Noninvasive Photoacoustic Imaging Research Articles

Discovering a New Drug Against Acute Kidney Injury by Using a Tailored Photoacoustic Imaging Probe.

Acute kidney injury (AKI) has become an increasing concern for patients due to the widespread clinical use of nephrotoxic drugs. Currently, the early diagnosis of AKI is still challenging and the available therapeutic drugs cannot meet the clinical demand. Herein, this work has investigated the key redox couple involved in AKI and develops a tailored photoacoustic (PA) imaging probe (AB-DiOH) which can reversibly respond to hypochlorite (ClO-)/glutathione (GSH) with high specificity and sensitivity. This probe enables the real-time monitoring of AKI by noninvasive PA imaging, with better detection sensitivity than the blood test. Furthermore, this probe is utilized for screening nephroprotective drugs among natural products. For the first time, astragalin is discovered to be a potential new drug for the treatment of AKI. After oral administration, astragalin can be efficiently absorbed by the animal body, alleviate kidney injury, and meanwhile induce no damage to other normal tissues. The treatment mechanism of astragalin has also been revealed to be the simultaneous inhibition of oxidative stress, ferroptosis, and cuproposis. The developed PA imaging probe and the discovered drug candidate provide a promising new tool and strategy for the early diagnosis and effective treatment of AKI.

Contrast enhanced photoacoustic detection of fibrillar collagen in the near infrared region-I.

Fibrillar collagen accumulation emerges as a promising biomarker in several diseases, such as desmoplastic tumors and unstable atherosclerotic plaque. Gold nanorods (GNRs) hold great potential as contrast agents in high-resolution, biomedically safe, and non-invasive photoacoustic imaging (PAI). This study presents the design and characterization of a specialized imaging tool which exploits GNR assisted targeted photoacoustic imaging that is tailored for the identification of fibrillar collagen. In addition to the photoacoustic characterization of collagen in the NIR 1 and 2 regions, we demonstrate the detailed steps of conjugating a decoy to GNRs. This study serves as a proof of concept, that demonstrates that conjugated collagenase-1 (MMP-1) generates a distinct and collagen-specific photoacoustic signal, facilitating real-time visualization in the wavelength range of 700-970 nm (NIR I). As most of the reported studies utilized the endogenous contrast of collagen in the NIR II wavelength that has major limitations to perform in vivo deep tissue imaging, the approach that we are proposing is unique and it highlights the promise of MMP-1 decoy-functionalized GNRs as novel contrast agents for photoacoustic imaging of collagen in the NIR 1 region. To our knowledge this is the first time functionalized GNRs are optimized for the detection of fibrillar collagen and utilized in the field of non-invasive photoacoustic imaging that can facilitate a better prognosis of desmoplastic tumors and broken atherosclerotic plaques.

Exploring the Protective Effect against 7,12-Dimethylbenz[a]anthracene-Induced Breast Tumors of Palmitoylethanolamide.

Breast cancer remains a global health burden, and the need for effective therapies is of chief importance. The current study explored the in vivo chemoprotective activity of palmitoylethanolamide (PEA) against 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast tumor in rats. Results of noninvasive photoacoustic imaging showed real-time progression in the tumor area and volume in DMBA-induced rats, while there was a reduction in tumor area and volume in PEA-treated tumor-bearing rats. The increase in the average oxygen saturation (sO2 %) and decrease in the average total hemoglobin (HbT %) indicated the PEA-mediated attenuation of hypoxia-induced neovascularization in DMBA-induced rats. Histopathological investigations confirmed the efficacy of PEA in mitigating breast carcinoma, hepatotoxicity and nephrotoxicity driven by DMBA. Moreover, PEA-mediated alterations in the metabolic activity of the tumor microenvironment were evidenced by decreased glucose and lactate dehydrogenase enzyme level in the blood plasma and mammary tissue. PEA also maintained the redox balance by inhibiting nitric oxide level, reducing malondialdehyde (a product of lipid peroxidation), and increasing the level of antioxidant enzyme reduced glutathione. PEA altered the expression of apoptosis-related genes (BAX, P53,BCL-XL, CASPASE-8, and CASPASE-9) and induced the activity of Caspase-3 protein in the mammary tissue of tumor-bearing rats, indicating its apoptosis inducing ability. Taken together, the findings of this study suggest that PEA may have a protective effect against DMBA-induced breast tumors.

