This Perspective explores and explains the fundamental dogma of nanoparticle delivery to tumours and answers two central questions: ‘how many nanoparticles accumulate in a tumour?’ and ‘how does this number affect the clinical translation of nanomedicines?’

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Analysis of nanoparticle delivery to tumours

Photoacoustic (PA) imaging, also called optoacoustic imaging, is a new biomedical imaging modality based on the use of laser-generated ultrasound that has emerged over the last decade. It is a hybrid modality, combining the high-contrast and spectroscopic-based specificity of optical imaging with the high spatial resolution of ultrasound imaging. In essence, a PA image can be regarded as an ultrasound image in which the contrast depends not on the mechanical and elastic properties of the tissue, but its optical properties, specifically optical absorption. As a consequence, it offers greater specificity than conventional ultrasound imaging with the ability to detect haemoglobin, lipids, water and other light-absorbing chomophores, but with greater penetration depth than purely optical imaging modalities that rely on ballistic photons. As well as visualizing anatomical structures such as the microvasculature, it can also provide functional information in the form of blood oxygenation, blood flow and temperature. All of this can be achieved over a wide range of length scales from micrometres to centimetres with scalable spatial resolution. These attributes lend PA imaging to a wide variety of applications in clinical medicine, preclinical research and basic biology for studying cancer, cardiovascular disease, abnormalities of the microcirculation and other conditions. With the emergence of a variety of truly compelling in vivo images obtained by a number of groups around the world in the last 2–3 years, the technique has come of age and the promise of PA imaging is now beginning to be realized. Recent highlights include the demonstration of whole-body small-animal imaging, the first demonstrations of molecular imaging, the introduction of new microscopy modes and the first steps towards clinical breast imaging being taken as well as a myriad of in vivo preclinical imaging studies. In this article, the underlying physical principles of the technique, its practical implementation, and a range of clinical and preclinical applications are reviewed.

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Biomedical photoacoustic imaging

Photoacoustic tomography (PAT) is probably the fastest-growing area of biomedical imaging technology, owing to its capacity for high-resolution sensing of rich optical contrast in vivo at depths beyond the optical transport mean free path (~1 mm in human skin). Existing high-resolution optical imaging technologies, such as confocal microscopy and two-photon microscopy, have had a fundamental impact on biomedicine but cannot reach the penetration depths of PAT. By utilizing low ultrasonic scattering, PAT indirectly improves tissue transparency up to 1000-fold and consequently enables deeply penetrating functional and molecular imaging at high spatial resolution. Furthermore, PAT promises in vivo imaging at multiple length-scales; it can image subcellular organelles to organs with the same contrast origin — an important application in multiscale systems biology research.

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Multiscale photoacoustic microscopy and computed tomography.

The life sciences can benefit greatly from imaging technologies that connect microscopic discoveries with macroscopic observations. One technology uniquely positioned to provide such benefits is photoacoustic tomography (PAT), a sensitive modality for imaging optical absorption contrast over a range of spatial scales at high speed. In PAT, endogenous contrast reveals a tissue's anatomical, functional, metabolic, and histologic properties, and exogenous contrast provides molecular and cellular specificity. The spatial scale of PAT covers organelles, cells, tissues, organs, and small animals. Consequently, PAT is complementary to other imaging modalities in contrast mechanism, penetration, spatial resolution, and temporal resolution. We review the fundamentals of PAT and provide practical guidelines for matching PAT systems with research needs. We also summarize the most promising biomedical applications of PAT, discuss related challenges, and envision PAT's potential to lead to further breakthroughs.

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A practical guide to photoacoustic tomography in the life sciences

Cholinesterase Inhibitors in Alzheimer's Disease

In this study, we monitor the progress of vasculature in early tumor growth using photoacoustic imaging over a 20 day period after subcutaneous inoculation of breast cancer tumor cells in a mouse. With 532 nm laser pulses employed as an irradiation source, the photoacoustic images were obtained through the photoacoustic signals received by a hydrophone in orthogonal mode. The morphological characteristics of vasculature in tumor region are clearly resolved in the photoacoustic images, and the change in structure as well as the increase in density can be identified. Moreover, the average photoacoustic signal strength of vasculature in tumor region, which is highly correlated with the total hemoglobin concentration of blood, is enhanced during early tumor growth. These results indicate the feasibility of detecting early stage tumor and monitoring the progress of anti-angiogenic therapy by photoacoustic imaging.

