In this study, a new cyanine-based photosensitizer Cy-N-Rh was developed for photodynamic therapy. Based on fluorescence resonance energy transfer (FRET) mechanism, utilizing the absorption of the donor rhodamine (Rh), the acceptor heptamethine cyanine unit (Cy) was indirectly excited to produce singlet oxygen ( 1 O 2 ). The efficiency of energy transfer from the donor Rh to the acceptor Cy was 78.5%. Meanwhile, the singlet oxygen yield of Cy-N-Rh (Φ Δ = 12.00%) was much higher than that of the acceptor Cy (Φ Δ = 4.35%) without FRET. Moreover, the dual cation gave Cy-N-Rh with excellent mitochondria-targeting ability with Pearson’s correlation coefficients of 0.90 and 0.91, respectively. In the MTT test, Cy-N-Rh had low dark cytotoxicity with cell survival rate above 90% and high photo cytotoxicity with cell survival rate below 40%. The cell apoptosis assay also demonstrated the role of the photosensitizer Cy-N-R visually. More importantly, Cy-N-Rh fulfilled two-photon excitation fluorescence imaging under the 800 nm femtosecond laser. All results indicate that this design strategy provides a new method for the development of higher-level cyanine photosensitizers.
The PI3K/AKT/mTOR signaling pathway is one of the most common abnormal activation pathways in tumor cells, and has associated with multiple functions such as tumor cell growth, proliferation, migration, invasion, and tumor angiogenesis. Here, a series of 3-amino-1 H -indazole derivatives were synthesized, and their antiproliferative activities against HT-29, MCF-7, A-549, HepG2 and HGC-27 cells were evaluated. Among them, W24 exhibited the broad-spectrum antiproliferative activity against four cancer cells with IC 50 values of 0.43–3.88 μM. Mechanism studies revealed that W24 inhibited proliferation by affecting the DNA synthesis, induced G 2 /M cell cycle arrest and apoptosis by regulating Cyclin B1, BAD and Bcl-xL, meanwhile induced the change of intracellular ROS and mitochondrial membrane potential in HGC-27 cells. Moreover, W24 inhibited the migration and invasion of HGC-27 cells by decreasing EMT pathway related proteins and reducing the mRNA expression levels of Snail, Slug and HIF-1α. Furthermore, W24 displayed low tissue toxicity profile and good pharmacokinetic properties in vivo . Therefore, 3-amino-1 H -indazole derivatives might serve as a new scaffold for the development of PI3K/AKT/mTOR inhibitor and anti-gastric cancer reagent.
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