Synthesis Of Biotin-based Fluorescent Small Molecule 3A And Its Effect On Targeted Imaging Of Breast Cancer

Objective:Deguelin, an natural isoflavonoids extract from leguminous plants, has potent anti-tumor effect. It has been shown chemotherapeutic and chemopreventive effect in many cancers, such as lung cancer, breast cancer, stomach cancer as well as colon cancer. It has been demonstrated that deguelin induces apoptosis, causes cell cycle arrest, restrains cell proliferation or inhibits angiogenesis. But some studies show that deguelin could damage the heart, lungs and nervous system, when does are more than effective concentration. Targeting drug delivery system(TTDS), often named as targeting agents, is a very important technology in the pharmaceutical fields at present. It makes drugs selectively gather in the lesion site by the carriers. It not only can reduce the dose of drug, but also can decrease the side effects. The TTDS is a new way to therapy diseases with personalized medicine. A tool of targeted imaging-3A was designed and synthesized based on the biotin as a targeted groups, and deeply studied the effect of targeted imaging on the breast cancer cells. It would lay the foundation for synthesis of deguelin-based targetable fluorescent and its effect on therapy of breast cancer. It also provides scientific basis for the research of efficient and personalized targeting agents. The contents are as follows:(1) The targeted imaging-3A was designed and synthesized consisting of easily cleavable disulfide bond, biotin as a targeted groups and the fluorescence Piperazine Rhodol.(2) The compound 3A exhibited a strong absorption peak at 510 nm in its absorption spectrum, and its fluorescence emission signal was strong at 544 nm. Both peak increased in intensity by the addition of GSH and Hcys. No significant spectroscopic changes were detected upon exposure to thiol-free amino acids or biologically relevant metal cations. The stability of 3A was increased with the increase of pH value in the presence of GSH.(3) In the flow cytometry, the absorption rate of 3A for MCF-7, MDA-MB-231 breast cancer cells raised with increasement of 3A. When the concentration of 3A was 20 μM, cellular absorption of breast cancer cells was close to saturation, and there was no obvious growth rate on the absorption of Hs 578 Bst normal breast cell.(4) In the test of living cell fluorescence imaging, with the increase of drug concentration of 3A, the fluorescent signal of MCF-7 and MDA-MB-231 breast cancer cells was enhanced. When the concentration of 3A was 20 μM, strong fluorescent signal was detected in MCF-7 and MDA-MB-231. Fluorescence were decreased significantly of MCF-7 and MDA-MB-231 with biotin pretreatment.(5) In the cell activity experiment, the compound 3A had no obvious inhibitory effect on the cell activity of MCF-7, MDA-MB-231 and Hs 578 Bst with the increasement of carnitine concentration(0-20 μM) and duration of action. The conclusion is that the compound 3A specificity targeted MCF-7 and MDA-MB-231. The disulfide bond in 3A was specificity cleavable by thiol-containing amino acids in cells, and then fluorescent group was released. But there was no obvious effect on Hs 578 Bst. It had no inhibitory effect on the cell activity of MCF-7, MDA-MB-231 and Hs 578 Bst.