Drug Design Targeting T-Cell Factor-Driven Epithelial-Mesenchymal Transition as a Therapeutic Strategy for Colorectal Cancer.

Metastasis is the cause of 90% of mortality in cancer patients. For metastatic colorectal cancer (mCRC), the standard-of-care drug therapies only palliate the symptoms but are ineffective, evidenced by a low survival rate of ∼11%. T-cell factor (TCF) transcription is a major driving force in CRC, and we have characterized it to be a master regulator of epithelial-mesenchymal transition (EMT). EMT transforms relatively benign epithelial tumor cells into quasi-mesenchymal or mesenchymal cells that possess cancer stem cell properties, promoting multidrug resistance and metastasis. We have identified topoisomerase IIα (TOP2A) as a DNA-binding factor required for TCF-transcription. Herein, we describe the design, synthesis, biological evaluation, and in vitro and in vivo pharmacokinetic analysis of TOP2A ATP-competitive inhibitors that prevent TCF-transcription and modulate or reverse EMT in mCRC. Unlike TOP2A poisons, ATP-competitive inhibitors do not damage DNA, potentially limiting adverse effects. This work demonstrates a new therapeutic strategy targeting TOP2A for the treatment of mCRC and potentially other types of cancers.

Antibacterial effects of carbon dots in combination with other antimicrobial reagents.

This study was designed to investigate the antimicrobial effects of CDots in combination with other antimicrobial reagents, including H2O2, Na2CO3, and AcOH (acetic acid). CDots were synthesized and passivated with 2,2'-(ethylenedioxy)bis(ethylamine) (EDA). The minimal inhibitory concentration (MIC) of CDots was 64 µg/mL on both Gram negative bacteria E.coli cells and Gram positive bacteria Bacillus subtilis cells. When CDots were combined with H2O2, antibacterial synergistic effects were observed based on the fractional inhibitory concentration (FIC) index, and further confirmed by an isobologram analysis and viable cell number counting methods. With the combination treatment of 10 µg/mL CDots with 8.82 mM H2O2, the viable E.coli cell numbers decreased 2.46 log, which was significant lower than the log reduction from 8.82 mM H2O2 (1.57 log) or 10 µg/mL CDots (0.14 log) treatment alone. However, the combination of CDots with Na2CO3 or AcOH did not show synergistic effects, instead, exhibiting indifference effects according to the FIC index. This study indicated that the combination of CDots with their synergistic antimicrobial reagents, such as H2O2, could reach the goal of inhibiting bacteria growth by using lower concentration of each individual chemical in the combination than using one chemical treatment alone, reduce the risks imposed on environmental health and the possibilities of the development of microbial resistances.

Photoexcited State Properties of Carbon Dots from Thermally Induced Functionalization of Carbon Nanoparticles.

Carbon dots are small carbon nanoparticles with various surface passivation schemes, in which more effective has been the deliberate chemical functionalization of the nanoparticles for brighter fluorescence emissions, though the synthesis method is more tedious and subject to some limitations in the selection of functionalization molecules. Another more popular synthesis method has been the carbonization of organic species, with the method being more efficient and versatile, but less controllable in the synthesis and for the desired dot structure and performance. In this work, a hybrid approach combining the advantageous characteristics of the two synthesis methods was applied to the preparation of carbon dots with polyethyleneimine (PEI) for surface passivation, where pre-processed and selected small carbon nanoparticles were functionalized with PEI in microwave-induced thermal reactions. The optical absorption and fluorescence emission properties were evaluated, and the results suggested that the carbon dots thus prepared shared the same photoexcited state characteristics with those from the deliberate chemical functionalization, including comparable fluorescence colors and other properties. A further demonstration on the similarity in photoexcited state properties was based on the same visible light-activated bactericidal functions of the PEI-carbon dots as those found in carbon dots from the deliberate chemical functionalization. The advantages and potential limitations of the hybrid approach for more controllable yet versatile and efficient syntheses of carbon dots are highlighted and discussed.