Introduction: Cerenkov Luminescence Imaging (CLI) is a biomedical imaging technique derived from the emission of light from a charged supra-relativistic subatomic particle in a dielectric medium [1]. CLI has entered clinical trials for multimodal imaging using FDA-approved radiotracers for Positron Emission Tomography (PET) [1, 2]. Clear advantages include faster imaging speeds, lower service cost, higher resolution, and no external light source required [1,2]. However, CL’s current limitations are based upon the emission spectrum which can be modified with the aid of CL contrast agents, to enhance and/or down-convert the signal without increasing the radioactive dose for patients [1]. Previous studies have focused on designing down-converting dyes or nanoparticles to convert CL into red-light, referred to as Cerenkov Radiation Energy Transfer (CRET), to reduce background signal from tissue absorption [3]. Hyperbolic metamaterials (HMMs), an artificial medium consisting of alternating nanoscale layers, have demonstrated the potential to enhance CL by multiple factors, [4] providing an opportunity to develop novel in vivo contrast agents. Here, we propose a novel HMM theranostic agent to enhance CLI for multimodal cancer diagnosis and treatment.
Methods: HMMs were fabricated using nanofabrication. Eu2O3 nanoparticles (NPs) were characterized using Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), and spectroscopy to confirm optical properties needed as a downconverter for CL. Eu2O3 NPs (100μL; 10mg/mL, 10% methanol) were imaged on HMMs using IVIS spectrum (n=3) (lex = 300nm; 620nm filter). Eu2O3 NPs, as CL downconverters, were radiolabeled with yttrium-90 ([90Y]) and CRET emission (100μL; 370kBq) was recorded via IVIS Spectrum (n=3) with no external excitation (620nm and open filter). Eu2O3 NPs were radiolabeled by mixing Eu2O3 NPs (1mL; 10mg/mL, 10% methanol) with [90Y]90YCl3 (51μL; 74MBq) at 95°C for 1 h. The product was analyzed using radio-TLC (n=3). Cerenkov emission ([90Y] 100μL; 370kBq) was recorded via IVIS Spectrum (n=3) with no external excitation (open filter).
Results: TEM images displayed sizes of Eu2O3NPs ranging from 118-250nm in good agreement with DLS results of Eu2O3 NPs (10mg/mL), which calculated a hydrodynamic size of 189.2nm in 10% methanol. Eu2O3 NPs had.an absorption peak of 270nm with two emission peaks at 600nm and 700nm. TLC demonstrated [90Y]90Y-Eu2O3 NPs had a purity of 69.5%. ROIs showed HMMs increase Eu2O3NPs’ luminescence up to 70%, [90Y] 90Y-Eu2O3 NPs’ CRET signal up to 50%, and [90Y] CL signal up to 88%.
Conclusion: So far, these promising findings show that HMMs can be used to enhance CLI for multimodal cancer imaging of therapy. Next steps include translating these HMMs to a preclinical theranostic agent (using 90Y) with CL signal enhancement for multimodal cancer theranostics.
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Figure 1 – Luminescence Enhancement using HMMs: The set of materials tested include a control (glass slide), 4P-HMM, and 7P-HMM to demonstrate the effect of number of periods on light propagation (n = 3). The various types of light interaction include luminescence (Eu2O3 NPs), Cerenkov Radiation Energy Transfer (CRET) ([90Y]90Y-Eu2O3 NPs), and Cerenkov Luminescence ([90Y]). A 10% methanol solution containing Eu2O3 NPs, [90Y]90Y-Eu2O3NPs, or [90Y] was pipetted on top of HMM substrates with a total volume of 100 μL and imaged using IVIS Spectrum (n = 3).
Author
CUNY Graduate Center