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.

Fully Active Delivery of Nanodrugs In Vivo via Remote Optical Manipulation.

The active delivery of nanodrugs has been a bottleneck problem in nanomedicine. While modification of nanodrugs with targeting agents can enhance their retention at the lesion location, the transportation of nanodrugs in the circulation system is still a passive process. The navigation of nanodrugs with external forces such as magnetic field has been shown to be effective for active delivery, but the existing techniques are limited to specific materials like magnetic nanoparticles. In this study, an alternative actuation method is proposed based on optical manipulation for remote navigation of nanodrugs in vivo, which is compatible with most of the common drug carriers and exhibits significantly higher manipulation precision. By the programmable scanning of the laser beam, the motion trajectory and velocity of the nanodrugs can be precisely controlled in real time, making it possible for intelligent drug delivery, such as inverse-flow transportation, selective entry into specific vascular branch, and dynamic circumvention across obstacles. In addition, the controlled mass delivery of nanodrugs can be realized through indirect actuation by the microflow field. The developed optical manipulation method provides a new solution for the active delivery of nanodrugs, with promising potential for the treatment of blood diseases such as leukemia and thrombosis.

Acid and Hypoxia Tandem-Activatable Deep Near-Infrared Nanoprobe for Two-Step Signal Amplification and Early Detection of Cancer.

The early detection of cancers can significantly change outcomes even with existing treatments. However, ~50% of cancers still cannot be detected until they reach an advanced stage, highlighting the great challenges in the early detection. Here, an ultrasensitive deep near-infrared (dNIR) nanoprobe that is successively responsive to tumor acidity and hypoxia is reported. It is demonstrated that the new nanoprobe specifically detects tumor hypoxia microenvironment based on deep NIR imaging in ten different types of tumor models using cancer cell lines and patient-tissue derived xenograft tumors. By combining the acidity and hypoxia specific two-step signal amplification with a deep NIR detection, the reported nanoprobe enables the ultrasensitive visualization of hundreds of tumor cells or small tumors with a size of 260 µm in whole-body imaging or 115 µm metastatic lesions in lung imaging. As a result, it reveals that tumor hypoxia can occur as early as the lesions contain only several hundred cancer cells.

Multiparameter Longitudinal Imaging of Immune Cell Activity in Chimeric Antigen Receptor T Cell and Checkpoint Blockade Therapies.

Longitudinal multimodal imaging presents unique opportunities for noninvasive surveillance and prediction of treatment response to cancer immunotherapy. In this work we first designed a novel granzyme B activated self-assembly small molecule, G-SNAT, for the assessment of cytotoxic T lymphocyte mediated cancer cell killing. G-SNAT was found to specifically detect the activity of granzyme B within the cytotoxic granules of activated T cells and engaged cancer cells in vitro. In lymphoma tumor-bearing mice, the retention of cyanine 5 labeled G-SNAT-Cy5 correlated to CAR T cell mediated granzyme B exocytosis and tumor eradication. In colorectal tumor-bearing transgenic mice with hematopoietic cells expressing firefly luciferase, longitudinal bioluminescence and fluorescence imaging revealed that after combination treatment of anti-PD-1 and anti-CTLA-4, the dynamics of immune cell trafficking, tumor infiltration, and cytotoxic activity predicted the therapeutic outcome before tumor shrinkage was evident. These results support further development of G-SNAT for imaging early immune response to checkpoint blockade and CAR T-cell therapy in patients and highlight the utility of multimodality imaging for improved mechanistic insights into cancer immunotherapy.

Small-Molecule Photoacoustic Imaging Probe with Aggregation-Enhanced Amplitude for Real-Time Visualization of Acute Kidney Injury.

Acute kidney injury (AKI) has become a growing issue for patients with the extensive use of all kinds of drugs in clinic. Photoacoustic (PA) imaging provides a noninvasive and real-time imaging method for studying kidney injury, but it has inherent shortages in terms of high background signal and low detection sensitivity for exogenous imaging agents. Intriguingly, J-aggregation offers to tune the optical properties of the dyes, thus providing a platform for developing new PA probes with desired performance. In this study, a small-molecule PA probe (BDP-3) was designed and synthesized. We serendipitously discovered that BDP-3 can transform into renal clearable nanoaggregates under physiological conditions. The hydrodynamic diameter of the BDP-3 increased from 0.64 ± 0.11 to 3.74 ± 0.39 nm when the content of H2O increased from 40 to 90%. In addition, it was surprising that such a transforming process can significantly enhance its PA amplitude (2.06-fold). On this basis, PA imaging with BDP-3 was applied as a new method for the noninvasive detection of AKI induced by anticancer drugs, traditional Chinese medicine, and clinical contrast agents in animal models and exhibited higher sensitivity than the conventional serum index test, demonstrating great potential for further clinical diagnostic applications.

