Photoacoustic Dual-modality Imaging Research Articles

Novel activated NIR-II fluorescence/Ratio photoacoustic probe for dual-modality accurate imaging of palladium ions overload in mouse liver

Palladium contaminants can pose risks to human health and the natural environment. Once Pd2+ enters the body, it can bind with DNA, proteins, and other macromolecules, disrupting cellular processes and causing serious harm to health. Therefore, it becomes critical to develop simple, highly selective and precise methods for detecting Pd2+in vivo. Here, we have successfully developed the first activated second near‐infrared region fluorescence (NIR-II FL) and ratio photoacoustic (PA) probe NYR-1 for dual-modal accurate detection of Pd2+ levels. NYR-1 is capable of rapidly (< 60 s) and sensitively detection of Pd2+ in solution, providing switched on NIR-II FL920 and ratio PA808/PA720 dual-mode signal change. More notably, the probe NYR-1 was successfully used for non-invasive imaging of Pd2+ overload in mouse liver by NIR-II FL/Ratio PA dual-modality imaging technology for the first time. Thus, this work opens up a promising dual-modal detection method for the precise detection of Pd2+ in organisms and in the environment.

Single Side-Chain-Modulatory of Hemicyanine for Optimized Fluorescence and Photoacoustic Dual-Modality Imaging of H2S In Vivo.

Near-infrared fluorescence (NIRF)/photoacoustic (PA) dual-modality imaging integrated high-sensitivity fluorescence imaging with deep-penetration PA imaging has been recognized as a reliable tool for disease detection and diagnosis. However, it remains an immense challenge for a molecule probe to achieve the optimal NIRF and PA imaging by adjusting the energy allocation between radiative transition and nonradiative transition. Herein, a simple but effective strategy is reported to engineer a NIRF/PA dual-modality probe (Cl-HDN3) based on the near-infrared hemicyanine scaffold to optimize the energy allocation between radiative and nonradiative transition. Upon activation by H2S, the Cl-HDN3 shows a 3.6-fold enhancement in the PA signal and a 4.3-fold enhancement in the fluorescence signal. To achieve the sensitive and selective detection of H2S in vivo, the Cl-HDN3 is encapsulated within an amphiphilic lipid (DSPE-PEG2000) to form the Cl-HDN3-LP, which can successfully map the changes of H2S in a tumor-bearing mouse model with the NIRF/PA dual-modality imaging. This work presents a promising strategy for optimizing fluorescence and PA effects in a molecule probe, which may be extended to the NIRF/PA dual-modality imaging of other disease-relevant biomarkers.

A Mitochondria-Targeted NIR-II Molecule Fluorophore for Precise Cancer Phototheranostics.

Subcellular organelle mitochondria are becoming a key player and a driver of cancer. Mitochondrial targeting phototheranostics has attracted increasing attention for precise cancer therapy. However, those phototheranostic systems still face great challenges, including complex and multiple components, light scattering, and insufficient therapeutic efficacy. Herein, a molecular fluorophore IR-TPP-1100 was tactfully designed by molecular engineering for mitochondria-targeted fluorescence imaging-guided phototherapy in the second near-infrared window (NIR-II). IR-TPP-1100 not only exhibited prominent photophysical properties and high photothermal conversion efficiency but also achieved excellent mitochondria-targeting ability. The mitochondria-targeting IR-TPP-1100 enabled NIR-II fluorescence and photoacoustic dual-modality imaging of mitochondria at the organism level. Moreover, it integrated photothermal and photodynamic therapy, obtaining remarkable tumor therapeutic efficacy by inducing mitochondrial apoptosis. These results indicate that IR-TPP-1100 has great potential for precise cancer therapy and provides a promising strategy for developing mitochondria-targeting NIR-II phototheranostic agents.

