Coordination-directed self-assembly of nano-cages: metal ion-change, ligand-extending, shape-control and transdermal drug delivery.

The combination of different pyridyl ligands and metal ions has proven to be a very reliable strategy for controlling the coordination mode of the heterometallic coordination nano-cages. Adjusting the length of the ligands could result in the selective synthesis of several heterometallic coordination nano-cages, either [8Rh + 2M]-4L, [8Rh + 2M]-5L or [8Rh + 4M]-6L cages, derived from the very same precursors (LH3tzdc) through half-sandwich rhodium self-assembly. Moreover, a series of [8Rh + 4M]-6L cages was chosen to exemplify the preparation. The rigidity of various pyridyl donor ligands caused the vertical nano-cage to be energetically preferred and was able to change the self-assembly process through ligand flexibility to selectively give the inclined nano-cage and cross nano-cage.

Nanoarchitectonics of Indocyanine Green/Doxorubicin-Loaded Hydroxyl Boron Nitride Nanosheets for Chemophotothermal Therapy.

Biocompatible hydroxylated boron nitride nanosheets were effectively loaded with indocyanine green and doxorubicin using successive assembly. The indocyanine green/doxorubicin-loaded hydroxyl boron nitride nanosheets (ICG/DOX@OH-BNNS) integrated photothermal therapy and chemotherapy into a single nano vehicle. It had been confirmed that ICG/DOX@OH-BNNS could produce reactive oxygen species and exhibit excellent photothermal effects and light-triggered faster DOX release with NIR laser irradiation. On the other hand, the fluorescence of DOX in ICG/DOX@OH-BNNS was also used for visualizing subcellular location. Compared with individual chemotherapy and photothermal therapy, the combined treatment of ICG/DOX@OH-BNNS could synergistically induce the apoptosis and death of A549 cells and suppress S180 tumor growth in vivo.

Synthesis of 2-methoxybenzamide derivatives and evaluation of their hedgehog signaling pathway inhibition.

Aberrant hedgehog (Hh) signaling is implicated in the development of a variety of cancers. Smoothened (Smo) protein is a bottleneck in the Hh signal transduction. The regulation of the Hh signaling pathway to target the Smo receptor is a practical approach for development of anticancer agents. We report herein the design and synthesis of a series of 2-methoxybenzamide derivatives as Hh signaling pathway inhibitors. The pharmacological data demonstrated that compound 21 possessed potent Hh pathway inhibition with a nanomolar IC50 value, and it prevented Shh-induced Smo from entering the primary cilium. Furthermore, mutant Smo was effectively suppressed via compound 21. The in vitro antiproliferative activity of compound 21 against a drug-resistant cell line gave encouraging results.

Design and biological evaluation of phenyl imidazole analogs as hedgehog signaling pathway inhibitors.

The hedgehog (Hh) signaling pathway is involved in diverse aspects of cellular events. Aberrant activation of Hh signaling pathway drives oncogenic transformation for a wide range of cancers, and it is therefore a promising target in cancer therapy. In the principle of association and ring-opening, we designed and synthesized a series of Hh signaling pathway inhibitors with phenyl imidazole scaffold, which were biologically evaluated in Gli-Luc reporter assay. Compound 25 was identified to possess high potency with nanomolar IC50 , and moreover, it preserved the inhibition against wild-type and drug-resistant Smo-overexpressing cells. A molecular modeling study of compound 25 expounded its binding mode to Smo receptor, providing a basis for the further structural modification of phenyl imidazole analogs.

Synthesis and Evaluation of Aminothiazole Derivatives as Hedgehog Pathway Inhibitors.

A series of aminothiazole derivatives bearing the benzimidazole moiety were synthesized and evaluated in Gli luciferase reporter assays. Lead optimization led to the discovery of potent hedgehog pathway antagonist 18 (2-[3-(1H-benzimidazol-2-yl)-4-chloroanilino]-N-[4-(trifluoromethyl)phenyl]-1,3-thiazole-4-carboxamide), with IC50 values in nanomolar range. The molecular basis ascribed to hindering sonic hedgehog-driven Smoothened (Smo) localization within the primary cilium (PC). Moreover, compound 18 inhibited Gli1 mRNA expression in mutant Smo cell line and displayed moderate cytotoxicity against DAOY cancer cell.

Nano Pd-Decorated Manganese Dioxide Nanosheets for Effective Photothermal Chemotherapy.

A drug delivery system based on the palladium and manganese dioxide composite (FP-Pd@MnO2) is designed and prepared for the first time. The FP-Pd@MnO2 allows doxorubicin (DOX) loading as high as 58% in weight. The rapid release of DOX from FP-Pd@MnO2 is regulated via pH reduction, ascending glutathione concentration, and near-infrared (NIR) stimulus, which is advantageous to control drug release in the tumor site. The photothermal effect of FP-Pd@MnO2 with wide and strong NIR optical absorbance is positively correlated with its concentration. As irradiated with an 808 nm laser, MDA-MB-231 cells and its tumor on mice with FP-Pd@MnO2/DOX administration are significantly suppressed, corroborating the preferable curative effect of combined photothermal therapy and chemotherapy with this agent.

Analysis of Meiotic Double-Strand Break Initiation in Mammals.

The repair of programmed DNA double-strand breaks (DSBs) physically tethers homologous chromosomes in meiosis to allow for accurate segregation through meiotic cell divisions. This process, known as recombination, also results in the exchange of alleles between parental chromosomes and contributes to genetic diversity. In mammals, meiotic DSBs occur predominantly in a small fraction of the genome, at sites known as hotspots. Studies of the formation and repair of meiotic DSBs in mammals are challenging, because few cells undergo meiotic DSB formation at a given time. To better understand the initiation and control of meiotic recombination in mammals, we have devised a highly sensitive method to map the sites of meiotic DSBs genome wide. Our method first isolates DNA bound to DSB repair proteins and then specifically sequences the associated single-stranded DNA. This protocol has generated the first meiotic DSB maps in several mammals and the only map of meiotic DSBs in humans.

The normal function of the cancer kinase Mirk/dyrk1B is to reduce reactive oxygen species.

Mirk kinase is a gene upregulated and sometimes amplified in pancreatic cancers and in ovarian cancers, but expressed at very low levels in most normal diploid cells except for skeletal muscle. The muscle cell function of Mirk kinase selected for by cancer cells is unknown. It is now shown that Mirk protein is expressed at low levels and is largely nuclear in cycling skeletal muscle C2C12 myoblasts, but is translocated to the cytoplasm and upregulated when myoblasts initiate differentiation, as shown by immunofluorescence staining and by cell fractionation. Either Mirk depletion or Mirk kinase inhibition increased ROS levels in cycling C2C12 myoblasts. However, Mirk protein is localized in the cytoplasm of mature muscle fibers, specifically in the fast twitch fibers of human skeletal muscle where toxic ROS levels are generated by muscle contraction. C2C12 myoblasts at high density in differentiation media fuse to form differentiated postmitotic myotubes that can contract. A Mirk kinase inhibitor induced a dose-dependent increase in ROS in this model for fast twitch fibers of human skeletal muscle. Efficient Mirk depletion in SU86.86 pancreatic cancer cells by an inducible shRNA decreased expression of eight antioxidant genes. Thus both cancer cells and differentiated myotubes utilize Mirk kinase to relieve oxidative stress.