Photoacoustic imaging in cancer detection, diagnosis, and treatment guidance

Abstract

Imaging modalities play an important role in the clinical management of cancer, including screening, diagnosis, treatment planning and therapy monitoring. Owing to increased research efforts during the past two decades, photoacoustic imaging (a non-ionizing, noninvasive technique capable of visualizing optical absorption properties of tissue at reasonable depth, with the spatial resolution of ultrasound) has emerged. Ultrasound-guided photoacoustics is noted for its ability to provide in vivo morphological and functional information about the tumor within the surrounding tissue. With the recent advent of targeted contrast agents, photoacoustics is now also capable of in vivo molecular imaging, thus facilitating further molecular and cellular characterization of cancer. This review examines the role of photoacoustics and photoacoustic-augmented imaging techniques in comprehensive cancer detection, diagnosis and treatment guidance.

Figure 1

(a) Block diagram of a typical PAI system. (b) Absorption spectra of endogenous chromophores in the body. The optical absorption of these endogenous chromophores is wavelength-dependent; therefore, PA signal intensity at different optical wavelengths can be used to characterize optical properties of tissue. Data for the absorption coefficient was obtained from [22]. The “optical window” (600–1100 nm) is the wavelength range where tissue absorption is at a minimum. (c) Extinction spectra of common exogenous contrast agents with peaks in the optical window.

Figure 2

(a) Overlaid maximum amplitude projections of PA images at 764 nm and 584 nm showing a tumor and its surrounding vasculature, respectively. The image clearly shows the vessel branching and structure around the tumor. Adapted with permission from [4]. (b) Images of the breast of 57 year old woman with invasive ductal carcinoma: (i) X-ray mammogram; (ii) sonogram; (iii) PA image at 1064 nm. The X-ray mammogram and the sonogram depict the gross anatomical features of the tumor, but donot provide functional information. The high PA amplitude corresponds to abundant vasculature associated with malignant tumors. The PA image clearly depicts that higher vascular densities are present in the tumor periphery and the core of the tumor has minimum vasculature. Adapted with permission from [21]. (c) Pancreatic tumor cells were inoculated on a rat hind leg on day 1. PAI was used to monitor angiogenesis associated with the tumor growth. PA images obtained from the tumor region on days 3, 7, 8 and 10 are maximum intensity projections of the photoacoustic source strength in the xy-plane (i.e. top view on the tumor tissue). Adapted with permission from [5]. (d) In vivo functional imaging of a mouse brain with a glioblastoma xenograft obtained using PAI. Spectroscopic PAI (wavelengths from 764 nm to 824 nm) was used to detect hypoxia in a braintumor. The heat map represents the percentage oxygen saturation (SO₂) in the blood vessels (blue = hypoxic; red = hyperoxic). The area indicated by the red arrow is the tumor. Adapted with permission from [31]. (e) A comparison of normal and brain tumor vasculature SO₂in three mice. Three normal vessels and three tumor vessels were chosen from each SO₂image that had been processed from spectroscopic PA images, such as the one shown in (d). The results clearly indicate that the percentage SO₂ in tumors is lower than the surrounding normal tissue, thus indicating hypoxia. Adapted with permission from [31].

Figure 3

Various optical- and ultrasound-based imaging techniques can be combined with PAI to provide structural, functional and biomechanical properties of the tissue. (a)In vivo 3D USI and PAI of a subcutaneous tumor in a mouse injected with gold nanorods. The subcutaneous tumor appears as a bump in the 3D ultrasound image. The PA image shows the heterogenous localization of nanorods in tumor, which preferentially accumulate there owing to the enhanced permeation and retention effect [69]. (b)In vivo PAI and OCT of the skin on the back of a nude mouse. The image represents a data fusion of OCT (structure of the skin) and PA (microvasculature) images. Adapted with permission from [64]. (c) Noninvasive in vivo fluorescence (FL) image acquired 24 hours after ICG injection in a mouse with melanoma cells implanted in brain. Noninvasive in vivo PA images were acquired with skin and skull intact, showing the vasculature in the brain. Adapted with permission from [70]. (d) Gray-scale ultrasound image (left), PA image (center), and elasticity (right) images of a tissue-mimicking phantom with a single inclusion. The inclusion had higher optical contrast and was harder compared to the background. (e) MMUS (top) and PA (bottom) images of a tissue-mimicking phantom with samples containing (left to right):a mixture of Fe₃O₄ nanoparticles and Au nanospheres; Au nanospheres only; PVA only (no nanoparticles); and Fe₃O₄ nanoparticles only. The MMUS colormap represents the displacement of the inclusions. The pure PVA sample (no nanoparticles) did not displace under magnetic excitation and showed no PA contrast. The Au nanospheres also do not displace, but have high optical absorption and hence produce greater PA signals compared with Fe₃O₄ nanoparticles. The two samples containing Fe₃O₄ nanoparticles had a displacement of about 100 µm [71].

Figure 4

(a) PAI can guide therapeutic procedures by providing an accurate biodistribution map of therapy agents. The white dotted lines represent the lymph node. The red regions indicate areas of higher accumulation of GNTs (i.e. in the lymph nodes). Therapeutic localization and dosage can be decided based on the guidance provided by the PA image regarding the location of GNTs. Adapted with permission from [73]. (b) Doxorubicin is encapsulated in the PLGA core, and the silver metal nanoparticles on the surface provide PA contrast for monitoring therapeutic response. Adapted with permission from [75]. (c) Therapeutic efficacy can be monitored in context of the anatomical map of the tumor tissue. USI and PAI can be used to monitor temperature increase during thermal therapy procedures. A mouse was injected with optically absorbing gold nanorods that acted as both PA and photothermal agents. The tumor region was then irradiated with continuous-wave laser light at the peak absorption wavelength. Images taken after 0, 30 and 60 seconds of treatment indicate that the relative temperature rise in the tumor is 25 °C. Each image represents a 10.5 mm × 20 mm field of view.