Dual/Multi-Modal Image-Guided Diagnosis and Therapy Based on Luminogens with Aggregation-Induced Emission.

The combination of multiple imaging methods has made an indelible contribution to the diagnosis, surgical navigation, treatment, and prognostic evaluation of various diseases. Due to the unique advantages of luminogens with aggregation-induced emission (AIE), their progress has been significant in the field of organic fluorescent contrast agents. Herein, this manuscript summarizes the recent advancements in AIE molecules as contrast agents for optical image-based dual/multi-modal imaging. We particularly focus on the exceptional properties of each material and the corresponding application in the diagnosis and treatment of diseases.

Three-Pronged Attack by Hybrid Nanoplatform Involving MXenes, Upconversion Nanoparticle and Aggregation-Induced Emission Photosensitizer for Potent Cancer Theranostics.

Inspired by the excellent photothermal conversion ability and inherent nanomedicine platform property of MXenes, efficient reactive oxygen species production and prominent fluorescence emission feature of aggregation-induced emission (AIE)-active photosensitizers (PSs), as well as the extending excitation wavelength capability of upconversion nanoparticles (UCNPs), a versatile nanoplatform comprised of Ti3 C2 nanosheets (NSs), AIE-active PSs and UCNPs is intelligently fabricated. This three-pronged strategy takes advantages of each component simultaneously, and realizes fluorescence imaging/photoacoustic imaging/photothermal imaging triple-modal imaging-guided photothermal/photodynamic synergetic therapy under 808 nm laser irradiation. The introduction of UCNPs actualizes the long wavelength-activation of AIE-active PSs, which significantly increases the tissue penetration depth. Spatially isolation of AIE-active PSs and Ti3 C2 NSs is beneficial for suppressing the fluorescence quenching effect of Ti3 C2 NSs, bringing about ultimately brilliant fluorescence. The covalently bonded polymer surface endows the nanoplatform with excellent physiological stability and efficient tumor accumulation. These outputs reveal a win-win cooperation of multiple inorganic/organic nanocomposites for phototheranostics, and present great potential for future clinical translations.

Acidic microenvironment responsive polymeric MOF-based nanoparticles induce immunogenic cell death for combined cancer therapy.

BACKGROUND: The complex tumor microenvironment and non-targeting drugs limit the efficacy of clinical tumor therapy. For ensuring the accurate delivery and maximal effects of anticancer drugs, it is important to develop innovative drug delivery system based on nano-strategies. RESULT: In this study, an intracellular acidity-responsive polymeric metal organic framework nanoparticle (denoted as DIMP) has been constructed, which can co-deliver the chemotherapy agent of doxorubicin (DOX) and phototherapy agent of indocyanine green (ICG) for breast carcinoma theranostics. Specifically, DIMP possesses a suitable and stable nanometer size and can respond to the acidic microenvironment in cells, thus precisely delivering drugs into target tumor sites and igniting the biological reactions towards cell apoptosis. Following in vivo and in vitro results showed that DIMP could be effectively accumulated in tumor sites and induced powerful immunogenic cell death (ICD) effect. CONCLUSION: The designed DIMP displayed its effectiveness in combined photo-chemotherapy with auxiliary of ICD effect under a multimodal imaging monitor. Thus, the present MOF-based strategy may offer a potential paradigm for designing drug-delivery system for image-guided synergistic tumor therapy.

Core-Shell-Structured Covalent-Organic Framework as a Nanoagent for Single-Laser-Induced Phototherapy.

Imaging-guided phototherapy, including photothermal therapy and photodynamic therapy, has been emerging as a promising avenue for precision cancer treatment. However, the utilization of a single laser to induce combination phototherapy and multiple-model imaging remains a great challenge. Herein, we report, the first of its kind, a covalent-organic framework (COF)-based magnetic core-shell nanocomposite, Fe3O4@COF-DhaTph, that is used as a multifunctional nanoagent for cancer theranostics under single 660 nm NIR irradiation. Besides significant photothermal and photodynamic effects, it still permits triple-modal magnetic resonance/photoacoustic/near-infrared thermal (IR) imaging due to its unequaled magnetic and optical performance. We believe that the results obtained herein could obviously promote the application of COF-based multifunctional nanomaterials in cancer theranostics.

Cascaded Amplifier Nanoreactor for Efficient Photodynamic Therapy.

Photodynamic therapy (PDT) utilizes reactive oxygen species (ROS) to treat established diseases and has attracted growing attention in the field of cancer therapy. However, in a tumor microenvironment (TME), the inherent hypoxia and high level of antioxidants severely hamper the efficacy of ROS generation. Here, we describe a cascaded amplifier nanoreactor based on self-assembled nanofusiforms for persistent oxygenation to amplify ROS levels. The nanofusiform assembly is capable of photothermal and photodynamic treatment and regulation of redox oxidation stress by antioxidant depletion to prevent ROS tolerance. The Pt nanozyme decoration of the nanofusiform enables efficient oxygen supplements via Pt nanozyme-catalyzed decomposition of H2O2 overexpressed in TME and generation of O2. Furthermore, the temperature elevation resulted from the photothermal effect of the nanofusiform increases the catalase-like catalytic activity of the Pt nanozyme for boosted oxygen generation. Thus, such a triple cascade strategy using nanozyme-based nanofusiforms amplifies the ROS level by continuous oxygenation, enhancing the efficacy of PDT in vitro and in vivo. Meanwhile, an in vivo multi-modal imaging including near-infrared fluorescence imaging, photothermal imaging, and magnetic resonance imaging achieves precise tumor diagnosis. The rationally designed nanofusiform acts as an efficient ROS amplifier through multidimension strengthening of continuous oxygenation, providing a potential smart nanodrug for cancer therapy.

