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Noninvasive and accurate detection of liver fibrosis is extremely significant for well-timed intervention and treatment to prevent or reverse its progression. Fluorescence imaging probes hold great potential for imaging of liver fibrosis, but they always encounter the inherent limitation of shallow penetration depth, which compromises their ability of in vivo detection. To overcome this issue, an activatable fluoro-photoacoustic bimodal imaging probe (IP) is herein developed for specific visualization of liver fibrosis. The probe IP is constructed on a near-infrared thioxanthene-hemicyanine dye that is caged with gamma-glutamyl transpeptidase (GGT) responsive substrate and linked with integrin-targeted peptide (cRGD). Such molecular design permits IP to effectively accumulate in the liver fibrosis region through specific recognition of cRGD towards integrin and activate its fluoro-photoacoustic signal after interaction with overexpressed GGT to precisely monitor the liver fibrosis. Thus, our study presents a potential strategy to design dual-target fluoro-photoacoustic imaging probes for noninvasive detection of early-stage liver fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Precise detection of early osteolytic metastases is crucial for their treatment but remains challenging in the clinic because of the limited sensitivity and specificity of traditional imaging techniques. Although fluorescence imaging offers attractive features for the diagnosis of osteolytic metastases, it is hampered by limited penetration depth. To address this issue, a fluoro-photoacoustic dual-modality imaging probe comprising a near-infrared dye caged by a cathepsin K (CTSK)-cleavable peptide sequence on one side and functionalized with osteophilic alendronate through a polyethylene glycol linker on the other side is reported. Through systematic in vitro and in vivo experiments, it is demonstrated that in response to CTSK, the probe generated both near-infrared fluorescent and photoacoustic signals from bone metastatic regions, thus offering a potential strategy for detecting deep-seated early osteolytic metastases., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Numerous polymeric agents have been widely applied in biology and medicine by virtue of the facile chemical modification, feasible nano-engineering approaches and fine-tuned pharmacokinetics. To endow polymeric imaging agents with ability to monitor and measure subtle molecular or cellular alterations at diseased sites, activatable polymeric probes that can elicit signal changes in response to biomolecular interactions or the analytes of interest have to be developed. Herein, this review aims to provide a systemic interpretation and summarization of the design methodology and imaging utility of recently emerged activatable polymeric probes. An introduction of activatable probes allowing for precise imaging and classification of polymeric imaging agents is reported first. Then, we give a detailed discussion of the contemporary design approaches toward activatable polymeric probes in diverse imaging modes for the detection of various stimuli and their imaging applications. Finally, current challenges and future advances are discussed and highlighted., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Imaging to evaluate tumor-associated neutrophils (TANs) is imperative for cancer immunotherapy but remains challenging. We herein report an activatable semiconducting polymer nanoprobe (SPCy) for near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging of neutrophil elastase (NE), a biomarker of TANs. SPCy comprises a semiconducting polymer conjugated with a hemicyanine (hemi-Cy) dye caged by a NE-cleavable peptide as the side chain. After systemic administration, SPCy passively targets the tumor and reacts with NE to "uncage" the hemi-Cy, leading to enhanced NIRF and PA signals of the hemi-Cy but unchanged signals of the SP. Such NE-activated ratiometric NIRF and enhanced PA signals of SPCy correlate with the intratumoral population of TANs. Thus, this study not only presents the first TAN-specific PA probe, but also provides a general molecular design strategy for PA imaging of other immune-related biomarkers to facilitate screening of cancer immunotherapeutics., (© 2022 Wiley-VCH GmbH.)

Development of real-time non-invasive imaging probes to assess infiltration and activation of cytotoxic T cells (CTLs) is critical to predict the efficacy of cancer immunotherapy, which however remains challenging. Reported here is an activatable semiconducting polymer nanoprobe (SPNP) for near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging of a biomarker (granzyme B) associated with activation of CTLs. SPNP comprises a semiconducting polymer (SP) conjugated with a granzyme B cleavable and dye-labeled peptide as the side chain, both of which emit NIRF and PA signals. After systemic administration, SPNP passively targets the tumor and in situ reacts with granzyme B to release the dye-labeled peptide, leading to decreased NIRF and PA signals from the dye but unchanged signals from the polymer. Such ratiometric NIRF and PA signals of SPNP correlate well with the expression level of granzyme B and intratumoral population of CTLs. Thus, this study not only presents the first PA probes for in vivo imaging of immune activation but also provides a molecular design strategy that can be generalized for molecular imaging of other immune-related biomarkers., (© 2020 Wiley-VCH GmbH.)

