The recent classification of curcumin （Cur） as a pan-assay interference compound （PAINS） and an invalid metabolic panaceas （IMPS） candidate demonstrated the controversial nature of Cur as a drug lead owing to it...The recent classification of curcumin （Cur） as a pan-assay interference compound （PAINS） and an invalid metabolic panaceas （IMPS） candidate demonstrated the controversial nature of Cur as a drug lead owing to its aggregation in aqueous phase and inherent instability in vivo. Here, we report a simple prodrug approach to generate nanoparticles of Cur in situ that allow it to function reproducibly as an anticancer and an anti-inflammatory agent. Diphosphorylated curcumin （Cur-2p）, a precursor of Cur and a substrate of alkaline phosphatase （ALP）, exhibited drastically improved chemical stability and low aggregation in water. After conversion to curcumin around or inside cancer cells by ALP, Cur-2p selectively inhibited cancer cells that overexpressed ALP, but did not affect normal cells. Moreover, the intravitreal injection of Cur-2p resulted in excellent intraocular biocompatibility with no apparent damage to the morphology and visual function of retina, as shown by fundus imaging, optical coherence tomography （OCT）, and histological observation. A rodent model of uveitis showed that Cur-2p significantly suppressed the inflammation response compared with Cur. As a rational approach to investigate and apply PAINS and IMPS candidates, this work presents a straightforward method to maximize the potential of drug leads and ultimately fulfil the promises and potential clinical benefits of PAINS and IMPS candidates.展开更多
Three new hydrogelators based on the conjugates of three naturally occurring biological building blocks:nu-cleobase,saccharide,and amino acids,were explored.Being synthesized via a facile solid phase peptide synthesis...Three new hydrogelators based on the conjugates of three naturally occurring biological building blocks:nu-cleobase,saccharide,and amino acids,were explored.Being synthesized via a facile solid phase peptide synthesis route,the hydrogelators self-assemble in water to afford supramolecular nanofibers and hydrogels.Transmission electron microscopy,oscillation rheometry,and circular dichroism reveal that the hydrogels consist of largely he-lix-based nanofibers of the widths of 5-12 nm and exhibit storage moduli up to 1 kPa.These hydrogelators also exhibit excellent cell-compatibility.This work illustrates a new platform for constructing molecular soft materials for nanobiotechnology.展开更多
文摘The recent classification of curcumin （Cur） as a pan-assay interference compound （PAINS） and an invalid metabolic panaceas （IMPS） candidate demonstrated the controversial nature of Cur as a drug lead owing to its aggregation in aqueous phase and inherent instability in vivo. Here, we report a simple prodrug approach to generate nanoparticles of Cur in situ that allow it to function reproducibly as an anticancer and an anti-inflammatory agent. Diphosphorylated curcumin （Cur-2p）, a precursor of Cur and a substrate of alkaline phosphatase （ALP）, exhibited drastically improved chemical stability and low aggregation in water. After conversion to curcumin around or inside cancer cells by ALP, Cur-2p selectively inhibited cancer cells that overexpressed ALP, but did not affect normal cells. Moreover, the intravitreal injection of Cur-2p resulted in excellent intraocular biocompatibility with no apparent damage to the morphology and visual function of retina, as shown by fundus imaging, optical coherence tomography （OCT）, and histological observation. A rodent model of uveitis showed that Cur-2p significantly suppressed the inflammation response compared with Cur. As a rational approach to investigate and apply PAINS and IMPS candidates, this work presents a straightforward method to maximize the potential of drug leads and ultimately fulfil the promises and potential clinical benefits of PAINS and IMPS candidates.
基金This work was supported by National Institutes of Health(No.NIH R01CA142746).
文摘Three new hydrogelators based on the conjugates of three naturally occurring biological building blocks:nu-cleobase,saccharide,and amino acids,were explored.Being synthesized via a facile solid phase peptide synthesis route,the hydrogelators self-assemble in water to afford supramolecular nanofibers and hydrogels.Transmission electron microscopy,oscillation rheometry,and circular dichroism reveal that the hydrogels consist of largely he-lix-based nanofibers of the widths of 5-12 nm and exhibit storage moduli up to 1 kPa.These hydrogelators also exhibit excellent cell-compatibility.This work illustrates a new platform for constructing molecular soft materials for nanobiotechnology.
