Photoacoustic imaging is a promising method for visualizing biological tissues with optical absorbers. This article provides an overview of the rapidly developing field of photoacoustic imaging. Photoacoustics, the physical basis of photoacoustic imaging, is analyzed briefly. The merits of photoacoustic technology, compared with optical imaging and ultrasonic imaging, are described. Various imaging techniques are also discussed, including scanning tomography, computed tomography and original detection of photoacoustic imaging. Finally, some biomedical applications of photoacoustic imaging are summarized.

Photoacoustic imaging in biomedicine

Photoacoustic (PA) imaging as a fast-developing imaging technique has great potential in biomedical and clinical applications. It is a noninvasive imaging modality that depends on the light-absorption coefficient of the imaged tissue and the injected PA-imaging contrast agents. Furthermore, PA imaging provides superb contrast, super spatial resolution, and high penetrability and sensitivity to tissue functional characteristics by detecting the acoustic wave to construct PA images. In recent years, a series of PA-imaging contrast agents are developed to improve the PA-imaging performance in biomedical applications. Here, recent progress of PA contrast agents and their biomedical applications are outlined. PA contrast agents are classified according to their components and function, and gold nanocrystals, gold-nanocrystal assembly, transition-metal chalcogenides/MXene-based nanomaterials, carbon-based nanomaterials, other inorganic imaging agents, small organic molecules, semiconducting polymer nanoparticles, and nonlinear PA-imaging contrast agents are discussed. The applications of PA contrast agents as biosensors (in the sensing of metal ions, pH, enzymes, temperature, hypoxia, reactive oxygen species, and reactive nitrogen species) and in bioimaging (lymph nodes, vasculature, tumors, and brain tissue) are discussed in detail. Finally, an outlook on the future research and investigation of PA-imaging contrast agents and their significance in biomedical research is presented.

Photoacoustic Imaging: Contrast Agents and Their Biomedical Applications.

Precise nanomedicine has been extensively explored for efficient cancer imaging and targeted cancer therapy, as evidenced by a few breakthroughs in their preclinical and clinical explorations. Here, we demonstrate the recent advances of intelligent cancer nanomedicine, and discuss the comprehensive understanding of their structure-function relationship for smart and efficient cancer nanomedicine including various imaging and therapeutic applications, as well as nanotoxicity. In particular, a few emerging strategies that have advanced cancer nanomedicine are also highlighted as the emerging focus such as tumor imprisonment, supramolecular chemotherapy, and DNA nanorobot. The challenge and outlook of some scientific and engineering issues are also discussed in future development. We wish to highlight these new progress of precise nanomedicine with the ultimate goal to inspire more successful explorations of intelligent nanoparticles for future clinical translations.

Precise nanomedicine for intelligent therapy of cancer

Phototherapies including photothermal therapy (PTT) and photodynamic therapy (PDT) have gained considerable attention due to their high tumor ablation efficiency, excellent spatial resolution and minimal side effects on normal tissue. In contrast to inorganic nanoparticles, near-infrared (NIR) absorbing organic nanoparticles bypass the issue of metal-ion induced toxicity and thus are generally considered to be more biocompatible. Moreover, with the guidance of different kinds of imaging methods, the efficacy of cancer phototherapy based on organic nanoparticles has shown to be optimizable. In this review, we summarize the synthesis and application of NIR-absorbing organic nanoparticles as phototherapeutic nanoagents for cancer phototherapy. The chemistry, optical properties and therapeutic efficacies of organic nanoparticles are firstly described. Their phototherapy applications are then surveyed in terms of therapeutic modalities, which include PTT, PDT and PTT/PDT combined therapy. Finally, the present challenges and potential of imaging guided PTT/PDT are discussed.

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Recent progress in the development of near-infrared organic photothermal and photodynamic nanotherapeutics.