Transcytosis-Inducing Multifunctional Albumin Nanomedicines with Deep Penetration Ability for Image-Guided Solid Tumor Treatment.

Transcytosis is an active transcellular transportation pathway that has garnered interest for overcoming the limited deep penetration of nanomedicines in solid tumors. In this study, a charge-convertible nanomedicine that facilitates deep penetration into solid tumors via transcytosis is designed. It is an albumin-based calcium phosphate nanomedicine loaded with IR820 (mAlb-820@CaP) for high-resolution photoacoustic imaging and enhanced photothermal therapy. Biomineralization on the surface stabilizes the albumin-IR820 complex during circulation and provides calcium ions (Ca2+ ) for tissue penetration on degradation in an acidic environment. pH-triggered transcytosis of the nanomedicine enabled by caveolae-mediated endocytosis and calcium ion-induced exocytosis in 2D cellular, 3D spheroid, and in vivo tumor models is demonstrated. Notably, the extravasation and penetration ability of the nanomedicine is observed in vivo using a high-resolution photoacoustic system, and nanomedicine shows the most potent photothermal antitumor effect in vivo. Overall, the strategy provides a versatile theragnosis platform for both noninvasive photoacoustic imaging and high therapeutic efficiency resulting from deep penetration of nanomedicine.

Understanding Breast Cancers through Spatial and High-Resolution Visualization Using Imaging Technologies.

Simple SummaryBreast cancer tissue is not composed solely of cancer cells but exists in a complex microenvironment consisting of surrounding cells and proteins, including fibroblasts, immune cells, blood vessels, and extracellular matrix. The malignant transformation and metastasis of breast cancer occur due to the interaction between cancer cells and surrounding environmental cells and/or proteins. Therefore, it is extremely important to visualize the three-dimensional structure of breast cancer cells and their surrounding environment both invasively and noninvasively and to understand their relationship; this review aims to provide an overview of the tissue transparency techniques, optical observation methods, spatial transcriptomic analysis, and noninvasive medical imaging methods used for understanding malignant breast cancers.Breast cancer is the most common cancer affecting women worldwide. Although many analyses and treatments have traditionally targeted the breast cancer cells themselves, recent studies have focused on investigating entire cancer tissues, including breast cancer cells. To understand the structure of breast cancer tissues, including breast cancer cells, it is necessary to investigate the three-dimensional location of the cells and/or proteins comprising the tissues and to clarify the relationship between the three-dimensional structure and malignant transformation or metastasis of breast cancers. In this review, we aim to summarize the methods for analyzing the three-dimensional structure of breast cancer tissue, paying particular attention to the recent technological advances in the combination of the tissue-clearing method and optical three-dimensional imaging. We also aimed to identify the latest methods for exploring the relationship between the three-dimensional cell arrangement in breast cancer tissues and the gene expression of each cell. Finally, we aimed to describe the three-dimensional imaging features of breast cancer tissues using noninvasive photoacoustic imaging methods.

Design Principles Governing the Development of Theranostic Anticancer Agents and Their Nanoformulations with Photoacoustic Properties.

The unmet need to develop novel approaches for cancer diagnosis and treatment has led to the evolution of theranostic agents, which usually include, in addition to the anticancer drug, an imaging agent based mostly on fluorescent agents. Over the past few years, a non-invasive photoacoustic imaging modality has been effectively integrated into theranostic agents. Herein, we shed light on the design principles governing the development of theranostic agents with photoacoustic properties, which can be formulated into nanocarriers to enhance their potency. Specifically, we provide an extensive analysis of their individual constituents including the imaging dyes, drugs, linkers, targeting moieties, and their formulation into nanocarriers. Along these lines, we present numerous relevant paradigms. Finally, we discuss the clinical relevance of the specific strategy, as also the limitations and future perspectives, and through this review, we envisage paving the way for the development of theranostic agents endowed with photoacoustic properties as effective anticancer medicines.