Reversibly Photoswitching Upconversion Nanoparticles for Super-Sensitive Photoacoustic Molecular Imaging.

Photoacoustic (PA) imaging uses light excitation to generate the acoustic signal for detection and improves tissue penetration depth and spatial resolution in the clinically relevant depth of living subjects. However, strong background signals from blood and pigments have significantly compromised the sensitivity of PA imaging with exogenous contrast agents. Here we report a nanoparticle-based probe design that uses light to reversibly modulate the PA emission to enable photoacoustic photoswitching imaging (PAPSI) in living mice. Such a nanoprobe is built with upconverting nanocrystals and photoswitchable small molecules and can be switched on by NIR light through upconversion to UV energy. Reversibly photoswitching of the nanoprobe reliably removed strong tissue background, increased the contrast-to-noise ratio, and thus improved imaging sensitivity. We have shown that PAPSI can image 0.05 nM of the nanoprobe in hemoglobin solutions and 104 labeled cancer cells after implantation in living mice using a commercial PA imager.

Tumor Microenvironment-Regulated and Reported Nanoparticles for Overcoming the Self-Confinement of Multiple Photodynamic Therapy.

The efficiency of photodynamic therapy (PDT) highly depends on the tumor oxygenation state. However, PDT itself can not only cause oxygen depletion but also prevent oxygen supply in tumors. Such self-confinement effect significantly limits the efficacy of PDT, especially fractionated PDT (fPDT). Herein, we proposed a multifunctional nanoparticle system having a four-pronged pipelined therapeutic scheme to address this issue. It performed in situ oxygen supply and tumor microenvironment modulation together to effectively maintain tumor oxygenation even after multiple PDT fractions. It also introduced a new photosensitizer that not only was highly efficient in producing ROS but also could visually report tumor oxygenation state in a real-time fashion. All these functions were integrated into a single nanoparticulate system to obtain pipeline-style teamwork, which was then applied for the fPDT on a mice tumor model, and achieved significantly better tumor oxygenation even after multiple PDT fractions, ending up with a better tumor inhibition efficiency.

Carbon-coated FeCo nanoparticles as sensitive magnetic-particle-imaging tracers with photothermal and magnetothermal properties.

The low magnetic saturation of iron oxide nanoparticles, which are developed primarily as contrast agents for magnetic resonance imaging, limits the sensitivity of their detection using magnetic particle imaging (MPI). Here, we show that FeCo nanoparticles that have a core diameter of 10 nm and bear a graphitic carbon shell decorated with poly(ethylene glycol) provide an MPI signal intensity that is sixfold and fifteenfold higher than the signals from the superparamagnetic iron oxide tracers VivoTrax and Feraheme, respectively, at the same molar concentration of iron. We also show that the nanoparticles have photothermal and magnetothermal properties and can therefore be used for tumour ablation in mice, and that they have high optical absorbance in a broad near-infrared region spectral range (wavelength, 700-1,200 nm), making them suitable as tracers for photoacoustic imaging. As sensitive multifunctional and multimodal imaging tracers, carbon-coated FeCo nanoparticles may confer advantages in cancer imaging and hyperthermia therapy.

Exploring the Condensation Reaction between Aromatic Nitriles and Amino Thiols To Optimize In†Situ Nanoparticle Formation for the Imaging of Proteases and Glycosidases in Cells.

The condensation reaction between 6-hydroxy-2-cyanobenzothiazole (CBT) and cysteine has been shown for various applications such as site-specific protein labelling and in vivo cancer imaging. This report further expands the substrate scope of this reaction by varying the substituents on aromatic nitriles and amino thiols and testing their reactivity and ability to form nanoparticles for cell imaging. The structure-activity relationship study leads to the identification of the minimum structural requirement for the macrocyclization and assembly process in forming nanoparticles. One of the scaffolds made of 2-pyrimidinecarbonitrile and cysteine joined by a benzyl linker was applied to design fluorescent probes for imaging caspase-3/7 and ß-galactosidase activity in live cells. These results demonstrate the generality of this system for imaging hydrolytic enzymes.

