Abstract
We describe novel imaging protocols that allow detection of small cancer cell colonies deep inside tissue phantoms with high sensitivity and specificity. We compare fluorescence excited in Styryl-9M molecules by femtosecond pulses at near IR wavelengths, where Styryl-9M shows the largest dependence of the two-photon absorption (2PA) cross section on the local environment. We show that by calculating the normalized ratio of the two-photon excited fluorescence (2PEF) intensity at 1200 nm and 1100 nm excitation wavelengths we can achieve high sensitivity and specificity for determining the location of cancer cells surrounded by normal cells. The 2PEF results showed a positive correlation with the levels of MDR1 proteins expressed by the cells, and, for high MDR1 expressors, as few as ten cancer cells could be detected. Similar high sensitivity is also demonstrated for tumor colonies induced in mouse external ears. This technique could be useful in early cancer detection, and, perhaps, also in monitoring dormant cancer deposits.
Highlights
Optical imaging of cancer is becoming an increasingly useful instrument for refining early diagnosis [1,2,3,4], developing targeted therapies [5,6] and monitoring of patient response to therapy [1,7]
Because the relative 2PEF at 1100 nm does not depend on the composition of the phantom, the ratio given by Eq (1) effectively discriminates the pixel corresponding to the cancer cells from those where the signal originates from the normal cells
We have shown that a commercially available near-IR fluorescent organic dye, Styryl-9M, can be used for sensitive quantitative imaging of small cancer cell colonies embedded deep in biological tissue phantoms
Summary
Optical imaging of cancer is becoming an increasingly useful instrument for refining early diagnosis [1,2,3,4], developing targeted therapies [5,6] and monitoring of patient response to therapy [1,7]. Two-photon excited fluorescence (2PEF) offers potential improvements over conventional one-photon excitation techniques, which include better 3D resolution, higher depth efficacy, higher specificity and lower scattering. Despite these advantages, few chromophores have been developed for use in tissues in the near-IR region. We develop a novel in vivo dual-wavelength near-IR imaging technique that uses two-photon excitation of fluorescence of Syryl-9M by loosely focused 1 kHz repetition rate high peak intensity femtosecond laser pulses. We show that under these conditions Syryl-9M can detect as few as 10 cells in a biologically relevant phantom This outstanding characteristic should bode very well for development of new highly efficient near-IR clinical imaging agents
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