Cherenkov luminescence mediated excitation of discrete lanthanide optical probes

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Precision medicine requires tools that visualize diseased cells to enable diagnosis, facilitate surgical resection, and monitor therapeutic response. Technologies to identify the interface of cancer and healthy tissues require the ability to illuminate cancer cells with exceptional selectivity over healthy cells. This also requires optical imaging probes that can selectively illuminate cancer in vivo. To date, molecular optical dyes utilized for preclinical and clinical imaging studies are comprised of lipophilic organic molecules with limited water solubility, predominantly hepatic clearance profile, residing in an “always on” state. These significant drawbacks motivate investigation of alternative optical probes that exhibit improved water solubility and pharmacokinetics paired with the ability to produce signal only in the target tissues of interest. Luminescent lanthanide complexes with emissive properties in the first NIR (near-infrared) window provide a highly water soluble and biocompatible alternative to lipophilic organic fluorophores with predominantly hepatic clearance profiles. Excitation of luminescent lanthanides is most efficient at wavelengths of 250–350 nm. While the resulting, effective Stokes-shift of is conveniently large, the short-wavelength excitation is incompatible with the first biological optical imaging window of 550–1000 nm. This has prevented application of discrete luminescent lanthanide complexes as optical probes for in vivo imaging applications to date. Our group has pioneered the application of Cherenkov radiation (CR) of radionuclides for the in situ excitation of discrete lanthanide complexes. CR is produced by isotopes decaying under emission of charged particles in dielectric media and exhibits a maximum intensity below 400 nm. We have demonstrated that luminescent lanthanide antenna complexes are ideal acceptors for Cherenkov radiation-mediated energy transfer (CRET). Here, we propose to devise and implement targeted CRET lanthanide probes to image cancer heterogeneity with multiplexed, optical imaging in vivo.