A Near-Infrared Phosphorescent Nanoprobe Enables Quantitative, Longitudinal Imaging of Tumor Hypoxia Dynamics during Radiotherapy.

Hypoxia plays a key role in tumor resistance to radiotherapy. It is important to study hypoxia dynamics during radiotherapy to improve treatment planning and prognosis. Here, we describe a luminescent nanoprobe, composed of a fluorescent semiconducting polymer and palladium complex, for quantitative longitudinal imaging of tumor hypoxia dynamics during radiotherapy. The nanoprobe was designed to provide high sensitivity and reversible response for the subtle change in hypoxia over a narrow range (0-30 mmHg O2), which spans the oxygen range where tumors have limited radiosensitivity. Following intravenous administration, the nanoprobe efficiently accumulated in and distributed across the tumor, including the hypoxic region. The ratio between emissions at 700 and 800 nm provided quantitative mapping of hypoxia across the entire tumor. The nanoprobe was used to image tumor hypoxia dynamics over 7 days during fractionated radiotherapy and revealed that high fractional dose (10 Gy) was more effective in improving tumor reoxygenation than low dose (2 Gy), and the effect tended to persist longer in smaller or more radiosensitive tumors. Our results also indicated the importance of the reoxygenation efficiency of the first fraction in the prediction of the radiation treatment outcome. In summary, this work has established a new nanoprobe for highly sensitive, quantitative, and longitudinal imaging of tumor hypoxia dynamics following radiotherapy, and demonstrated its value for assessing the efficacy of radiotherapy and radiation treatment planning. SIGNIFICANCE: This study presents a novel nanoagent for the visualization and quantification of tumor hypoxia.

A Magneto-Optical Nanoplatform for Multimodality Imaging of Tumors in Mice.

Multimodality imaging involves the use of more imaging modes to image the same living subjects and is now generally preferred in clinics for cancer imaging. Here we present multimodality-Magnetic Particle Imaging (MPI), Magnetic Resonance Imaging (MRI), Photoacoustic, Fluorescent-nanoparticles (termed MMPF NPs) for imaging tumor xenografts in living mice. MMPF NPs provide long-term (more than 2 months), dynamic, and accurate quantification, in vivo, of NPs and in real time by MPI. Moreover, MMPF NPs offer ultrasensitive MPI imaging of tumors (the tumor ROI increased by 30.6 times over that of preinjection). Moreover, the nanoparticle possessed a long-term blood circulation time (half-life at 49 h) and high tumor uptake (18% ID/g). MMPF NPs have been demonstrated for imaging breast and brain tumor xenografts in both subcutaneous and orthotopic models in mice via simultaneous MPI, MRI, fluorescence, and photoacoustic imaging with excellent tumor contrast to normal tissues.

Magnetic Particle Imaging in Neurosurgery.

BACKGROUND: Magnetic particle imaging (MPI) is a novel radiation-free tomographic imaging method that provides a background-free, signal attenuation-free, direct quantification of the spatial distribution of superparamagnetic iron-oxide nanoparticles (SPIONs) with high temporal resolution (milliseconds), high spatial resolution (<1 mm), and extreme sensitivity (µmol). The technique is based on nonlinear magnetization of the SPIONs when exposed to an oscillating magnetic field. MPI was first described in 2001. Since then, the technique has been applied to experimental imaging of diseases affecting different organs in the human body. The aim of this paper is to review the potential applications of MPI in the field of neurosurgery. METHODS: A nonsystematic review of the existing literature on the use of MPI in neurosurgical diseases was performed. RESULTS: MPI has been used for the detection of locoregional invasion of brain tumors, tracking, and monitoring the viability of neural stem cells implanted for neuroregenerative purposes, diagnosis of cerebral ischemia, and diagnosis and morphofunctional assessment of brain aneurysms. CONCLUSIONS: MPI is at a preclinical stage. In the future, human-sized MPI scanners, along with the optimal toxicity profile of SPIONs will allow diagnostic applications in neurosurgical diseases.

Janus Iron Oxides @ Semiconducting Polymer Nanoparticle Tracer for Cell Tracking by Magnetic Particle Imaging.