Biodegradable hollow mesoporous organosilica nanotheranostics (HMON) for multi-mode imaging and mild photo-therapeutic-induced mitochondrial damage on gastric cancer.

BACKGROUND: CuS-modified hollow mesoporous organosilica nanoparticles (HMON@CuS) have been preferred as non-invasive treatment for cancer, as near infrared (NIR)-induced photo-thermal effect (PTT) and/or photo-dynamic effect (PDT) could increase cancer cells' apoptosis. However, the certain role of HMON@CuS-produced-PTT&PDT inducing gastric cancer (GC) cells' mitochondrial damage, remained unclear. Moreover, theranostic efficiency of HMON@CuS might be well improved by applying multi-modal imaging, which could offer an optimal therapeutic region and time window. Herein, new nanotheranostics agents were reported by Gd doped HMON decorated by CuS nanocrystals (called HMON@CuS/Gd). RESULTS: HMON@CuS/Gd exhibited appropriate size distribution, good biocompatibility, L-Glutathione (GSH) responsive degradable properties, high photo-thermal conversion efficiency (82.4%) and a simultaneous reactive oxygen species (ROS) generation effect. Meanwhile, HMON@CuS/Gd could efficiently enter GC cells, induce combined mild PTT (43-45 °C) and PDT under mild NIR power density (0.8 W/cm2). Surprisingly, it was found that PTT might not be the only factor of cell apoptosis, as ROS induced by PDT also seemed playing an essential role. The NIR-induced ROS could attack mitochondrial transmembrane potentials (MTPs), then promote mitochondrial reactive oxygen species (mitoROS) production. Meanwhile, mitochondrial damage dramatically changed the expression of anti-apoptotic protein (Bcl-2) and pro-apoptotic protein (Bax). Since that, mitochondrial permeability transition pore (mPTP) was opened, followed by inducing more cytochrome c (Cyto C) releasing from mitochondria into cytosol, and finally activated caspase-9/caspase-3-depended cell apoptosis pathway. Our in vivo data also showed that HMON@CuS/Gd exhibited good fluorescence (FL) imaging (wrapping fluorescent agent), enhanced T1 imaging under magnetic resonance imaging (MRI) and infrared thermal (IRT) imaging capacities. Guided by FL/MRI/IRT trimodal imaging, HMON@CuS/Gd could selectively cause mild photo-therapy at cancer region, efficiently inhibit the growth of GC cells without evident systemic toxicity in vivo. CONCLUSION: HMON@CuS/Gd could serve as a promising multifunctional nanotheranostic platform and as a cancer photo-therapy agent through inducing mitochondrial dysfunction on GC.

Multifunctional low-temperature photothermal nanodrug with in vivo clearance, ROS-Scavenging and anti-inflammatory abilities.

Harsh photothermal temperatures, long-term body retention of nanoagents, elevated ROS and inflammation induction all threaten the normal tissues, thus hindering the translation of photothermal therapy (PTT) from bench to clinical practice. To resolve these problems, we have developed a disassembled theranostic nanodrug Qu-FeIIP based on the quercetin coordination. Herein, quercetin is not only the heat shock protein (Hsp 70) inhibitor but also the skeleton of Qu-FeIIP, realizing near-infrared light induced low-temperature PTT (45 °C) to ablate tumor completely without heat stress to normal tissues. Owing to the ROS scavenging ability of quercetin, Qu-FeIIP effectively reduces intracellular ROS and in vivo inflammatory factors (TNF-α, IL-6, IFN-γ) levels. Simultaneously, quercetin-Fe coordination is weakened when scavenging ROS, which triggers the Qu-FeIIP disassembling, resulting in effective clearance of nanoparticles from main organs 168 h post intravenous injection. Additionally, the photoacoustic and magnetic resonance dual-imaging capability of Qu-FeIIP offers excellent spatial resolution and imaging depth not only for precise tumor diagnosis but also for monitoring the nanodrug disassembling in vivo. Thus, Qu-FeIIP intrinsically integrates precise diagnosis, excellent low-temperature PTT efficacy, ROS elimination and anti-inflammatory action, dynamic disassembly and renal clearance ability into a single nanodrug, which is very promising for future clinical cancer treatment.

The spatiotemporal pattern of pure tone processing: A single-trial EEG-fMRI study.