Biomedical Photoacoustic Imaging With Unknown Spatially Distributed Ultrasound Sensor Array.

With the growth of interest in different medical study on biological function, non-invasive photoacoustic imaging of biological tissue attracts the interests for researchers. To eliminate the limited angle effect of photoacoustic imaging based on ultrasound linear array, spatially distributed ultrasound sensor array is applied. The accurate sensor array position determines the quality of the imaging results. In this study, we proposed three methods based on photoacoustic and ultrasound signals to enhance the imaging quality using a 256-element full-ring array. Groups of photoacoustic and ultrasound signals are used to regress the position of each element sensor. In phantom study and mouse brain study, photoacoustic imaging results can both yield details clearly with average error rate of less than 1% (50 [Formula: see text]). The performance of our three methods have proved that they can be potentially applied to other ultrasound-based medical imaging studies with unknown distributed positions of sensor array to enhance the imaging quality. The proposed methods can contribute to precise biomedical imaging with unknown distributed positions of sensor array in different application scenarios.

A high-contrast photoacoustic agent with near-infrared emission.

Benzobisthiadiazole as a typical electron acceptor, has been widely used to design fluorescent dyes and photoacoustic (PA) agents. With the strategy of constructing donor-acceptor-donor (D-A-D) type of electron characteristics, benzobisthiadiazole derivatives tend to behave stable in near-infrared absorption and emission, which is beneficial to PA imaging. In this chapter, two molecular design strategies are combined to improve the photoacoustic imaging effects of new PA contrast agent IR-1302 NPs, by installing strengthened conjugated bridges and electron donors. The nanoparticles exhibit high-contrast noninvasive photoacoustic imaging in tumor models with longer wavelength absorption and emission and show potential as a clinic contrast agent.

Multimodal Photoacoustic Imaging-Guided Regression of Corneal Neovascularization: A Non-Invasive and Safe Strategy.

Corneal neovascularization (CNV) is one of the main factors that induce blindness worldwide. However, current medical treatments cannot achieve non‐invasive and safe inhibition of CNV. A noninvasive photoacoustic imaging (PAI)‐guided method is purposed for the regression of CNV. PAI can monitor the oxygen saturation of cornea blood vessels through the endogenous contrast of hemoglobin and trace administrated drugs by themselves as exogenous contrast agents. An indocyanine green (ICG)‐based nanocomposite (R‐s‐ICG) is prepared for CNV treatment via eye drops and subconjunctival injections. It is demonstrated that R‐s‐ICG can enrich corneal tissues and pathological blood vessels rapidly with minor residua in normal eyeball tissues. Anti‐CNV treatment‐driven changes in the blood vessels are assessed by real‐time multimodal PAI in vivo, and then a safe laser irradiation strategy through the canthus is developed for phototherapy and gene therapy synergistic treatment. The treatment leads to the efficient inhibition of CNV with faint damages to normal tissues.

Non-Invasive Photoacoustic Imaging of In Vivo Mice with Erythrocyte Derived Optical Nanoparticles to Detect CAD/MI

Coronary artery disease (CAD) causes mortality and morbidity worldwide. We used near-infrared erythrocyte-derived transducers (NETs), a contrast agent, in combination with a photoacoustic imaging system to identify the locations of atherosclerotic lesions and occlusion due to myocardial-infarction (MI). NETs (≈90 nm diameter) were fabricated from hemoglobin-depleted mice erythrocyte-ghosts and doped with Indocyanine Green (ICG). Ten weeks old male C57BL/6 mice (n = 9) underwent left anterior descending (LAD) coronary artery ligation to mimic vulnerable atherosclerotic plaques and their rupture leading to MI. 150 µL of NETs (20 µM ICG,) was IV injected via tail vein 1-hour prior to photoacoustic (PA) and fluorescence in vivo imaging by exciting NETs at 800 nm and 650 nm, respectively. These results were verified with histochemical analysis. We observed ≈256-fold higher PA signal from the accumulated NETs in the coronary artery above the ligation. Fluorescence signals were detected in LAD coronary, thymus, and liver. Similar signals were observed when the chest was cut open. Atherosclerotic lesions exhibited inflammatory cells. Liver demonstrated normal portal tract, with no parenchymal necrosis, inflammation, fibrosis, or other pathologic changes, suggesting biocompatibility of NETs. Non-invasively detecting atherosclerotic plaques and stenosis using NETs may lay a groundwork for future clinical detection and improving CAD risk assessment.

