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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:759.)
© 2001 American Heart Association, Inc.

Vascular Biology

Photodynamic Therapy With Motexafin Lutetium Induces Redox-Sensitive Apoptosis of Vascular Cells

Zhiping Chen; Kathryn W. Woodburn; Can Shi; Daniel C. Adelman; Campbell Rogers; Daniel I. Simon

From the Cardiovascular Division (Z.C., C.S., C.R., D.I.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Harvard-M.I.T. Division of Health Sciences and Technology (C.R.), Massachusetts Institute of Technology, Cambridge, Mass; and Pharmacyclics, Inc (K.W.W., D.C.A.), Sunnyvale, Calif.

Correspondence to Daniel I. Simon, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Tower 3, Boston, MA 02115. E-mail dsimon{at}rics.bwh.harvard.edu

Abstract—Motexafin lutetium is a photosensitizer that accumulates in atherosclerotic plaque and, after activation by far-red light, produces cytotoxic singlet oxygen. The combination of photosensitizer and illumination, known as photodynamic therapy (PDT), has been shown to reduce atheroma formation in animal models and is under clinical investigation. However, the effects of PDT with motexafin lutetium on isolated vascular cells are unknown. This study was designed to characterize the effects of PDT on vascular cell viability and to define the cell-death pathway for this agent. Fluorescence microscopy of RAW macrophages and human vascular smooth muscle cells revealed time-dependent uptake of motexafin lutetium. Illumination of motexafin lutetium–loaded cells with 732-nm light (2 J/cm²) impaired cellular viability and growth (IC₅₀ 5 to 20 µmol/L). Depletion of intracellular glutathione potentiated (P=0.035) and the addition of antioxidant N-acetylcysteine attenuated (P=0.002) cell death, suggesting that the intracellular redox state influences motexafin lutetium action. PDT was associated with the loss of mitochondrial membrane potential, mitochondrial release of cytochrome c, and caspase activation. PDT promoted phosphatidylserine externalization and induced apoptotic DNA fragmentation, with the number of apoptotic cells increasing from 7±2% to 34±3% of total cells. Reducing plaque cellularity by the induction of apoptosis may be one mechanism by which PDT reduces plaque burden, possibly modulates plaque vulnerability, and inhibits restenosis in vivo.

Key Words: apoptosis • photodynamic therapy • vascular cells • reactive oxygen species • atherosclerosis

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