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Enhanced Anti-Inflammatory Efficacy Through Targeting to Macrophages: Synthesis and In Vitro Evaluation of Folate-Glycine-Celecoxib

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Abstract

As an effective COX-2 inhibitor, celecoxib is widely used in anti-inflammation therapy. However, it may cause cardiovascular risks and renal adverse effects. In the present study, we aimed to construct a celecoxib prodrug with enhanced anti-inflammatory efficacy and reduced adverse effects using folate in order to target activated macrophages. Folate-glycine-celecoxib was synthesized and identified by 1H-NMR, MS, and FTIR analyses. The cytotoxicity of folate-glycine-celecoxib was tested on murine macrophage cells (RAW264.7) using thiazolyl blue tetrazolium bromide. Cellular uptake studies were employed to determine targeting ability toward folate receptors via flow cytometry and confocal microscopy. Anti-inflammatory efficacy of folate-glycine-celecoxib was investigated by measuring the concentration of LPS-induced nitric oxide (NO). Folate-glycine-celecoxib exhibited lower cytotoxicity than conventional celecoxib, and this conjugate could be targetedly transported into RAW264.7 cells through binding with folate receptors on cell surface. Through targeting to RAW264.7 cells, folate-glycine-celecoxib exhibited better effects than equimolar celecoxib in NO inhibition, suggesting greater anti-inflammatory activity. These findings demonstrated that the prodrug folate-glycine-celecoxib had potential to treat inflammatory disease with low cytotoxicity and high targeting ability.

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Acknowledgments

We are grateful to the Key Laboratory of Drug Targeting and Drug Delivery Systems for the kindly provision of RAW264.7 cells. This research was financially supported by the National Natural Science Foundation of China (no. 81373338).

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  1. Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan Province, China

    Yongquan Li, Yu Xiao & Zongning Yin

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  1. Yongquan Li
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Correspondence to Zongning Yin.

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Li, Y., Xiao, Y. & Yin, Z. Enhanced Anti-Inflammatory Efficacy Through Targeting to Macrophages: Synthesis and In Vitro Evaluation of Folate-Glycine-Celecoxib. AAPS PharmSciTech 18, 729–737 (2017). https://doi.org/10.1208/s12249-016-0556-5

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