In vivo assessment of inflammation in carotid atherosclerosis by noninvasive photoacoustic imaging.

Objectives: The objective of this study was to demonstrate the feasibility of using noninvasive photoacoustic imaging technology along with novel semiconducting polymer nanoparticles for in vivo identifying inflammatory components in carotid atherosclerosis and assessing the severity of inflammation using mouse models.Methods and Results: Healthy carotid arteries and atherosclerotic carotid arteries were imaged in vivo by the noninvasive photoacoustic imaging system. Molecular probes PBD-CD36 were used to label the inflammatory cells to show the inflammation information by photoacoustic imaging. In in vivo imaging experiments, we observed the maximum photoacoustic signal enhancement of 4.3, 5.2, 8 and 16.3 times between 24 h post probe injection and that before probe injection in four carotid arteries belonging to three atherosclerotic mice models. In the corresponding carotid arteries stained with CD36, the ratio of 0.043, 0.061, 0.082 and 0.113 was found between CD36 positive (CD36(+)) expression area and intima-media area (P < 0.05). For the CD36(+) expression less than 0.008 in eight arteries, no photoacoustic signal enhancement was found due to the limited system sensitivity. The photoacoustic signal reflects CD36(+) expression in plaques, which shows the feasibility of using photoacoustic imaging for in vivo assessment of carotid atherosclerosis.Conclusion: This research demonstrates a semiconducting polymer nanoparticle along with photoacoustic technology for noninvasive imaging and assessment of inflammation of carotid atherosclerotic plaques in vivo.

Tracking Pharmacodynamics of Vascular Targeted Therapy with Photoacoustic Imaging.