Recent developments in multimodality fluorescence imaging probes

Croconaine nanoparticles with enhanced tumor accumulation for multimodality cancer theranostics

Glutathione (GSH), one of the most significant reducing species in vivo, plays important roles in a variety of diseases and cellular functions. Precise quantification of GSH via advanced noninvasive photoacoustic imaging (PAI) is of vital significance for the early diagnosis and prompt treatment of GSH-related deep-seated diseases, which stresses the need for custom-design of GSH-sensitive PAI probes with changeable near-infrared spectroscopy (NIR) absorption. In this work, a novel intelligent tumor microenvironment-activated ratiometric PAI nanoprobe is first developed with the intention of specific ultrasensitive detection of intratumoral GSH by overcoming the limitations of previously reported fluorescent or PA imaging sensors. This special ratiometric PAI nanoprobe (CR-POM) is synthesized through the self-assembly of croconaine (CR) dye and molybdenum-based polyoxometalate (POM) clusters with opposite NIR absorbance change in response to GSH. The resulting amplified ratiometric absorbance (Ab866/Ab700), the relatively low limit of detection value (0.51 mM), and the unique acidity-activated self-aggregation contribute to the prolonged intratumoral retention and enhanced tumor accumulation of CR-POM for accurate quantification of intratumoral GSH (0.5-10 mM). Featuring the additional merit of 64Cu radiolabeling for whole-body positron-emission tomography imaging, the smartly designed CR-POM nanoprobe will open new horizons for real-time noninvasive monitoring of biodistribution and simultaneous accurate quantification of GSH levels, especially in tumor and other GSH-related pathophysiological processes.

Tumor Microenvironment-Activated Ultrasensitive Nanoprobes for Specific Detection of Intratumoral Glutathione by Ratiometric Photoacoustic Imaging

Chemotherapy is currently the major therapeutic method against cancer However, chemo drugs are usually lacking in the specificity towards cancer cells over normal cells In this study, we prepared a novel multifunctional trimeric prodrug by linking the chemo drug camptothecin (CPT) and the exceptional photostable near infrared (NIR) croconaine dye (CR) via a glutathione (GSH)-sensitive disulfide linker Compared with CPT, our novel trimeric CR-(SS-CPT)2 is more hydrophobic and bulky, making it highly effcient to be encapsulated into biocompatible polymeric nanocarrier The prodrug underwent rapid drug release specifically in cancer cells with high GSH concentration The hyperthermia produced by CR upon laser irradiation could further accelerate the break of disulfide bond, which makes the release of CPT even more controllable We further loaded the CR-(SS-CPT)2 into folate modified lipid-polymer nanoparticles, which demonstrated high in vivo tumor accumulation and retention The biodistribution of these nanoparticles can be directly monitored in real time via NIR fluorescence and photoacoustic imaging Under the imaging guided chemo- and photothermal- synergistic therapy, the tumors were completely ablated with no recurrence The design not only highly enhanced the therapeutic specificity and effeciency of CPT, but also provide a "all in one" nanomedicine for imaging-guided dual modality therapy

Redox-responsive dual chemophotothermal therapeutic nanomedicine for imaging-guided combinational therapy

To meet the criteria of effective theranostics, biocompatible nanomedicine endowing intrinsic therapeutic and imaging properties have gained extraordinary momentum. In this study, an ultra-stable near-infrared (NIR) dye croconaine (CR780) was engineered with arginine-glycine-aspartic acid (RGD) peptide and polyethylene glycol (PEG), which was then self-assembled into uniform nanoparticles (NPs). These RGD-CR780-PEG5K assemblies were radiolabeled with 125I through a facile standard Iodo-Gen method. The resulting [125I]RGD-CR780-PEG5K NPs showed effective accumulation in αvβ3 integrin expressing glioblastoma, as evidenced by single photon emission computed tomography (SPECT)/CT and NIR fluorescence imaging. More importantly, high-resolution photoacoustic imaging revealed that these NPs selectively targeted to angiogenic tumor vessels. With the favorable tumor selective accumulation and high photothermal conversion efficiency, the [125I]RGD-CR780-PEG5K NPs allowed thorough tumor ablation and inhibition of tumor relapse at a relatively low laser energy (0.5 W/cm2). Overall, this work offers a proper methodology to fabricate tumor-targeted multi-modal nanotheranostic agents, providing great opportunity for precision imaging and cancer therapy.

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Fei Yu

Papers

Croconaine nanoparticles with enhanced tumor accumulation for multimodality cancer theranostics

Tumor Microenvironment-Activated Ultrasensitive Nanoprobes for Specific Detection of Intratumoral Glutathione by Ratiometric Photoacoustic Imaging

Redox-responsive dual chemophotothermal therapeutic nanomedicine for imaging-guided combinational therapy

Radiolabeled Angiogenesis-Targeting Croconaine Nanoparticles for Trimodality Imaging Guided Photothermal Therapy of Glioma.