Endogenous CO imaging in bacterial pneumonia with a NIR fluorescent probe

Bacterial pneumonia is a serious respiratory illness that poses a great threat to human life. Rapid and precise diagnosis of bacterial pneumonia is crucial for symptomatic clinical treatment. Endogenous carbon monoxide (CO) is regarded as a significant indicator of bacterial pneumonia; herein, we developed a near-infrared (NIR) probe for fluorescence and photoacoustic (PA) dual-mode imaging of endogenous CO in bacterial pneumonia. NO2-BODIPY could rapidly and specifically react with CO to produce strong NIR fluorescence as well as ratiometric PA signals. NO2-BODIPY has outstanding features including fast response, fluorescence/PA dual mode signals, good specificity, and a low limit of detection (LOD = 20.3 nM), which enables it to image endogenous CO in cells and bacterial pneumonia mice with high sensitivity and high contrast ratio. In particular, NO2-BODIPY has two-photon excited (1340 nm, σ1 = 1671 GM) NIR fluorescence and has been utilized to image endogenous CO in bacterial pneumonia mice with deep tissue penetration. NO2-BODIPY has been demonstrated a good capability of fluorescence/PA dual-mode imaging of CO in bacterial pneumonia mice, providing a precise manner to diagnose bacterial pneumonia.

Donor-acceptor-donor small molecules for fluorescence/photoacoustic imaging and integrated photothermal therapy.

Here, a D-A-D type fluorescent conjugated molecule with a high molar absorption coefficient and emission at 1120 nm in the near-infrared region was synthesized. Conjugated molecules and two polyethylene glycol polymers with different lipophilic ends are assembled into water-soluble nanoparticles to improve their biocompatibility. Then, their physical and chemical properties were studied and compared. Compared with phospholipid-based PEG, styrene-based PEG can reduce the π-π stacking between molecules and the quenching caused by molecular aggregation. It has more advantages in particle size and fluorescence performance and can be better used in biological imaging. In addition, the Nano-particles have good photo-thermal conversion efficiency; the temperature rises to 62.8°C after 980 nm irradiation for 6 min, which can be used as a potential near-infrared II photothermal therapeutic agent. In vivo imaging experiments confirmed that nanomaterials have fluorescence, photoacoustic dual-modal imaging and good biological safety. STATEMENT OF SIGNIFICANCE: In this work, we constructed D-A-D type dual donor fluorescent molecules using BBTD, CPDT and EDOT, and used amphiphilic polymers to improve their biocompatibility. Compared with DSPE NPs, PS-NPs can reduce intermolecular π-π stacking and increase quantum yield (QY=0.98 %). Deep penetration and low biological toxicity make it have biomedical value and realize the integration of multi-functional collaborative imaging. This work can still be further improved and supplemented, and the molecular structure can be optimized to improve its application in biomedical imaging.

γ-Glutamyltransferase-Activatable Fluoro-Photoacoustic Reporter for Highly Sensitive Diagnosis of Acute Liver Injury and Tumor.

γ-Glutamyltransferase (GGT) has been recognized as an important clinical biomarker that is closely related to many diseases. Visualizing the GGT fluctuation facilitates early disease-related diagnosis and therapy. Herein, an activated probe (NIR-GGT) for the imaging of GGT activity was prepared. The probe consists of a stable NIR fluorophore with the tunable amino group decorated with the γ-glutamate group as a GGT-sensing unit linked by a self-elimination group. NIR-GGT can sensitively recognize GGT and cause a strong turn-on fluorescent and photoacoustic signal. The up-regulation of the GGT expression in acetaminophen-induced acute liver injury was imaged using NIR-GGT. The probe can track changes in the GGT level in the early stages of drug-induced acute liver injury (DIALI) and its remedy process by fluorescent and photoacoustic dual-modality imaging with a high temporal-spatial resolution. NIR-GGT can also be used to differentiate between tumor and para-carcinowa tissues in vivo. The probe may be a potential tool for the diagnosis of early-stage DIALI and accurate tumor resection in the clinical field.

NIR-II fluorescence and PA imaging guided activation of STING pathway in photothermal therapy for boosting cancer immunotherapy by theranostic thermosensitive liposomes.