HomeRadiology: Imaging CancerVol. 2, No. 1 PreviousNext Research HighlightsFree AccessTracking Pharmacodynamics of Vascular Targeted Therapy with Photoacoustic ImagingGary D. LukerGary D. LukerGary D. LukerPublished Online:Jan 31 2020https://doi.org/10.1148/rycan.2020204004MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In Take-Away Points■ Major Focus: To investigate feasibility of noninvasive photoacoustic imaging for quantifying pharmacodynamics of vascular-targeted therapy in tumors.■ Key Result: Photoacoustic imaging measured time- and dose-dependent effects of an investigation of a vascular disrupting agent in two preclinical models of cancer.■ Impact: Photoacoustic imaging can successfully monitor pharmacodynamics of tumor vasculature during therapy, supporting applications in drug development and clinical translation for precision medicine.Imaging methods to analyze pharmacodynamics, the activity of a compound on its therapeutic target, potentially will increase development of new drugs for cancer and enable precision therapy for patients. Vascular disrupting agents represent a new class of anticancer compounds designed to target immature blood vessels typically associated with tumors. Success of these agents remains limited by a viable peripheral rim of cancer cells perfused by adjacent normal blood vessels and intertumor differences in susceptibility to hypoxia. Photoacoustic imaging, which uses low-intensity, nonionizing laser pulses to generate ultrasound waves for an image, provides an excellent method to image tumor blood vessels based on sensitive, high-contrast detection of hemoglobin. Using a high-resolution photoacoustic imaging instrument, Johnson et al measured the effects of the vascular disrupting agent OXi4503 in two different mouse models of colon cancer. In both models, photoacoustic imaging revealed initial ablation of internal blood vessels and subsequent regrowth of tumor vasculature over 16 days of treatment. For well-perfused tumors with extensive immature blood vessels, reductions in tumor blood vessels correlated highly with reductions in tumor volume over time. While poorly perfused tumors with larger, more mature blood vessels showed modest reductions in tumor blood vessels, changes in tumor vasculature did not predict effects on tumor volume. Treatment failures in poorly perfused tumors mirror past studies demonstrating resistance of such tumors to vascular disrupting therapy. Photoacoustic imaging also measured dose-dependent reductions in tumor blood vessels, establishing an approach to optimize doses and dosing schedules. These results establish photoacoustic imaging as a preclinical imaging method to advance development of vascular-targeted therapies. Furthermore, since photoacoustic instruments have entered clinical testing, this research supports future clinical applications of photoacoustic methods for pharmacodynamic imaging.Highlighted ArticleJohnson SP, Ogunlade O, Lythgoe MF, Beard P, Pedley RB. Longitudinal photacoustic imaging of the pharmacodynamics effect of vascular targeted therapy on tumors. Clin Cancer Res 2019;25:7436–7447. doi: 10.1158/1078-0432.CCR-19-036Highlighted ArticleJohnson SP, Ogunlade O, Lythgoe MF, Beard P, Pedley RB. Longitudinal photacoustic imaging of the pharmacodynamics effect of vascular targeted therapy on tumors. Clin Cancer Res 2019;25:7436–7447. doi: 10.1158/1078-0432.CCR-19-036 Crossref, Medline, Google ScholarArticle HistoryPublished online: Jan 31 2020 FiguresReferencesRelatedDetailsRecommended Articles Irreversible Electroporation versus Radiofrequency Ablation: A Comparison of Local and Systemic Effects in a Small-Animal ModelRadiology2016Volume: 280Issue: 2pp. 413-424Midterm Safety and Efficacy of Irreversible Electroporation of Malignant Liver Tumors Located Close to Major Portal or Hepatic VeinsRadiology2017Volume: 285Issue: 3pp. 1023-1031Local-Regional Treatment of Hepatocellular Carcinoma: A Primer for RadiologistsRadioGraphics2022Volume: 42Issue: 6pp. 1670-1689Nonthermal Ablation by Using Intravascular Oxygen Radical Generation with WST11: Dynamic Tissue Effects and Implications for Focal TherapyRadiology2016Volume: 281Issue: 1pp. 109-118Animal Models of Hepatocellular Carcinoma for Local-Regional Intraarterial TherapiesRadiology: Imaging Cancer2022Volume: 4Issue: 4See More RSNA Education Exhibits Novel Image-Guided Micro-Invasive Percutaneous Treatments of Breast Lesions: Where Do We Stand?Digital Posters2019Imaging Features at the Periphery – Hemodynamics, Pathophysiology and Impact on LI-RADS CategorizationDigital Posters2020A Practical Guide of Locoregional Treatment for Patients with Hepatocellular CarcinomaDigital Posters2019 RSNA Case Collection Adult colo-colonic intussusceptionRSNA Case Collection2020Cerebral Cavernous Venous MalformationRSNA Case Collection2021Pseudocirrhosis of Hepatic Breast MetastasesRSNA Case Collection2020 Vol. 2, No. 1 Metrics Altmetric Score PDF download

An Activatable Cancer-Targeted Hydrogen Peroxide Probe for Photoacoustic and Fluorescence Imaging.

