Stable Synthetic Bacteriochlorins for Photodynamic Therapy: Role of Dicyano Peripheral Groups, Central Metal Substitution (2H, Zn, Pd), and Cremophor EL Delivery

Authors

  • Dr. Ying-Ying Huang,

    1. Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Boston, MA 02114 (USA)
    2. Department of Dermatology, Harvard Medical School, 50 Staniford Street, Boston, MA 02114 (USA)
    3. Department of Pathology, Guangxi Medical University, Nanning, Guangxi 530021 (P.R.China)
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  • Dr. Thiagarajan Balasubramanian,

    1. Department of Chemistry, North Carolina State University, 2620 Yarbrough Drive, Raleigh, NC 27695 (USA)
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  • Dr. Eunkyung Yang,

    1. Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130 (USA)
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  • Dr. Dianzhong Luo,

    1. Department of Pathology, Guangxi Medical University, Nanning, Guangxi 530021 (P.R.China)
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  • Dr. James R. Diers,

    1. Department of Chemistry, University of California, Springs Road, Riverside, CA 92521 (USA)
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  • Prof. David F. Bocian,

    1. Department of Chemistry, University of California, Springs Road, Riverside, CA 92521 (USA)
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  • Prof. Jonathan S. Lindsey,

    1. Department of Chemistry, North Carolina State University, 2620 Yarbrough Drive, Raleigh, NC 27695 (USA)
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  • Prof. Dewey Holten,

    1. Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130 (USA)
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  • Dr. Michael R. Hamblin

    Corresponding author
    1. Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Boston, MA 02114 (USA)
    2. Department of Dermatology, Harvard Medical School, 50 Staniford Street, Boston, MA 02114 (USA)
    3. Harvard-MIT Division of Health Sciences and Technology, 77 Massachusetts Ave, Cambridge, MA 02139 (USA)
    • Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Boston, MA 02114 (USA)
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Abstract

A series of four stable synthetic bacteriochlorins was tested in vitro in HeLa cells for their potential in photodynamic therapy (PDT). The parent bacteriochlorin (BC), dicyano derivative (NC)2BC and corresponding zinc chelate (NC)2BC–Zn and palladium chelate (NC)2BC–Pd were studied. Direct dilution of a solution of bacteriochlorin in an organic solvent (N,N-dimethylacetamide) into serum-containing medium was compared with the dilution of bacteriochlorin in Cremophor EL (CrEL; polyoxyethylene glycerol triricinoleate) micelles into the same medium. CrEL generally reduced aggregation (as indicated by absorption and fluorescence) and increased activity up to tenfold (depending on bacteriochlorin), although it decreased cellular uptake. The order of PDT activity against HeLa human cancer cells after 24 h incubation and illumination with 10 J cm−2 of near-infrared (NIR) light is (NC)2BC–Pd (LD50=25 nM) > (NC)2BC > (NC)2BC–Zn ≈ BC. Subcellular localization was determined to be in the endoplasmic reticulum, mitochondria and lysosomes, depending on the bacteriochlorin. (NC)2BC–Pd showed PDT-mediated damage to mitochondria and lysosomes, and the greatest production of hydroxyl radicals as determined using a hydroxyphenylfluorescein probe. The incorporation of cyano substituents provides an excellent motif for the enhancement of the photoactivity and photostability of bacteriochlorins as PDT photosensitizers.

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