Enzymatic formation of curcumin in vitro and in vivo
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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 Curin 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.
Keywordsenzymatic formation curcumin nanoparticles drug discovery anti-cancer anti-inflammatory
This work was partially supported by National Institutes of Health (No. R01CA142746 and R21AI130560), National Science Foundation (No. MRSEC-1420382), Zhejiang Provincial Natural Science Foundation of China (No. LR18H300002), the National Natural Science Foundation of China (No. 31671022).
- Yang, Y.; Mu, J.; Xing, B. Photoactivated drug delivery and bioimaging. Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol. 2017, 9, doi: 10.1002/wnan.1408.Google Scholar
- Olivera, A.; Moore, T. W.; Hu, F.; Brown, A. P.; Sun, A. M.; Liotta, D. C.; Snyder, J. P.; Yoon, Y.; Shim, H.; Marcus, A. I. et al. Inhibition of the NF-kB signaling pathway by the curcumin analog, 3,5-bis(2-pyridinylmethylidene)-4-piperidone (EF31): Anti-inflammatory and anti-cancer properties. Int. Immunopharmacol. 2012, 12, 368–377.CrossRefGoogle Scholar
- Zhuang, X. Y.; Xiang, X. Y.; Grizzle, W.; Sun, D. M.; Zhang, S. Q.; Axtell, R. C.; Ju, S. W.; Mu, J. Y.; Zhang, L. F.; Steinman, L. et al. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol. Ther. 2011, 19, 1769–1779.CrossRefGoogle Scholar
- Zhang, X. L.; Tian, Y. L.; Li, Z.; Tian, X. Y.; Sun, H. B.; Liu, H.; Moore, A.; Ran, C. Z. Design and synthesis of curcumin analogues for in vivo fluorescence imaging and inhibiting copper-induced cross-linking of amyloid beta species in Alzheimer’s disease. J. Am. Chem. Soc. 2013, 135, 16397–16409.CrossRefGoogle Scholar
- Dahl, R.; Sergienko, E. A.; Su, Y.; Mostofi, Y. S.; Yang, L.; Simao, A. M.; Narisawa, S.; Brown, B.; Mangravita-Novo, A.; Vicchiarelli, M. et al. Discovery and validation of a series of aryl sulfonamides as selective inhibitors of tissue-nonspecific alkaline phosphatase (TNAP). J. Med. Chem. 2009, 52, 6919–6925.CrossRefGoogle Scholar
- Takahashi, N.; Duprez, L.; Grootjans, S.; Cauwels, A.; Nerinckx, W.; DuHadaway, J. B.; Goossens, V.; Roelandt, R.; Van Hauwermeiren, F.; Libert, C. et al. Necrostatin-1 analogues: Critical issues on the specificity, activity and in vivo use in experimental disease models. Cell Death Dis. 2012, 3, e437.CrossRefGoogle Scholar