Crosstalk-Assisted Augmented Activity of Polyphenolic Molecules: A Study Using Fluorescence Lifetime Imaging Microscopy

Self-assembly of small molecules has always been an attractive topic of research in the field of physical chemistry. Fluorescence lifetime imaging microscopy (FLIM) expands our understanding by offering a molecular-level perspective to gain deeper knowledge about the microenvironments. In this work, we have unveiled the self-aggregation mechanism of two naturally occurring polyphenolic molecules named gallic acid (GA) and its derivative methyl gallate (MG), resulting in ineffectiveness as a drug molecule. GA prefers rod-like morphology, in contrast to MG, which shows a cotton-like structure. However, when both are present in an equimolar ratio, the cross-assembly manifests a fibrillar structure that loses its initial individualities. Using FLIM, we have unveiled the mechanism of structural transition and morphological information on the aggregated assemblies. Although the parental polyphenols construct significantly rigid morphologies, the cross-assembly manifests improper packing due to mismatch in their backbone, as evident from lifetime information using FLIM. Furthermore, under physiological conditions, the cross-assembly disintegrates; however, the parental molecules prevail their architectures. The co-polyphenols show prominent dose-dependent cytotoxicity and mitigate the progression of cancer cells compared to the individual polyphenols, opening up a convenient way to enhance a drug's efficacy.