https://iopscience.iop.org/article/10.1088/0031-9155/53/15/013/pdf

Noninvasive photoacoustic imaging of the developing vasculature during early tumor growth

Photoacoustic imaging(PAI) is a noninvasive, nonionizing modality based on the differences in light absorption of various biological tissues.PAI utilizes the endogenous contrast characteristics of traditional optical imaging, while benefiting from high spatial resolution of the ultrasound imaging. A PAI system was developed to reconstruct the two-dimensional cross section image and to visualize the cerebrovascular activities of mouse in vivo. The spatial resolution of the PAI system was determined to be 0.110 mm by a two-point-source phantom with the Rayleigh criterion. The potential applications of the system were clearly demonstrated by successfully mapping a traumatic lesion in the mouse brain cerebral cortex, by its ability to monitor physiological changes in the brain due to carotid ligation and drug stimulation, and two-dimensional sliced images of a traumatic mouse brain at different depths were also provided. Our experimental results indicate that PAI has the potential for studying of traumatic brain injury and physiological functions of the brain.

https://aapm.onlinelibrary.wiley.com/doi/pdf/10.1118/1.2757088

Functional imaging of cerebrovascular activities in small animals using high-resolution photoacoustic tomography.

Characterization of Lipid-Rich Aortic Plaques by Intravascular Photoacoustic Tomography: Ex Vivo and In Vivo Validation in a Rabbit Atherosclerosis Model With Histologic Correlation

We present a fast full-view photoacoustic imaging system for visualizing tissue structures using a linear transducer array with combined scan. In this system, a 128-element linear transducer array was used to detect photoacoustic signals by combined scanning of electronic scan and mechanical scan. An improved limited-field filtered back projection algorithm with directivity factors was applied to reconstruct the optical absorption distribution. The experiments of phantoms and in vivo blood vessels in a rat brain were performed with this system. And a clear view of the curve boundaries of objects and the network of blood vessels of rat's brain were acquired. The experimental results demonstrate the multi-element photoacoustic imaging system has the ability of imaging complicated structures of objects.

Fast full-view photoacoustic imaging by combined scanning with a linear transducer array

The optoacoustic technique is a noninvasive imaging method with high spatial resolution. It potentially can be used to monitor anatomical and physiological changes. Photodynamic therapy PDT-induced vascular damage is one of the important mechanisms of tumor destruction, and real-time monitoring of vascu- lar changes can have therapeutic signicance. A unique optoacoustic system is developed for neovascular imaging during tumor photo- therapy. In this system, a single-pulse laser beam is used as the light source for both PDT and for concurrently generating ultrasound sig- nals for optoacoustic imaging. To demonstrate its feasibility, this sys- tem is used to observe vascular changes during PDT treatment of chicken chorioallantoic membrane CAM tumors. The photosensi- tizer used in this study is protoporphyrin IX PpIX and the laser wave- length is 532 nm. Neovascularization in tumor angiogenesis is visu- alized by a series of optoacoustic images at different stages of tumor growth. Damage of the vascular structures by PDT is imaged before, during, and after treatment. Rapid, real-time determination of the size of targeted tumor blood vessels is achieved, using the time difference of positive and negative ultrasound peaks during the PDT treatment. The vascular effects of different PDT doses are also studied. The ex- perimental results show that a pulsed laser can be conveniently used to hybridize PDT treatment and optoacoustic imaging and that this integrated system is capable of quantitatively monitoring the structural change of blood vessels during PDT. This method could be potentially used to guide PDT and other phototherapies using vascular changes during treatment to optimize treatment protocols, by choosing appro- priate types and doses of photosensitizers and doses of light. © 2007

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Sihua Yang

Papers

Noninvasive photoacoustic imaging of the developing vasculature during early tumor growth

Functional imaging of cerebrovascular activities in small animals using high-resolution photoacoustic tomography.

Characterization of Lipid-Rich Aortic Plaques by Intravascular Photoacoustic Tomography: Ex Vivo and In Vivo Validation in a Rabbit Atherosclerosis Model With Histologic Correlation

Fast full-view photoacoustic imaging by combined scanning with a linear transducer array

Real-time optoacoustic monitoring of vascular damage during photodynamic therapy treatment of tumor.