Discriminative detection of invasive and noninvasive breast cancers is crucial for their effective treatment and prognosis. However, activatable probes able to do so in vivo are rare. Herein, we report an activatable polymeric reporter (P-Dex) that specifically turns on near-infrared (NIR) fluorescent and photoacoustic (PA) signals in response to the urokinase-type plasminogen activator (uPA) overexpressed in invasive breast cancer. P-Dex has a renal-clearable dextran backbone that is linked with a NIR dye caged with an uPA-cleavable peptide substrate. Such a molecular design allows P-Dex to passively target tumors, activate NIR fluorescence and PA signals to effectively distinguish invasive MDA-MB-231 breast cancer from noninvasive MCF-7 breast cancer, and ultimately undergo renal clearance to minimize the toxicity potential. Thus, this polymeric reporter holds great promise for the early detection of malignant breast cancer., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Photoacoustic (PA) imaging agents detect disease tissues and biomarkers with increased penetration depth and enhanced spatial resolution relative to traditional optical imaging, and thus hold great promise for clinical applications. However, existing PA imaging agents often encounter the issues of slow body excretion and low-signal specificity, which compromise their capability for in vivo detection. Herein, a fluoro-photoacoustic polymeric renal reporter (FPRR) is synthesized for real-time imaging of drug-induced acute kidney injury (AKI). FPRR simultaneously turns on both near-infrared fluorescence (NIRF) and PA signals in response to an AKI biomarker (γ-glutamyl transferase) with high sensitivity and specificity. In association with its high renal clearance efficiency (78% at 24 h post-injection), FPRR can detect cisplatin-induced AKI at 24 h post-drug treatment through both real-time imaging and optical urinalysis, which is 48 h earlier than serum biomarker elevation and histological changes. More importantly, the deep-tissue penetration capability of PA imaging results in a signal-to-background ratio that is 2.3-fold higher than NIRF imaging. Thus, the study not only demonstrates the first activatable PA probe for real-time sensitive imaging of kidney function at molecular level, but also highlights the polymeric probe structure with high renal clearance., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Optical imaging has played a pivotal role in biology and medicine, but it faces challenges of relatively low tissue penetration and poor signal-to-background ratio due to light scattering and tissue autofluorescence. To overcome these issues, second near-infrared fluorescence, self-luminescence, and photoacoustic imaging have recently emerged, which utilize an optical region with reduced light-tissue interactions, eliminate real-time light excitation, and detect acoustic signals with negligible attenuation, respectively. Because there are only a few endogenous molecules absorbing or emitting above the visible region, development of contrast agents is essential for those deep-tissue optical imaging modalities. Organic semiconducting agents with π-conjugated frameworks can be synthesized to meet different optical imaging requirements due to their easy chemical modification and legible structure-property relation. Herein, the deep-tissue optical imaging applications of organic semiconducting agents including small-molecule agents and nanoparticle derivatives are summarized. In particular, the molecular engineering and nanoformulation approaches to further improve the tissue penetration and detection sensitivity of these optical imaging modalities are highlighted. Finally, current challenges and potential opportunities in this emerging subfield of biomedical imaging are discussed., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Theranostics provides opportunities for precision cancer therapy. However, theranostic probes that simultaneously turn on their diagnostic signal and pharmacological action only in respond to a targeted biomarker have been less exploited. We herein report the synthesis of a macrotheranostic probe that specifically activates its near-infrared fluorescence (NIRF), photoacoustic (PA), and photothermal signals in the presence of a cancer-overexpressed enzyme for imaging-guided cancer therapy. Superior to the small-molecule counterpart probe, the macrotheranostic probe has ideal biodistribution and renal clearance, permitting passive targeting of tumors, in situ activation of multimodal signals, and effective photothermal ablation. Our study thus provides a macromolecular approach towards activatable multimodal phototheranostics., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Photoacoustic (PA) imaging as a new hybrid imaging modality holds great promise for real-time in vivo monitoring of biological processes with deep tissue penetration and high spatial resolution. To endow PA imaging with the ability to provide real-time molecular information at disease sites, molecular probes that can change their PA signals responding to the target or event of interest have to be developed. This review focuses on the recent development of smart activatable PA probes for molecular imaging. A brief summary of PA imaging agents is given first, followed by the detailed discussion of the contemporary design approaches toward activatable PA probes for different imaging applications. At last, the current challenges are highlighted.

Despite the great potential of photoacoustic imaging in the life sciences, the development of smart activatable photoacoustic probes remains elusive. On page 3662, K. Pu and co-workers report a facile nanoengineering approach based on semiconducting oligomer nano-particles to develop ratiometric photoacoustic probes with amplified brightness and enhanced sensing capability for accurate photoacoustic mapping of pH in the tumors of living mice., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Optical theranostic nanoagents that seamlessly and synergistically integrate light-generated signals with photothermal or photodynamic therapy can provide opportunities for cost-effective precision medicine, while the potential for clinical translation requires them to have good biocompatibility and high imaging/therapy performance. We herein report an intraparticle molecular orbital engineering approach to simultaneously enhance photoacoustic brightness and photothermal therapy efficacy of semiconducting polymer nanoparticles (SPNs) for in vivo imaging and treatment of cancer. The theranostic SPNs have a binary optical component nanostructure, wherein a near-infrared absorbing semiconducting polymer and an ultrasmall carbon dot (fullerene) interact with each other to induce photoinduced electron transfer upon light irradiation. Such an intraparticle optoelectronic interaction augments heat generation and consequently enhances the photoacoustic signal and maximum photothermal temperature of SPNs by 2.6- and 1.3-fold, respectively. With the use of the amplified SPN as the theranostic nanoagent, it permits enhanced photoacoustic imaging and photothermal ablation of tumor in living mice. Our study thus not only introduces a category of purely organic optical theranostics but also highlights a molecular guideline to amplify the effectiveness of light-intensive imaging and therapeutic nanosystems.