Iron oxides nanoparticles tailored for magnetic particle imaging (MPI) have been synthesized, and their MPI signal intensity is three-times that of commercial MPI contrast (Ferucarbotran, also called Vivotrax) and seven-times that of MRI contrast (Feraheme) at the same Fe concentration. MPI tailored iron oxide nanoparticles were encapsulated with semiconducting polymers to produce Janus nanoparticles that possessed optical and magnetic properties for MPI and fluorescence imaging. Janus particles were applied to cancer cell labeling and in vivo tracking, and as few as 250 cells were imaged by MPI after implantation, corresponding to an amount of 7.8 ng of Fe. Comparison with MRI and fluorescence imaging further demonstrated the advantages of our Janus particles for MPI-super sensitivity, unlimited tissue penetration, and linear quantitativity.

Core-Shell MnSe@Bi2 Se3 Fabricated via a Cation Exchange Method as Novel Nanotheranostics for Multimodal Imaging and Synergistic Thermoradiotherapy.

MnSe@Bi2 Se3 core-shell nanostructures with highly integrated imaging and therapy functions are fabricated by a simple cation exchange method. Using those nanoparticles as a theranostic agent, a promise concept is further demonstrated to enhance conventional radiotherapy by: i) using X-ray absorbing agents to locally concentrate radiation energy and ii) employing near-infrared-light-triggered photothermal therapy to overcome hypoxia-associated radioresistance.

Tracking Cancer Metastasis In†Vivo by Using an Iridium-Based Hypoxia-Activated Optical Oxygen Nanosensor.

We have developed a nanosensor for tracking cancer metastasis by noninvasive real-time whole-body optical imaging. The nanosensor is prepared by the formation of co-micelles from a poly(N-vinylpyrrolidone)-conjugated iridium(III) complex (Ir-PVP) and poly(ε-caprolactone)-b-poly(N-vinylpyrrolidone) (PCL-PVP). The near-infrared phosphorescence emission of the nanosensor could be selectively activated in the hypoxic microenvironment induced by cancer cells. The detection ability of the nanosensor was examined in cells and different animal models. After intravenous injection, the nanosensor can be effectively delivered to the lung and lymph node, and cancer cell metastasis through bloodstream or lymphatics can be quickly detected with high signal-to-background ratio by whole-body imaging and organ imaging. Moreover, the nanosensor exhibits good biocompatibility both in vitro and in vivo. The nanosensor is believed to be a powerful tool for the diagnosis of cancer metastasis.

Hypoxia-specific ultrasensitive detection of tumours and cancer cells in vivo.

Highly sensitive and specific non-invasive molecular imaging methods are particularly desirable for the early detection of cancers. Here we report a near-infrared optical imaging probe highly specific to the hypoxic tumour microenvironment to detect tumour and cancer cells with the sensitivity to a few thousands cancer cells. This oxygen-sensitive, near-infrared emitting and water-soluble phosphorescent macromolecular probe can not only report the hypoxic tumour environment of various cancer models, including metastatic tumours in vivo, but can also detect a small amount of cancer cells before the formation of the tumour based on the increased oxygen consumption during cancer cell proliferation. Thus, the reported hypoxia-sensitive probe may offer an imaging tool for characterizing the tumour microenvironment in vivo, detecting cancer cells at a very early stage of tumour development and lymph node metastasis.

Near-IR-triggered photothermal/photodynamic dual-modality therapy system via chitosan hybrid nanospheres.

Gold nanorods (AuNR)- and indocyanine green (ICG)-encapsulated chitosan hybrid nanospheres (CS-AuNR-ICG NSs) were successfully prepared and used for photothermal and photodynamic combined therapy with a single irradiation. These nanospheres were characterized by transmission electron microscopy, dynamic light scattering and UV-Vis absorption spectra. The in vivo anticancer effects of the hybrid nanospheres were examined by photodynamic therapy (PDT), photothermal therapy (PTT), and PTT/PDT combined therapy. It was found that the hybrid nanospheres had spherical size of 180 nm and a broad adsorption from 650 nm to 900 nm. The spherical chitosan matrix could effectively load ICG and protect it from the rapid hydrolysis. In vivo near-infrared fluorescence imaging and biodistribution demonstrated that ICG and AuNR could be selectively delivered to the tumor site with high accumulation. With the irradiation by 808 nm laser, chitosan hybrid nanospheres were capable to simultaneously produce sufficient hyperthermia and reactive oxygen species to kill cancer cells at irradiation sites, resulting in the complete tumor disappearance in the most of tumor-bearing mice. Compared with photothermal therapy or photodynamic therapy alone, the combined therapy had a significantly synergistic effect and improved the therapeutic efficacy.

