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Photodynamic Therapy Agent with a Built-In Apoptosis Sensor for Evaluating Its Own Therapeutic Outcome in Situ

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Departments of Chemistry and Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Cite this: J. Med. Chem. 2006, 49, 13, 3850–3856
Publication Date (Web):May 28, 2006
https://doi.org/10.1021/jm060146u
Copyright © 2006 American Chemical Society

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    Abstract

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    Identifying the extent of apoptosis in cells or tissues after cancer therapy in real time would be a powerful firsthand tool for assessing therapeutic outcome. We combined therapeutic and imaging functions in one agent, choosing photodynamic therapy (PDT) as an appropriate cancer treatment modality. This agent induces photodamage in irradiated cells and simultaneously identifies apoptotic cells by near-infrared fluorescence. This photodynamic therapy agent with a built-in apoptosis sensor (PDT-BIAS) contains a fluorescent photosensitizer used as an anticancer drug, connected to a fluorescence quencher by a caspase-3 cleavable peptide linker. We demonstrated that cleavage of the peptide linker by caspase-3, one of the executioner caspases involved in apoptosis, results in a detectable increase of fluorescence in solution and in cancer cells after PDT treatment. The apoptosis involvement and drug effectiveness were confirmed by Apoptag and cell viability (MTT) assays supporting the ability of PDT-BIAS to induce and image apoptosis in situ.

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     Department of Chemistry.

     Department of Radiology.

    *

     To whom correspondence should be addressed. Phone:  1-215-898-3105. Fax:  1-215-746-8764. E-mail:  [email protected].

    Abbreviations:  DCM, dichloromethane; ESI-MS, electrospray ionization mass spectrometry; FRET, fluorescence resonance energy treansfer; HPLC, high performance liquid chromatography; MALDI-ToF, matrix assisted laser desorption/ionization−time-of-flight mass spectrometry; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide; NMP, 1-methyl-2-pyrrolidinone; RT, retention time; TFA, trifluoroacetic acid; TIS, triisopropylsilane; UV−vis, ultraviolet−visible spectroscopy.

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    Figure 1 showing purity, UV−vis, and MALDI-ToF of PP (3); Figure 2 showing purity, UV−vis, and MALDI-ToF of PPB (4); Figure 3 showing HPLC of scrambled sequence Pyro-GPLGLARK-(BHQ-3) (sPPB) incubated with caspase-3 for 180 min; Figure 4 showing accumulation of PPB (4) inside KB cells monitored by fluorescence microscopy; Figure 5 showing HepG2 cells incubated with scrambled sequence Pyro-GHSSK(BHQ-3)LQL and Pyro-GDEVDGSGK-(BHQ-3) (4) and activated by light monitored by confocal microscopy; ANOVA test for MTT study; Figure 6 showing preliminary in vivo experiment; synthesis of Fmoc-GD(Boc)E(Boc)VD(Boc)GS(Boc) GK(Mtt)-Sieber (1). This material is available free of charge via the Internet at http://pubs.acs.org.

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