Photothermal immunotherapy has shown great potential for efficient cancer treatment. However, the immunosuppressive tumor microenvironment forms a heavy barrier for photothermal-induced anti-tumor immunity by inhibiting dendritic cell (DC) maturation and cytotoxic T cell response. Moreover, the lack of reliable spatiotemporal imaging modalities makes photothermal immunotherapy difficult to guide tumor ablation and monitor therapeutic outcomes in real time. Herein, we designed a theranostic thermosensitive liposome (PLDD) as a versatile nanoplatform to boost the adaptive anti-tumor immunity of photothermal immunotherapy and to achieve multiple bioimaging modalities in a real-time manner. PLDD contains two major functional components: a multifunctional photothermal agent (DTTB) and an immune potentiator STING pathway agonist (DMXAA). Upon irradiation, the heat generated by DTTB induced the immunogenic cell death (ICD) of the tumor and dissociated the structure of thermosensitive liposome to release DMXAA, which ultimately activated the STING pathway and promoted the ICD-induced immune response by increasing DC cell maturation and T cell recruitment. Moreover, the DTTB in PLDD displayed excellent second near-infrared (NIR-II) fluorescence and photoacoustic (PA) dual-modal imaging, which provided omnibearing information on the tumor and guided the subsequent therapeutic operation. Therefore, this versatile PLDD with light-triggered promotion of anti-tumor immunity and multiple spatiotemporal imaging profiles holds great potential for the future development of cancer immunotherapy.

Cysteine-activated fluorescence/photoacoustic integrated probe for non-invasive diagnosis of drug-induced liver injury

Hepatotoxicity is a serious problem faced by clinical drugs, and long-term administration or overdose may lead to liver failure and even death of patients. Therefore, developing a reliable detection method for the early diagnosis and therapy of drug-induced liver injury (DILI) has significant meaning. Near-infrared fluorescence (NIRF) and photoacoustic (PA) dual-modality tomography probes can be used for imaging with high sensitivity and high-resolution of disease-related markers in deep tissues. Here, we developed a novel Cys-activated NIRF and PA dual-modality imaging probe (CDR) for early diagnosis of DILI, for the first time. The organic molecular probe CDR could respond rapidly to Cys, resulting in the absorption peak red-shifted from 560 nm to 725 nm, which also leads to the activation of the PA725 signal and NIRF765 signal. In addition, the new probe CDR could be used for NIRF/PA imaging of exogenous and endogenous Cys level in live cells and mice. More importantly, CDR has also been successfully used for in situ detection of Cys in early DILI mice and evaluate the therapeutic effect of NAC. Therefore, the CDR might become a powerful tool to research the physiological effect of Cys and evaluate the degree of DILI.

Dual-Modal Imaging and Synergistic Spinal Tumor Therapy Enabled by Hierarchical-Structured Nanofibers with Cascade Release and Postoperative Anti-adhesion.

Most treatments for spinal cancer are accompanied by serious side effects including subsequent tumor recurrence, spinal cord compression, and tissue adhesion, thus a highly effective treatment is crucial for preserving spinal and neurological functionalities. Herein, trilayered electrospun doxorubicin@bovine serum albumin/poly(ε-caprolactone)/manganese dioxide (DOX@BSA/PCL/MnO2) nanofibers with excellent antiadhesion ability, dual glutathione/hydrogen peroxide (GSH/H2O2) responsiveness, and cascade release of Mn2+/DOX was fabricated for realizing an efficient spinal tumor therapy. In detail, Fenton-like reactions between MnO2 in the fibers outermost layer and intra-/extracellular glutathione within tumors promoted the first-order release of Mn2+. Then, sustained release of DOX from the fibers' core layer occurred along with the infiltration of degradation fluid. Such release behavior avoided toxic side effects of drugs, regulated inflammatory tumor microenvironment, amplified tumor elimination efficiency through synergistic chemo-/chemodynamic therapies, and inhibited recurrence of spinal tumors. More interestingly, magnetic resonance and photoacoustic dual-modal imaging enabled visualizations of tumor therapy and material degradation in vivo, achieving rapid pathological analysis and diagnosis. On the whole, such versatile hierarchical-structured nanofibers provided a reference for rapid and potent theranostic of spinal cancer in future clinical translations.

Intrinsically Bioactive Manganese-Eumelanin Nanocomposites Mediated Antioxidation and Anti-Neuroinflammation for Targeted Theranostics of Traumatic Brain Injury.

