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Pyro-Gly-Pro-Leu-Gly-Leu-Ala-Arg-Lys(BHQ3) .


Zhang H.


Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2008 May 22 [updated 2008 Jul 21].


Photodynamic therapy (PDT), also known as photochemotherapy, uses light-activated photosensitizers (PS) in the presence of oxygen to kill cells (1). PDT has become a promising modality to treat skin, esophagus, and lung cancers, as well as other diseases such as atherosclerosis, macular degeneration, and rheumatoid arthritis (2). In PDT, light excites the singlet state of the PS, followed by intersystem transition from the singlet state to the triplet state; then, the energy is transferred from the triplet state of the PS to the triplet ground state of oxygen, 3O2(X3Σg-) (3O2 triplet state quenching) to generate singlet oxygen, 1O2(a1Δg) (3). The produced 1O2 is a major cytotoxic agent that has a short life time (<200 ns) and an average diffusion range (~20 nm, which is smaller than the diameter of a cell) (2). Such a short diffusion range requires the delivery of target-specific PS agents into subcellular compartments such as cytoskeletal tubulin, lysosomes, mitochondria, plasma membrane, and the nucleus, where they can generate 1O2 efficiently (2). A novel type of PS agent, called a photodynamic molecular beacon (PMB) or killer beacon, has been developed to meet this requirement (2, 4). A typical PMB consists of four modular components: a fluorescent PS, a quencher, a linker, and a delivery vehicle. The target-specific linkers keep the fluorescent PS and the quencher within effective distance of the Föster radius (3–6 nm) (2), which allows efficient fluorescence resonance energy transfer between the fluorescent PS and the quencher. As a result, the fluorescent PS is silent until the PMB meets the target, where the enzyme cleaves the linker and activates the fluorescence of the PS (4). Thus, the PS performs two functions by producing 1O2 to kill cells and by illuminating detectable fluorescence to image its own therapeutic outcome (5). Matrix metalloproteinases (MMPs) have been pharmaceutical targets for many years because they play important roles in many diseases such as atherosclerosis, lung pulmonary fibrosis, and cancer (4). MMPs in tumors aid the degradation of extracellular matrix, facilitate neoplastic cell motility, and direct cell invasion (4). Also known as matrilysin, MMP subtype-7 (MMP7) is one of only a few MMPs that are actually secreted by tumor cells (6). Pyro-Gly-Pro-Leu-Gly-Leu-Ala-Arg-Lys(BHQ3) (PPMMP7B) is a PMB specific for MMP7, and it is detectable with near-infrared (NIR) fluorescence imaging (4). PPMMP7B consists of the infrared fluorescence PS pyropheophorbide α (Pyro), a black hole quencher 3 (BHQ3), and a peptide linker (Gly-Pro-Leu-Gly-Leu-Ala-Arg-Lys (GPLGLARK)) (4). The peptide contains the tripeptide motif Pro-Leu-Gly for MMP7 recognition, and the cleavage site is located between the Gly and Leu residues. Pyro acts as the intracellular delivery vehicle and as the PS (absorption, 665 nm; emission, 675 nm and 720 nm) with good 1O2 production (50%). Pyro lacks dark toxicity (toxicity in absence of light) because of its low absorption between 450–600 nm. BHQ3 (absorption, 672 nm) can efficiently quench Pyro fluorescence via fluorescence resonance energy transfer (FRET). The cleavage of Pyro-Gly-Asp-Glu-Val-Asp-Gly-Ser-Gly-Lys(BHQ3) (PPB) by MMP7 separates the PS (Pyro) from the quencher (BHQ3) and restores the Pyro fluorescence for detection.

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