Combined near-IR photothermal therapy and chemotherapy using gold-nanorod/chitosan hybrid nanospheres to enhance the antitumor effect.

Motivated by the enhanced cytotoxicity of some chemotherapeutic agents at temperature rise, multifunctional chitosan nanospheres which co-carried gold nanorods and cisplatin were prepared. These hybrid nanospheres were characterized by dynamic light scattering, zeta potential, UV-Vis absorption spectra and transmission electron microscopy. It was demonstrated that these 120 nm-sized hybrid nanospheres could be selectively accumulated at the tumor site with about 11% injection dose per g of tumor, and produced local hyperthermia to an average temperature of 49 °C in tumor tissue after near-IR irradiation for 10 min. Due to the enhanced cytotoxicity of cisplatin at elevated temperatures, cisplatin-loaded hybrid nanospheres showed about one-second lower IC50 values than hybrid nanospheres alone in vitro and almost complete tumor growth inhibition in vivo. Compared with chemotherapy or photothermal treatment alone, the combined photothermal therapy and chemotherapy had a significantly synergistic effect and improved the therapeutic efficacy, which was supported by immunofluorescence staining and in vivo apoptosis imaging.

The effect of hydrophilic chain length and iRGD on drug delivery from poly(ε-caprolactone)-poly(N-vinylpyrrolidone) nanoparticles.

Poly(ε-caprolactone)-b-Poly(N-vinylpyrrolidone) (PCL-b-PVP) copolymers with different PVP block length were synthesized by xanthate-mediated reverse addition fragment transfer polymerization (RAFT) and the xanthate chain transfer agent on chain end was readily translated to hydroxy or aldehyde for conjugating various functional moieties, such as fluorescent dye, biotin hydrazine and tumor homing peptide iRGD. Thus, PCL-PVP nanoparticles were prepared by these functionalized PCL-b-PVP copolymers. Furthermore, paclitaxel-loaded PCL-PVP nanoparticles with satisfactory drug loading content (15%) and encapsulation efficiency (>90%) were obtained and used in vitro and in vivo antitumor examination. It was demonstrated that the length of PVP block had a significant influence on cytotoxicity, anti-BSA adsorption, circulation time, stealth behavior, biodistribution and antitumor activity for the nanoparticles. iRGD on PCL-PVP nanoparticle surface facilitated the nanoparticles to accumulate in tumor site and enhanced their penetration in tumor tissues, both of which improved the efficacy of paclitaxel-loaded nanoparticles in impeding tumor growth and prolonging the life time of H22 tumor-bearing mice.

Hollow core-porous shell structure poly(acrylic acid) nanogels with a superhigh capacity of drug loading.

Poly(acrylic acid) (PAA) nanogels with a hollow core-porous shell structure were prepared by the direct polymerization of an acrylic acid monomer in the presence of hydroxypropylcellulose (HPC) and a cross-linking agent, N,N-methylenebisacrylamide, followed by removal of HPC from the generated HPC-PAA nanoparticles in a basic environment. The properties of PAA nanogel were characterized by dynamic light scattering, FT-IR, transmission electron microscopy, and atomic force microscopy. It is found that the nanogels have a hollow core-porous shell structure. Protein, bovine serum albumin (BSA), and an antitumor agent, doxorubicin hydrochloride, were used as model drugs to investigate their loading abilities as versatile drug-delivery vehicles. The nanogel exhibits surprisingly high loading ability to both protein and small molecular drugs. For example, the maximum BSA loading capacity of PAA nanogel can reach as high as 800% (i.e., 1 mg of nanogel can load about 8.0 mg of BSA). This high loading capacity may be related with the hollow core-porous shell structure of PAA nanogels. PAA nanogels have also shown sustained drug release properties and can cross biological barriers to deliver loaded cargo inside cells. Considering the high stability of the materials, simple and mild preparation procedure, high loading capacity, sustained-release property, and ability to protect biological agents from denaturation, PAA nanogels should be promising drug-delivery carriers for drug-delivery systems.