Overproduced reactive oxygen species and the induced oxidative stress and neuroinflammation often result in secondary injury, which is associated with unfavorable prognosis in traumatic brain injury (TBI). Unfortunately, current medications cannot effectively ameliorate the secondary injury at traumatic sites. Here, it is reported that intrinsically bioactive multifunctional nanocomposites (ANG-MnEMNPs-Cur, AMEC) mediate antioxidation and anti-neuroinflammation for targeted TBI theranostics, which are engineered by loading the neuroprotective agent curcumin on angiopep-2 functionalized and manganese doped eumelanin-like nanoparticles. After intravenous delivery, efficient AMEC accumulation is observed in lesions of TBI mice models established by controlled cortical impact method, evidenced by T1 -T2 magnetic resonance and photoacoustic dual-modal imaging. Therapeutically, AMEC effectively alleviates neuroinflammation, protects blood-brain barrier integrity, relieves brain edema, reduces brain tissue loss, and improves the cognition of TBI mice. Mechanistically, following the penetration into the traumatic tissues via angiopep-2 mediated targeting effect, the efficacy of AMEC is synergistically improved by combined functional moieties of curcumin and eumelanin. This is achieved by the alleviation of oxidative stress, inhibition of neuroinflammation via M1-to-M2 macrophage reprogramming, and promotion of neuronal regeneration. The as-developed AMEC with well-defined mechanisms of action may represent a promising targeted theranostics strategy for TBI and other neuroinflammation-associated intracranial diseases.

Recent Progress in Small-Molecule Fluorescence and Photoacoustic Dual-Modal Probes for the In-Vivo Detection of Bioactive Molecules.

Intracellular bioactive molecules are essential for the maintenance of homeostasis in living organisms. Abnormal levels of them are closely related to the occurrence and development of some diseases. Hence, the direct and accurate visualization of these bioactive molecules is of vital importance for exploring their pathological roles. However, the low-content, short-lived, and widely distributed properties of bioactive molecules impede the comprehensive analysis of them dramatically. Fluorescence and photoacoustic dual-mode imaging technology provides a new solution to the above issue. Specifically, the combination of fluorescence and photoacoustic, which possesses the advantages of high resolution and in-depth tissue analysis, enables a more in-depth and systematic exploration of the pathogenic mechanisms of bioactive molecules. Moreover, due to the structural tailorability of small molecule probes, numerous small molecule dual-mode probes have been developed to meet the demand for real-time tracking and visualization of bioactive molecules in living cells or in vivo. Hence, in this review, we briefly summarize the key advances in small molecule fluorescence and photoacoustic dual-modal probes within recent years (2015-2021). A particular focus is placed on the design strategies and biological applications of probes for the detection of various bioactive molecules in vivo. Furthermore, the challenges and further prospects in this hot field are highlighted.

Biophysical characterization and in vitro imaging of carbonized MOFs

Nanoparticles have been widely used in biological imaging and treatments of various diseases, especially for studies of tumors, due to their high efficiency in drug delivery and many other functions. Metal-organic frameworks have been an important research area in recent years because of advantages such as large apertures, adjustable structural compositions, adjustable sizes, multifunctionality, high drug loading, good biocompatibility and so on, and they show promise as multifunctional drug carriers. In this study, a carbonized MOF with photothermal therapeutic potential and dual-mode imaging capability was prepared. The biophysical properties of MIL-100 and C-MIL nanoparticles were determined, such as particle size, zeta potential and saturation magnetization strength. CCK-8 cell assays and mouse HE sections confirmed that C-MIL nanoparticles have good in vitro and in vivo biocompatibility. The solution temperature of C-MIL nanoparticles reached 58.1 °C during sustained laser irradiation at 808 nm, which confirmed the photothermal potential of the nanoparticles. Moreover, in biological imaging, C-MIL nanoparticles showed the ability to support in vitro nuclear magnetic and photoacoustic dual-mode imaging. C-MIL nanoparticles provide new options for tumor therapy, drug delivery and biological imaging.

Peptide-based semiconducting polymer nanoparticles for osteosarcoma-targeted NIR-II fluorescence/NIR-I photoacoustic dual-model imaging and photothermal/photodynamic therapies