Reactive oxygen species play an important role in cancer, however, their promiscuous reactivity, low abundance, and short-lived nature limit our ability to study them in real time in living subjects with conventional noninvasive imaging methods. Photoacoustic imaging is an emerging modality for in vivo visualization of molecular processes with deep tissue penetration and high spatiotemporal resolution. Here, we describe the design and synthesis of a targeted, activatable probe for photoacoustic imaging, which is responsive to one of the major and abundant reactive oxygen species, hydrogen peroxide (H2O2). This bifunctional probe, which is also detectable with fluorescence imaging, is composed of a heptamethine carbocyanine dye scaffold for signal generation, a 2-deoxyglucose cancer localization moiety, and a boronic ester functionality that specifically detects and reacts to H2O2. The optical properties of the probe were characterized using absorption, fluorescence, and photoacoustic measurements; upon addition of pathophysiologic H2O2 concentrations, a clear increase in fluorescence and red-shift of the absorption and photoacoustic spectra were observed. Studies performed in vitro showed no significant toxicity and specific uptake of the probe into the cytosol in breast cancer cell lines. Importantly, intravenous injection of the probe led to targeted uptake and accumulation in solid tumors, which enabled noninvasive photoacoustic and fluorescence imaging of H2O2. In conclusion, the reported probe shows promise for the in vivo visualization of hydrogen peroxide. SIGNIFICANCE: This study presents the first activatable and cancer-targeted hydrogen peroxide probe for photoacoustic molecular imaging, paving the way for visualization of hydrogen peroxide at high spatiotemporal resolution in living subjects.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5407/F1.large.jpg.

Noninvasive Photoacoustic Imaging of Dendritic Cell Stimulated with Tumor Cell-Derived Exosome.

The tools to trigger dendritic cell (DC) activation and to verify DC migration in vivo are important for directing DC immunotherapy toward successful treatment. We evaluated whether tumor cell-derived exosome (TEX)-stimulated DC migration into lymph node (LN) in mouse could be tracked using gold nanoparticle (GN)-labeling and ultrasound (US)-guided photoacoustic imaging (PAI). GFP-transduced DC2.4 cells were used. RFP-tagged TEXs were purified from a stable 4T1 cell line overexpressing the exosomal CD63-RFP fusion protein. The TEX uptake by DCs was visualized using confocal laser scanning microscopy. GNs with surface plasmon resonance at 808nm were used for DC-labeling. DCs that migrated into axillary LN were longitudinally monitored by US-guided PAI and analyzed by silver staining and immunohistochemistry. TEXs were easily internalized in DCs, increased proliferation and migration capacities, and upregulated co-stimulatory molecules, CCR7 and TNF-α without cytotoxicity. The GN-labeling exerted no adverse effects on the biological functions of DCs. US-guided PAI and DC-labeling allowed for sensitive and longitudinal monitoring of TEX-stimulated DC migration toaxillary LN. TEXs efficiently activated DCs and GN-labeled DC migration into LN was successfully monitored using US-guided PAI, suggesting that TEXs are a good source for DC activation and US-guided PAI is a cost-effective and easy-to-use imaging modality for noninvasive tracking of DCs.

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

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.

Non-invasive photoacoustic detection of hidden underdrawings in paintings using air-coupled transducers

We demonstrate the application of a fully non-contact and non-invasive photoacoustic (PA) imaging system integrating a high sensitivity spherically focused air-coupled ultrasonic transducer, for the uncovering of hidden underdrawings in paintings. By selectively transforming optical absorption information into ultrasonic waves which propagate virtually unobstructed through the paint layers, PA signals provide specific imaging of underlying pencil sketches even for paints presenting high optical scattering and absorption properties. The developed system could be employed for case studies involving the investigation of paintings with historical significance, considerably complementing the capabilities of existing methods.

Stimuli-Responsive Nanotheranostics for Real-Time Monitoring Drug Release by Photoacoustic Imaging.

