Research And Biological Evaluation Of New Biological Imaging Probe

Fluorescence imaging technique is the most commom method for microscopic observation and now it is rapidly increasing the popularity in live animal applications. To help develop its full potential, optimized imaging systems and fluorescent contrast agents will be needed. To this end, this thesis is focused on the luminescence iridium (III) complexes and upconversion rare-earth nanoparticles for biological imaging and composed of three parts.1. Nonemissive Cyclometalated Iridium (III) Solvent Complexes as Cellular Reaction-based Luminescence ProbesWe synthesized a series of non-emissive cyclometalated iridium(III) solvent complexes which have been developed as reaction-based luminescence-turn-on agents for the imaging of living cells. Firstly,[Ir(ppy)2(DMSO)2]+PF6-(LIrl) was demonstrated as a nuclear dye. LIrl, without conjugation with a cell-penetrating molecular transporter, can rapidly and selectively light-up the nuclei of living cells over fixed cells, giving rise to a significant luminescence enhancement (200-fold), and shows very low cytotoxicity at the imaging concentration (incubation time <10min, LIrl concentration10μM). More importantly, in contrast to the reported nuclear stains that are based on luminescence enhancement through interaction with nucleic acids, complex LIrl as a nuclear stain has a reaction-based mode of action, which relies on its rapid reaction with histidine/histidine-containing proteins. The results have indicated that LIrl permeates the outer and nuclear membranes of living cells through an energy-dependent entry pathway within a few minutes. As determined by an inductively coupled plasma atomic emission spectroscopy (ICP-AEC), LIrl is accumulated in the nuclei of living cells and converted into an intensely emissive adduct. Furthermore, on the basis of these variations (including different varients of counterions, solvent ligands, and C∧N ligands), the structure-activity relationship study revealed some clear correlation about cellular uptake and localization of these complexes. Such novel reaction-based nuclear staining for visualizing exclusively the nuclei of living cells with a significant luminescence enhancement may extend the arsenal of currently available fluorescent stains for specific staining of cellular compartments.2. Antitumor Efficacy Studies of Novel Cationic Iridium Complexes in Vitro and in Vivo A series of cyclometalated iridium(Ⅲ) solvent complexes have been design, synthesized and potential antitumor of that have been evaluated in vitro and in vivo. In vitro, they can effectively inhibited the invasiveness and proliferation toward a panel of human tumor cell lines. In addition, complex1and2can induce cancer cells to undergo apoptosis. The effectiveness of complex1and2were further evaluated in S-180sarcoma-bearing mice model. Complex1and2show low toxicity in the body. More importantly, the most potent complex2shows significant in vivo antitumor activity comparable to that of cisplatin and increased life span in mice. These data demonstrate a novel type of cationic iridium complexes with strong in vitro and in vivo antitumor activity and will provide insights into the discovery and selection anticancer agents for cancer treatments.3. Samarium-153labeled upconversion rare-earth nanoparticles for specific contrast imaging and luminescence-guided surgery of hepatic neoplasmsEarly diagnosis and aggressive therapy are especially important for patients suffering from hepatocellular carcinoma (HCC) to improve survival and limit complications. Even though many advances are made in the treatment of malignant tumors, it is difficult to eliminate the minimal residual disease by chemotherapy, radiotherapy and operation. Here, we describe the development of Sm-153labeled upconversion rare-earth nanoparticles (UCNPs) that can be used for early detection of HCC and luminescence-guided surgery by contrast imaging. After systemic injection of Sm-153labeled UCNPs in mice, a high concentration particles was seen in liver within30min. Contrast between liver and tumor is up to tenfold, and useful contrast can last up to24h. No changes in behavior or activity are observed after treatment, indicating a lack of obvious toxicity with an injection dose of20mg/kg. Lumiescence highlight the margin between tumor and adjacent tissue, suggesting that the probe can identify tumor and normal tissue and facilitate surgical resection of liver neoplasms.