Fluorescence lifetime imaging of E-combretastatin uptake
and distribution in live mammalian cells

Bisby, RH; Botchway, SW; Hadfield, JA; McGown, A; Parker, AW; Scherer, KM

Abstract

To investigate within live mammalian cells the uptake and disposition of combretastatins, fluorescence lifetime imaging was used with two-photon excitation (2PE). Combretastatin A4 (CA4) and analogues are potential anticancer drugs due to their ability to inhibit angiogenesis. E(trans)-combretastatins are considerably less active than the Z(cis)-combretastatins proposed for clinical use. However the E combretastatins exhibit stronger intrinsic fluorescence with quantum yields and lifetimes that depend markedly on solvent polarity and viscosity. It is proposed that 2PE in the red and near-infrared tissue window may allow in situ isomerization of E-combretastatins to the more active Z-isomer, offering spatial and temporal control of drug activation and constitute a novel form of photodynamic therapy. In the present work we have characterised 2PE of E-CA4 and have used fluorescence lifetime imaging with 2PE to study uptake and intracellular disposition of E-CA4 and an analogue. The results show that these molecules accumulate rapidly in cells and are located mainly in lipidic environments such as lipid droplets. Within the droplets the local concentrations may be up to 2 orders of magnitude higher than that of the drug in the surrounding medium.

Citation

and distribution in live mammalian cells. European Journal of Cancer, 48(12), 1896-1903. https://doi.org/10.1016/j.ejca.2011.11.025

• Journal Article Type: Article
• Online Publication Date: Dec 29, 2011
• Publication Date: Dec 29, 2011
• Deposit Date: Jan 12, 2012
• Publicly Available Date: Apr 5, 2016
• Journal: European Journal of Cancer
• Print ISSN: 0959-8049
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 48
• Issue: 12
• Pages: 1896-1903
• DOI: https://doi.org/10.1016/j.ejca.2011.11.025
• Keywords: Combretastatin, fluorescence, lifetime, multiphoton, live cell, microscopy, drug uptake, lipid droplet, light, photodynamic therapy
• Publisher URL: http://dx.doi.org/10.1016/j.ejca.2011.11.025
• Related Public URLs: http://www.sciencedirect.com/science/journal/09598049/48/12