Molecular photoacoustic imaging (PA) is a promising technology to understand tumor pathology and guide precision therapeutics. Despite the capability of activatable PA probes to image tumor-specific biomarkers, limitations in their molecular structure hamper them from effective drug delivery and the drug release monitoring. Herein, we developed a perylene diimide (PDI) based theranostic platform that provides noninvasive PA imaging signals to monitor tumor-specific pH-responsive drug release.Methods: we first designed and synthesized an acid-responsive amine-substituted PDI derivative. The pH sensitive properties of the PDI was demonstrated by density functional theory (DFT) calculations, UV-vis experiments and PA studies. The theranostic platform (THPDINs) was fabricated by self-assembly of the acid-responsive PDI, a pH irrelevant IR825 dye, and anti-cancer drug doxorubicin (DOX). The PA properties in various pH environment, drug delivery, cytotoxicity, cell uptake, ratiometric PA imaging and anti-tumor efficacy of the THPDINs were investigated in vitro and in vivo by using U87MG glioma cell line and U87MG tumor model.Results: We found that our designed PDI was sensitive to the tumor specific pH environment, reflected by absorbance shift, PA intensity and aggregation morphology changes in aqueous solution. The as-synthesized pH sensitive PDI acted as a molecular switch in the THPDINs, in which the switch can be triggered in the mild acidic tumor microenvironment to accelerate DOX release. Meanwhile, the DOX release could be monitored by ratiometric PA imaging.Conclusions: We developed a multifunctional PDI based theranostic platform for noninvasive real-time ratiometric PA imaging of tumor acidic pH and monitoring of drug release in living mice simultaneously. This strategy will shed light on the development of smart activatable theranostic nanoplatforms and will significantly advance the application of PA theranostics in biology and medicine.

Non-invasive dynamic assessment of conjunctival melanomas by photoacoustic imaging

This study describes non-invasive photoacoustic imaging to detect and monitor the growth of conjunctival melanomas in vivo. Conjunctival melanomas were induced by injection of melanotic B16F10 cells into the subconjunctival space in syngeneic albino C57BL/6 mice. Non-invasive in vivo photoacoustic tomography was performed before, and after tumor induction up to 2 weeks. Spectral unmixing was performed to determine the location and to assess the distribution of melanin. The melanin photoacoustic signal intensity was quantified from the tumor-bearing and control eyes at all timepoints. For postmortem validation, total tumor and melanotic tumor volumes were measured using H&E stained tumor sections and were compared to in vivo photoacoustic imaging measurements. Photoacoustic imaging non-invasively detected eyes bearing conjunctival tumors of varying sizes. The melanin signal was detected as early as immediately following injection of melanotic tumor cells. Changes in tumor size over time were assessed with changes in the volume and intensity of the melanin signal. Four growing tumors and one regressing tumor were observed. Three tumors without significant change in signal intensity over time were observed, showing variable growth. Photoacoustic melanin signal on the last day of in vivo imaging correlated with postmortem total tumor volume (R2 = 0.81) and melanotic tumor volume (R2 = 0.80). The results of our study show that actively growing conjunctival melanomas can be quantified in a non-invasive manner using in vivo photoacoustic tomography. The photoacoustic melanin signal intensity correlated with total and melanotic tumor volume. This novel in vivo imaging platform may help to assess new treatment modalities to manage ocular tumors.

Blood Circulation, Biodistribution, and Pharmacokinetics of Dextran-Modified Black Phosphorus Nanoparticles.

Black phosphorus (BP) nanostructures have been receiving enormous attention in diverse bioapplications owing to their unique physicochemical properties. However, it is still challenging to investigate their blood circulation, biodistribution, and pharmacokinetics after administration due to the difficulty in quantifying them. Here, we report the quantification of blood circulation, biodistribution, and pharmacokinetics of dextran-modified BP nanoparticles (i.e., BP-DEX NPs) in balb/c mice through the highly sensitive noninvasive photoacoustic (PA) imaging and single-emission computed tomography/computed tomography (SPECT/CT) imaging. We first prepare water-soluble and biocompatible small BP-DEX NPs and label them with radioisotopes 99mTc. We then quantify their half-lives of distribution and elimination phases to be 0.2 and 9.5 h by counting the γ-emissions in the blood of mice administrated with BP-DEX NPs. We also show the dynamic variation of BP-DEX NPs in the tumor, liver, spleen, and kidney through in vivo PA imaging and illustrate the accumulation of nanoparticles in major organs by SPECT/CT imaging, which follows an order of spleen > liver > lung > kidney. Our work demonstrates the renal clearance and hepatobiliary excretion of BP-DEX NPs, which could be potentially translated for clinical in vivo imaging and therapy of cancer.

Noninvasive ratiometric photoacoustic imaging for molecular classification of breast cancer antigens

Noninvasive ratiometric photoacoustic imaging for molecular classification of breast cancer antigens