Current and future clinical applications for optical imaging of cancer: from intraoperative surgical guidance to cancer screening

Abstract

Optical imaging is an inexpensive, fast, and sensitive imaging approach for the noninvasive detection of human cancers in locations that are accessible by an optical imaging device. Light is used to probe cellular and molecular function in the context of cancer in the living body. Recent advances in the development of optical instrumentation make it possible to detect optical signals produced at a tissue depth of several centimeters. The optical signals can be endogenous contrasts that capture the heterogeneity and biological status of different tissues, including tumors, or extrinsic optical contrasts that selectively accumulate in tumors to be imaged after local or systemic delivery. The use of optical imaging is now being applied in the clinic and operating room for the localization and resection of malignant tumors in addition to screening for cancer.

Fig 1

Chemical structures, spectral properties, and working principles of indocyanine green (ICG) and 5-aminolevulinic acid (ALA) as fluorescent contrast agents for endoscopic tumor detection. Left panel: Chemical structure and spectral properties of ICG. Upon systemic injection, ICG is rapidly bound to blood proteins (such as albumin), and the resulting complexes (5-10 nm in size) are accumulated in tumors mainly via enhanced permeability and retention (EPR). Right panel: Nonfluorescent ALA is taken up by tumor cells and then induces the biosynthesis and accumulation of fluorescent protoporphyrin IX (PpIX). The proposed mechanisms for higher ALA uptake in brain tumors include a disrupted blood-brain barrier, increased neovascularization, and the overexpression of membrane transporters in malignant glioma tissue (45). ALA-induced PpIX levels in normal brain are very low creating tumor-to-normal tissue contrast ratios as high as 50-100.

Fig 2. 5-ALA metabolism

The oral administration of 5-ALA (20 mg/kg) leads to a selective accumulation of PPIX in tumor cells as well as epithelial tissues. 5-ALA is a prodrug that is metabolized intracellularly by the heme porphyrin synthesis pathway to form the fluorescent PPIX molecule.

Fig 3. Fluorescence-guided brain tumor resection

Following excitation with blue light (λ = 400 - 410 nm) emitted from a special filter attachment on the operative microscope, the PPIX, which has accumulated selectively in the malignant tissue, emits a red-violet light enabling the surgeon to resect the red-violet tumor tissue in a gross total fashion.

Fig 4

Photograph of a third generation DOT system.

Fig 5

CT image (a), recovered coronal μ_a image (b) and μ_s’ image (c), and photograph of the excised tissue (d) for from a breast cancer patient. The white/black arrows indicate the lesion location(s). Mammogram (e) and sonogram (f) of the left breast from a breast cancer patient. Recovered optical images in the coronal plane: μ_a (g) and μ_s’ (h) image. The axes (left and bottom) are the spatial scale (mm), whereas the color scale (right) is the μ_a or μ_s’ (mm^-1). 1D profiles of the recovered μ_a (i) and μ_s’ (j) along a horizontal cut line through the center of the cyst region for the patient. (k) Craniocaudal mammogram. (l) HbO₂ image. (m) Hb image. (n) H₂O image. The images shown are in the coronal plane at the level of the lesions. The color bar (right) is the recovered HbO₂ (μM), Hb (μM), or H₂O (%), while the axes (left and below) refer to the spatial coordinates (mm).

Fig 6

Recovered MD image (a) and VF image (b) for the malignant case. The color bar (right) indicates the size (μm) or VF (%). (c) Average values of recovered MD and VF. (d) The peak value of the recovered MD versus the peak value of VF in the lesion region. Pink: Malignant. Blue: Benign.

Fig 7

Schematic of a parallel plate DOT instrument (Adapted from Ref. 54).

Fig 8

Systemic delivery of NIR-dye-labeled targeting ligands that are conjugated to a magnetic iron oxide nanoparticle produces stronger optical signal in an orthotopic pancreatic cancer xenograft model than optical imaging using NIR-dye-labeled free peptides.