Although considerable research has been published on pure tone processing, its spatiotemporal pattern is not well understood. Specifically, the link between neural activity in the auditory pathway measured by functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) markers of pure tone processing in the P1, N1, P2, and N4 components is not well established. In this study, we used single-trial EEG-fMRI as a multi-modal fusion approach to integrate concurrently acquired EEG and fMRI data, in order to understand the spatial and temporal aspects of the pure tone processing pathway. Data were recorded from 33 subjects who were presented with stochastically alternating pure tone sequences with two different frequencies: 200 and 6400 Hz. Brain network correlated with trial-to-trial variability of the task-discriminating EEG amplitude was identified. We found that neural responses responding to pure tone perception are spatially along the auditory pathway and temporally divided into three stages: (1) the early stage (P1), wherein activation occurs in the midbrain, which constitutes a part of the low level auditory pathway; (2) the middle stage (N1, P2), wherein correlates were found in areas associated with the posterodorsal auditory pathway, including the primary auditory cortex and the motor cortex; (3) the late stage (N4), wherein correlation was found in the motor cortex. This indicates that trial-by-trial variation in neural activity in the P1, N1, P2, and N4 components reflects the sequential engagement of low- and high-level parts of the auditory pathway for pure tone processing. Our results demonstrate that during simple pure tone listening tasks, regions associated with the auditory pathway transiently correlate with trial-to-trial variability of the EEG amplitude, and they do so on a millisecond timescale with a distinct temporal ordering.

Iron oxide-carbon core-shell nanoparticles for dual-modal imaging-guided photothermal therapy.

Nanostructured materials that have low tissue toxicity, multi-modal imaging capability and high photothermal conversion efficiency have great potential to enable image-guided near infrared (NIR) photothermal therapy (PTT). Here, we report a bifunctional nanoparticle (BFNP, ∼16 nm) comprised of a magnetic Fe3O4 core (∼9.1 nm) covered by a fluorescent carbon shell (∼3.4 nm) and prepared via a one-pot solvothermal synthesis method using ferrocene as the sole source. The BFNP exhibits excitation wavelength-tunable, upconverted and near-infrared (NIR) fluorescence property due to the presence of the carbon shell, and superparamagnetic behavior resulted from the Fe3O4 core. BFNPs demonstrate dual-modal imaging capacity both in vitro and in vivo with fluorescent imaging excited under a varying wavelength from 405 nm to 820 nm and with T2-weighted magnetic resonance imaging (r2 = 264.76 mM-1 s-1). More significantly, BFNPs absorb and convert NIR light to heat enabling photothermal therapy as demonstrated mice bearing C6 glioblastoma. These BFNPs show promise as an advanced nanoplatform to provide imaging guided photothermal therapy.

CuS as a gatekeeper of mesoporous upconversion nanoparticles-based drug controlled release system for tumor-targeted multimodal imaging and synergetic chemo-thermotherapy.

In this work, a tumor-targeted multifunctional mesoporous upconversion nanoparticle-based drug controlled release system was developed for UCL/MRI/PAT guided synergetic chemo-thermotherapy. Herein, the core-shell mesoporous upconversion nanoparticles served as drug carrier exhibiting higher upconversion luminescence emission intensity, with CuS as a gatekeeper through a cleavable disulfide bond under the influence of glutathione. CuS could not only prevent drug from early release during the delivery but also improve the delivery system function with the ability of photothermal therapy and photoacoustic tomography. Hyaluronic acid grafted on the surface of mesoporous upconversion nanoparticles could interact with CD44 receptors over-expressed in tumor cells, facilitating the drug delivery system to accumulate in tumor tissues. The synergy between chemotherapy and photothermal therapy was studied in vitro and in vivo, showing powerful anti-tumor effect. In cooperation with the multi-mode imaging, the size, site and morphology of tumor were clearly observed throughout the disease's progression.

An efficient nano-based theranostic system for multi-modal imaging-guided photothermal sterilization in gastrointestinal tract.

Since understanding the healthy status of gastrointestinal tract (GI tract) is of vital importance, clinical implementation for GI tract-related disease have attracted much more attention along with the rapid development of modern medicine. Here, a multifunctional theranostic system combining X-rays/CT/photothermal/photoacoustic mapping of GI tract and imaging-guided photothermal anti-bacterial treatment is designed and constructed. PEGylated W18O49 nanosheets (PEG-W18O49) are created via a facile solvothermal method and an in situ probe-sonication approach. In terms of excellent colloidal stability, low cytotoxicity, and neglectable hemolysis of PEG-W18O49, we demonstrate the first example of high-performance four-modal imaging of GI tract by using these nanosheets as contrast agents. More importantly, due to their intrinsic absorption of NIR light, glutaraldehyde-modified PEG-W18O49 are successfully applied as fault-free targeted photothermal agents for imaging-guided killing of bacteria on a mouse infection model. Critical to pre-clinical and clinical prospects, long-term toxicity is further investigated after oral administration of these theranostic agents. These kinds of tungsten-based nanomaterials exhibit great potential as multi-modal contrast agents for directed visualization of GI tract and anti-bacterial agents for phothothermal sterilization.