title: Three-dimensional imaging and uptake of the anticancer drug combretastatin in cell spheroids and photoisomerization in gels with multiphoton excitation.
abstract: The uptake of E -combretastatins, potential prodrugs of the anticancer Z -isomers, into multicellular spheroids has been imaged by intrinsic fluorescence in three dimensions using two-photon excited fluorescence lifetime imaging with 625-nm ultrafast femtosecond laser pulses. Uptake is initially observed at the spheroid periphery but extends to the spheroid core within 30 min. Using agarose gels as a three-dimensional model, the conversion of Z(trans)→E(cis) via two-photon photoisomerization is demonstrated and the location of this photochemical process may be precisely selected within the micron scale in all three dimensions at depths up to almost 2 mm. We discuss these results for enhanced tissue penetration at longer near-infrared wavelengths for cancer therapy and up to three-photon excitation and imaging using 930-nm laser pulses with suitable combretastatin analogs.
authors.affiliation: Research Complex at Harwell, Central Laser Facility, STFC Rutherford Appleton Laboratory, Harwell Oxford, Didcot, OX11 0FA, United Kingdom.
authors.forename: Kathrin M
authors.initials: KM
authors.lastname: Scherer
authors.affiliation: University of Salford, Biomedical Research Centre, Kidscan Laboratories, Salford, Greater Manchester, M5 4WT, United Kingdom.
authors.forename: Roger H
authors.initials: RH
authors.lastname: Bisby
authors.affiliation: Research Complex at Harwell, Central Laser Facility, STFC Rutherford Appleton Laboratory, Harwell Oxford, Didcot, OX11 0FA, United Kingdom.
authors.forename: Stanley W
authors.initials: SW
authors.lastname: Botchway
authors.affiliation: University of Salford, Biomedical Research Centre, Kidscan Laboratories, Salford, Greater Manchester, M5 4WT, United Kingdom.
authors.forename: John A
authors.initials: JA
authors.lastname: Hadfield
authors.affiliation: University of Sheffield, Kroto Research Institute, Department of Materials Science and Engineering, Broad Lane, Sheffield, S3 7HQ, United Kingdom.
authors.forename: John W
authors.initials: JW
authors.lastname: Haycock
authors.affiliation: Research Complex at Harwell, Central Laser Facility, STFC Rutherford Appleton Laboratory, Harwell Oxford, Didcot, OX11 0FA, United Kingdom.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Parker
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001632:Bibenzyls / Q000737:chemistry / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D021621:Imaging, Three-Dimensional / Q000379:methods*; D036641:Microscopy, Fluorescence, Multiphoton / Q000379:methods*; D017785:Photons; D018874:Spheroids, Cellular / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001632:Bibenzyls; D005456:Fluorescent Dyes; C040105:combretastatin