the main treatment before and after surgery. Chemotherapy is successful in cancer to some degree, but has several limitations. The drawbacks are that it lacks suffucuent selectivity to the neoplasia, instability in some physiological environment and drug resistance in many cancer cells. In our previous studies, the designed and synthetic a series of organoselenium, selenium nanoparticles and metal complexes in our lab showed good anticancer activity on many cancer cell lines. This study used particle size and zeta potential to evaluate the stability of drug. MTT assay assess cell viability and scratch test, tumor invasion assay to evaluate whether drug can inhibit cancer cell migration and invasion. The expression of receptor and receptor competition assay was determined to assess selectivity to cancer cells. Further mechanistic studies analyze the cell cycle distribution by flow cytometry analysis. We used some fluorescence probes to examine intracellular reactive oxygen species generation and track intracellular drug and cellular uptake in cancer cells. Finally, we study the proposed signaling pathway induced by drug. These studies may provide new strategy for the rational design of cancer-targeting nanomedicine to treat human cancer. The main results are as follows:1. In this study, we designed and synthesized a conjugate of cancer-targeting selenadiazole derivative BSeC(benzo[1,2,5]selenadiazole-5-carboxylic acid) and the RGD(arginine–glycine–aspartate) peptide, which was used as a targeting molecule, using a PEI polymer as a linker. The results showed that BSeC–PEI–RGD formed core–shell spherical nanoparticles with improved stability in physiological and low pH solutions. The cancer-targeting design significantly enhanced cellular uptake of BSeC–PEI–RGD and decreased its cytotoxicity to normal cells. The nanoparticles could inhibit the migration and invasion of EJ and T24 bladder cancer cell and reduce cancer cell proliferation through the induction of reactive oxygen species(ROS)-dependent apoptosis and mitochondrial dysfunction. Further mechanistic studies using western blotting showed that BSeC–PEI–RGD triggered bladder cancer cell apoptosis by activating p38, JNK and p53 and by inactivating AKT and ERK. In summary, this study demonstrates the rational design of a polymer-based cancer-targeting nanosystem as a carrier of the selenadiazole derivative to treat bladder cancer.2. Tumor necrosis factor-related apoptosis-inducing ligand(TRAIL), as one of the most promising targeted drug for new cnacer therapeutics, is limitied in clinical application by the evolution of resistance in many cancer cell lines. The present study reports the synthesis of iron(II) polypyridyl complexes 2-5 have emerged as potent anticancer agents. Herein, we repoted that iron(II) polypyridyl complexes able to effectively inhibit growth and metastasis of cancer cells and synergistically enhance TRAIL-induced apoptosis. Further mechanistic studies using western blotting showed that iron(II) polypyridyl complexes triggered glioblastoma cancer cell apoptosis by activating JNK and p53 and by inactivating AKT and ERK. Moreover, the alternation in the expression levels of metastatic regulatory proteins, including uPA, MMP-2/-9 were also observed after iron(II) polypyridyl complexes treatment. In summary, these results demonstrate that iron(II) polypyridyl complexes exhibits the potential to be developed as a metal-based antimetastatic agent and chemosensitizer of TRAIL for the treatment of human glioblastoma cancer.3. In this study, we assess the anticancer ability of selenium nanoparticles with uPA and tumor extracellular environment target and anticancer mechanism. We examine particle size and zeta potential to assess the stability of nanoparticles. MTT assay and clone formation assay evaluate the anticancer ability and the results showed that two targeted nanoparticles had the selectivity to cancer cells. We designed a test to assess whether ACCP could target tumor extracellular environment, the results showed that cellular uptake of nanoparticles with ACCP peptide was increasing in tumor extracellular environment. Further mechanistic studies showed that targeted selenium nanoparticles triggered cancer cell apoptosis by activating caspases.