BackgroundThe overall survival rate of osteosarcoma (OS) patients has not been improved for 30 years, and the diagnosis and treatment of OS is still a critical issue. To improve OS treatment and prognosis, novel kinds of theranostic modalities are required. Molecular optical imaging and phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT), are promising strategies for cancer theranostics that exhibit high imaging sensitivity as well as favorable therapeutic efficacy with minimal side effect. In this study, semiconducting polymer nanoparticles (SPN-PT) for OS-targeted PTT/PDT are designed and prepared, using a semiconducting polymer (PCPDTBT), providing fluorescent emission in the second near-infrared window (NIR-II, 1000 - 1700 nm) and photoacoustic (PA) signal in the first near-infrared window (NIR-I, 650 - 900 nm), served as the photosensitizer, and a polyethylene glycolylated (PEGylated) peptide PT, providing targeting ability to OS.ResultsThe results showed that SPN-PT nanoparticles significantly accelerated OS-specific cellular uptake and enhanced therapeutic efficiency of PTT and PDT effects in OS cell lines and xenograft mouse models. SPN-PT carried out significant anti-tumor activities against OS both in vitro and in vivo.ConclusionsPeptide-based semiconducting polymer nanoparticles permit efficient NIR-II fluorescence/NIR-I PA dual-modal imaging and targeted PTT/PDT for OS.Graphic

Double-Clad Optical Fiber-Based Multi-Contrast Noncontact Photoacoustic and Fluorescence Imaging System

A noncontact photoacoustic and fluorescence dual-modality imaging system is proposed, which integrates a fiber-based fluorescence imaging system with noncontact photoacoustic imaging using a specially fabricated double-cladding fiber (DCF) coupler and a DCF lens. The performance of the DCF coupler and lens was evaluated, and the feasibility of this new imaging system was demonstrated using simple tubing phantoms with black ink and fluorophore. Our imaging results demonstrated that the multimodal imaging technique can simultaneously acquire photoacoustic and fluorescence images without coming into contact with the sample. Consequently, the developed method is the first noncontact scheme among multimodal imaging systems that is integrated with a photoacoustic imaging system, which can provide varied and complementary information about the sample.

NIR-II Excitation Phototheranostic Nanomedicine for Fluorescence/Photoacoustic Tumor Imaging and Targeted Photothermal-Photonic Thermodynamic Therapy.

The success of phototheranostics is hampered by some intrinsic defects, such as limited light penetration depth, heat resistance of tumor cells to photothermal therapy (PTT) induced by heat shock protein (HSP) and stress resistance against photodynamic therapy (PDT) caused by hypoxia microenvironment of tumor. Herein, a second near infrared (NIR-II) light excitation phototheranostic nanomedicine has been fabricated by integrating the semiconducting polymer, azo compound, and HSP inhibitor into a thermosensitive liposome, followed by modification with targeting aptamer, forming Lip(PTQ/GA/AIPH) for multimodal phototheranostics of triple-negative breast cancer (TNBC). The phototheranostic nanomedicine provides tumor targeting NIR-II fluorescence and photoacoustic dual-modal imaging, as well as NIR-II PTT. The released HSP inhibitor can effectively inhibit the activity of HSP for enhanced NIR-II PTT. Moreover, azo compound can be decomposed by the NIR-II photothermal activation, generating cytotoxic free radicals and realizing oxygen-irrelevant photonic thermodynamic therapy (PTDT) effects. Under the NIR-II laser irradiation, NIR-II fluorescence/photoacoustic dual-modal imaging guided enhanced NIR-II PTT and PTDT by Lip(PTQ/GA/AIPH), can achieve precise diagnosis and effective suppression of deep-seated TNBC with negligible side effects. This work develops a promising NIR-II excitation phototheranostic nanomedicine for spatiotemporally specific diagnosis and combination therapy of TNBC.

Prussian blue-based theranostics for ameliorating acute kidney injury

BackgroundAcute kidney injury (AKI) with high mortality rates is associated with an excess of reactive oxygen/nitrogen species (RONS) within kidney tissues. Recently, nanomedicine antioxidant therapy has been used to alleviate AKI. Herein, we synthesized ultrasmall Prussian blue nanozymes (PB NZs, 4.5 nm) as theranostic agents for magnetic resonance (MR)/photoacoustic (PA) dual-modal imaging guided AKI treatment.ResultsPB NZs exhibited multi-enzyme mimetic abilities, promoting the effective elimination of RONS both in vitro and in vivo. Moreover, benefiting from their imaging contrast properties, the rapid renal accumulation of PB NZs was verified by in vivo PA/MR dual-modal imaging. Due to their excellent enrichment in the kidney and unique multi-enzyme mimetic abilities, ultrasmall PB NZs displayed superior AKI treatment efficacy compared with that of amifostine in two clinically relevant types of AKI induced murine models (either by rhabdomyolysis or cisplatin).ConclusionOur findings suggested ultrasmall PB NZs, as nanozyme theranostics, have great potential for AKI management.Graphic abstract

