Trends in Biotechnology
ReviewPhotoacoustic imaging in cancer detection, diagnosis, and treatment guidance
Introduction
Cancer is a vicious disease that killed approximately 570 000 people in 2010 in the USA alone [1]. To develop successful therapeutic strategies and prevent recurrence of the disease, its structural, functional and metabolic properties need to be well characterized. Research efforts are focused not only on developing new treatments and discovering the root cause for the disease, but also on developing imaging technologies that can aid in early detection of cancer and can provide comprehensive real-time information on the tumor properties. Currently, ultrasound imaging (USI), magnetic resonance imaging (MRI), X-ray computed tomography (CT) and nuclear imaging techniques, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), are being used to detect tumors in patients [2]. With the development of various targeted contrast agents, these imaging techniques are also able to provide molecular information about the malignant tumor tissue. However, microscopic optical imaging techniques have higher resolution (∼0.1–100 μm) compared with USI (50–500 μm), MRI (10–100 μm), CT (50–200 μm), PET (1–2 mm) and SPECT (1–2 mm), and can detect a lower number of cancer cells per imaging voxel [3]. Traditional diffusive regime optical imaging techniques, such as diffuse optical tomography (DOT), have high detection sensitivity; however, their resolution is limited to approximately 5 mm. The need for an imaging technique that can provide high optical contrast images at a microscale resolution and at a reasonable penetration depth has now been filled by photoacoustic imaging (PAI).
PAI has shown tremendous potential in simultaneously providing structural, functional and molecular information in preclinical studies. PAI can visualize tumor location deep within a tissue, and is also able to provide information on tumor vasculature [4] or to monitor angiogenesis [5]. PAI can also obtain information on hemoglobin oxygen saturation at high resolution and contrast, without the use of exogenous contrast agents [4], which is a significant advantage when compared with other tumor hypoxia imaging techniques (e.g., blood oxygen level-dependent MRI and PET). Another advantage of PAI is its compatibility with widely available USI techniques [6]; when combined, PAI and USI can simultaneously provide anatomical and functional information on tumors. For example, an in vivo study on human breast tissue has shown that an ultrasound image can depict the structure of ductal carcinoma, whereas photoacoustic (PA) images show the associated scattered distribution of vascularization [7].
With the availability of various targeted contrast agents, such as gold nanoparticles (AuNPs), several new avenues have opened for in vivo molecular PAI. This has facilitated highly sensitive and specific detection of tumors. In addition, PAI, combined with other complementary imaging techniques, has shown promise in cancer treatment guidance. Although several reviews on the basics and applications of PAI have been published, no examination of the recent developments in molecular PAI of cancer and the ability of PAI to monitor treatment is currently available; hence, we review these topics here.
Section snippets
Basic principles of PAI
PAI (also known as optoacoustic imaging) capitalizes on the PA effect first described by Alexander Graham Bell in 1880 [8]. In this review, we provide only basic principles (Box 1) towards understanding PAI applicability to cancer detection and treatment guidance. Briefly, absorbed laser energy causes a rapid thermoelastic expansion of tissue, resulting in the generation of a wide-band ultrasound wave. The ultrasound wave is detected with a transducer that converts the mechanical acoustic waves
Cancer detection with endogenous PA contrast
Cancer detection using PAI with endogenous chromophores (e.g., hemoglobin and melanin) is an area of active research. For example, PAI has been used to monitor melanoma tumor growth over the course of two weeks [13]. Optical contrast was provided by a higher concentration of melanin in the tumor relative to the surrounding tissue. PAI has also been used to detect skin melanoma 4, 14. Figure 2a depicts a melanoma and surrounding vasculature obtained by spectroscopic PAI. The pseudo-colored image
Cancer detection with exogenous PA contrast agents
The sensitivity of the PAI technique to image deeply situated tumors can be increased dramatically by utilizing exogenous contrast agents. The NIR-absorbing dyes, such as IRDye800CW 22, 27, AlexaFluor 750 [28] and indocyanine green (ICG) [29], have been used to enhance PA contrast. However, among the exogenous contrast agents, AuNPs have attracted attention in nanoparticle-based PAI owing to their unique optical properties from the surface plasmon resonance (SPR) effect. Because of the SPR
Combination of PA with other imaging modalities
Assessing complementary structural, functional, metabolic and molecular information on a tumor with high accuracy is essential for cancer treatment. PAI primarily provides high-resolution images based on the optical contrast of tissue components, such as changes owing to abnormal vasculature or high melanin content; however, the overall anatomical structure of the tumor cannot be perceived by PAI alone. USI, a noninvasive technique, can be used to obtain anatomical details about the tumor and
PAI for guiding, monitoring and evaluating therapy
Imaging techniques play a significant role in cancer therapy, from precise planning and guiding to evaluation of efficacy. In particular, PAI has shown potential in aiding therapies by providing sequential monitoring of tumor functional properties, such as changes in tumor vasculature before, during and after therapeutic procedures. The therapeutic agents used for photodynamic therapy (PDT) or photothermal therapy (PTT) can also act as PA contrast agents, owing to their high optical absorption
Outlook
Overall, PAI could become a valuable tool for cancer detection and diagnosis, tumor characterization and treatment guidance. By differentiating the optical properties of tissues, PAI is well suited to measuring the functional properties of tumors in vivo. For example, multi-wavelength PAI can visualize vasculature and identify hypoxic conditions within a tumor. Current functional imaging techniques suffer from either poor spatial resolution or inadequate penetration depth. Conversely, PAI is
Acknowledgments
Partial support for this work provided by NIH under grants EB008101 and CA149740 is greatly acknowledged. The authors would also like to thank all researchers and scientists who contributed to the field of photoacoustics and, therefore, made this review paper possible.
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