Abstract
There is a need to image excised tissues during tumor-resection procedures in order to identify residual tumors at the margins and to guide their complete removal. The imaging of dysregulated cell-surface receptors is a potential means of identifying the presence of diseases with high sensitivity and specificity. However, due to heterogeneities in the expression of protein biomarkers in tumors, molecular-imaging technologies should ideally be capable of visualizing a multiplexed panel of cancer biomarkers. Here, we demonstrate that the topical application and quantification of a multiplexed cocktail of receptor-targeted surface-enhanced Raman scattering (SERS) nanoparticles (NPs) enables rapid quantitative molecular phenotyping (QMP) of the surface of freshly excised tissues to determine the presence of disease. In order to mitigate the ambiguity due to nonspecific sources of contrast such as off-target binding or uneven delivery, a ratiometric method is employed to quantify the specific vs. nonspecific binding of the multiplexed NPs. Validation experiments with human tumor cell lines, fresh human tumor xenografts in mice, and fresh human breast specimens demonstrate that QMP imaging of excised tissues agrees with flow cytometry and immunohistochemistry, and that this technique may be achieved in less than 15 minutes for potential intraoperative use in guiding breast-conserving surgeries.
Highlights
The quantitative molecular phenotyping (QMP) technology described here is a surface-imaging approach that can potentially identify residual tumors at the surgical margins, for which there is an unequivocal need for additional resection
Through a series of imaging experiments with fresh tumor xenografts and fresh human breast tissues, we have demonstrated that the topical application and quantification of receptor-targeted surface-enhanced Raman-scattering (SERS) NPs allows for the rapid (< 15 min) quantitative molecular phenotyping (QMP) of tissues to potentially enable the intraoperative detection of residual carcinoma at lumpectomy margins
Several features make this rapid QMP technique accurate and sensitive for the intraoperative examination of resected tissues, in excellent agreement with flow-cytometry and IHC validation data: (i) Multiplexed SERS NPs may be excited at a single illumination wavelength (785 nm), ensuring that all NP reporters in a measurement are interrogated identically in terms of illumination intensity, detection area, and effective excitation depth
Summary
Positive for tumor (tumor at the surface of the final excised specimen, i.e. “tumor on ink”). The relatively large size of SERS NPs (20–120 nm) hampers their extravasation and penetration into most tissues when delivered systemically While this feature has been utilized for the imaging of tumors through enhanced permeability and retention (EPR) mechanisms[25,26], these passive delivery effects complicate molecular-imaging efforts and can lead to a high degree of ambiguity when one wishes to determine if image contrast is due to true molecular binding rather than passive accumulation. In the study described here, we demonstrate the feasibility of utilizing SERS NPs to enable quantitative multiplexed molecular imaging of freshly excised human tissues for surgical-guidance applications. Other sources of misleading nonspecific contrast include off-target chemical binding, variations in detector working distance and illumination power, as well as uneven
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