Mild hyperthermia-enhanced chemo-photothermal synergistic therapy using doxorubicin-loaded gold nanovesicles

Gold nanovesicles (GVs) with unique plasmonic property and large cavity hold great potential as a stimuli-responsive nanocarrier to deliver drugs for efficient tumor chemotherapy and other therapies synergistically. Herein, we developed doxorubicin-loaded gold nanovesicles (DGVs), offering infrared thermal (IRT) and photoacoustic (PA) dual-modal imaging guided mild hyperthermia-enhanced chemo-photothermal cancer synergistic therapy. The DGVs are self-assembled by gold nanoparticles modified with amphiphilic copolymer in a predetermined concentration of doxorubicin through film rehydration method. Under the influence of laser excitation, the as-prepared DGVs exhibited good photothermal effect, which triggered the structural disruption of GVs and thus, allowed the efficient release of encapsulated DOX to enhance cell uptake for fluorescence imaging and tumor chemotherapy, respectively. In addition, DGVs also showed a strong PA and IRT signals in vivo. Our study demonstrated the potential of DGVs as stimuli-responsive drug delivery systems and cancer theranostics.

Hypoxia-activated probe for NIR fluorescence and photoacoustic dual-mode tumor imaging

SummaryConstruction of tumor microenvironment responsive probe with more than one imaging modality, in particular toward hypoxia of solid tumors, is an appealing yet significantly challenging task. In this work, we designed a hypoxia-activated probe TBTO (Triphenylamine-Benzothiadiazole-Triphenylamine derivative featuring four diethylamino N-Oxide groups) for in vivo imaging. TBTO could undergo bioreduction in a hypoxic microenvironment to yield compound TBT sharing both near-infrared (NIR) aggregation-induced emission and strong twisted intramolecular charge transfer features, which endows the probe with excellent performance in NIR fluorescence and photoacoustic dual-mode tumor imaging. This study offers useful insights into designing a new generation agent for clinical cancer diagnosis.

An affibody-conjugated nanoprobe for IGF-1R targeted cancer fluorescent and photoacoustic dual-modality imaging

Dual-modal molecular imaging that combines photoacoustic imaging with near-infrared fluorescence imaging integrates the benefits of both imaging modalities and may achieve more precise detection of disease. In this study, silver sulfide quantum dots (Ag2S QDs) with superior photoacoustic properties and a strong fluorescent emission in the NIR region were successfully synthesized. They were further modified with the insulin-like growth factor 1 receptor (IGF-1R) targeted small scaffold protein, Affibody (ZIGF-1) to achieved targeted photoacoustic/fluorescent dual-modal imaging of cancer. Our results showed that the prepared nanoprobe had good tumor targeting properties in vivo, and the probe also showed good biocompatibility without any significant toxicity.

Light‐Triggered Transformable Ferrous Ion Delivery System for Photothermal Primed Chemodynamic Therapy

Chemodynamic therapy (CDT) involves the catalytic generation of highly toxic hydroxyl radicals (. OH) from hydrogen peroxide (H2 O2 ) through metal-ion-mediated Fenton or Fenton-like reactions. Fe2+ is a classical catalyst ion, however, it suffers easy oxidation and systemic side-effects. Therefore, the development of a controllable Fe2+ delivery system is a challenge to maintain its valence state, reduce toxicity, and improve therapeutic efficacy. Reported here is a near-infrared (NIR) light-triggered Fe2+ delivery agent (LET-6) for fluorescence (FL) and photoacoustic (PA) dual-modality imaging guided, photothermal primed CDT. Thermal expansion caused by 808 nm laser irradiation triggers the transformation of LET-6 to expose Fe2+ from its hydrophobic layer, which primes the catalytic breakdown of endogenous H2 O2 within the tumor microenvironment, thus generating . OH for enhanced CDT. LET-6 shows remarkable therapeutic effects, both in vitro and in vivo, achieving 100 % tumor elimination after just one treatment. This high-performance Fe2+ delivery system provides a sound basis for future synergistic metal-ion-mediated cancer therapy.