Folate-targeted verrucarin A reduces the number of activated macrophages in a mouse model of acute peritonitis.

Bioorganic & Medicinal Chemistry Letters
Chelvam VenkateshPhilip S Low

Abstract

Activated macrophages contribute prominently to the progression and maintenance of almost all inflammatory and autoimmune diseases. Although non-specific elimination of these phagocytes has been shown to treat animal models of inflammatory disease, the same therapies have been compromised by unacceptable toxicities, because they also kill quiescent macrophages in healthy tissues. In the studies below, we exploit upregulation of folate receptor beta (FRβ) on inflammatory (but not resting) macrophages to target a cytotoxic drug selectively to the inflammatory subset of macrophages. Because many of these activated macrophages are nondividing, we also employ verrucarin A as the cytotoxic payload, since it kills both mitotic and nonmitotic cells by blocking protein synthesis. By inserting a redox-sensitive self-immolative linker between the folate and verrucarin A, we further assure that release of unmodified verrucarin A is triggered primarily after internalization by an FRβ-positive cell. The resulting folate-verrucarin A conjugate is shown to kill FR-expressing cells in vitro in a manner that can be inhibited by competition with 100-fold excess folic acid. The folate-verrucarin A conjugate is also shown to successfully treat a mu...Continue Reading

References

Jan 1, 1982·Advances in Experimental Medicine and Biology·R van FurthM Schadewijk-Nieuwstad
Oct 3, 2000·Arthritis and Rheumatism·P BarreraW B van den Berg
Apr 20, 2004·Advanced Drug Delivery Reviews·Philip S Low, Asok C Antony
Apr 20, 2004·Advanced Drug Delivery Reviews·Hala Elnakat, Manohar Ratnam
May 2, 2006·Arthritis Research & Therapy·Chrystal M PaulosPhilip S Low
Sep 5, 2006·Proceedings of the National Academy of Sciences of the United States of America·Jun YangPhilip S Low
Feb 13, 2008·Biochimica Et Biophysica Acta·Young-Mi Go, Dean P Jones
Dec 26, 2009·Journal of Autoimmunity·Yinon ShapiraYehuda Shoenfeld
Jul 30, 2010·Journal of Medicinal Chemistry·Wei Xia, Philip S Low
May 28, 2011·Arthritis and Rheumatism·Thommey P ThomasJames R Baker
Nov 26, 2011·Sub-cellular Biochemistry·Jun YangPhilip Low
Sep 7, 2012·Neoplasia : an International Journal for Oncology Research·Girma M WoldemichaelJames B McMahon
Jul 13, 2014·Journal of Leukocyte Biology·Jiayin ShenPhilip S Low
Dec 3, 2014·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Yehuda G AssarafJoseph A Reddy
Jul 6, 2015·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Behdokht BahramiMohammad Hojjat-Farsangi
Jan 7, 2016·Nanomedicine : Nanotechnology, Biology, and Medicine·Eugénia NogueiraArtur Cavaco-Paulo
Nov 21, 2017·Archives of Toxicology·Qinghua WuKamil Kuca
Feb 8, 2018·Nanomedicine : Nanotechnology, Biology, and Medicine·Scott PohPhilip S Low
Jun 11, 2019·Frontiers in Immunology·Wen-Tao MaDe-Kun Chen
Mar 11, 2020·Nature Reviews. Clinical Oncology·Mariana ScarantiUdai Banerji
Jan 22, 2021·Journal of Neuroinflammation·Petri EloAnne Roivainen

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