Leveraging Long-Distance Singlet-Oxygen Transfer for Bienzyme-Locked Afterglow Imaging of Intratumoral Granule Enzymes.

Dual-locked activatable optical probes, leveraging the orthogonal effects of two biomarkers, hold great promise for the specific imaging of biological processes. However, their design approaches are limited to a short-distance energy or charge transfer mechanism, while the signal readout relies on fluorescence, which inevitably suffers from tissue autofluorescence. Herein, we report a long-distance singlet oxygen transfer approach to develop a bienzyme-locked activatable afterglow probe (BAAP) that emits long-lasting self-luminescence without real-time light excitation for the dynamic imaging of an intratumoral granule enzyme. Composed of an immuno-biomarker-activatable singlet oxygen (1O2) donor and a cancer-biomarker-activatable 1O2 acceptor, BAAP is initially nonafterglow. Only in the presence of both immune and cancer biomarkers can 1O2 be generated by the activated donor and subsequently diffuse toward the activated acceptor, resulting in bright near-infrared afterglow with a high signal-to-background ratio and specificity toward an intratumoral granule enzyme. Thus, BAAP allows for real-time tracking of tumor-infiltrating cytotoxic T lymphocytes, enabling the evaluation of cancer immunotherapy and the differentiation of tumor from local inflammation with superb sensitivity and specificity, which are unachievable by single-locked probes. Thus, this study not only presents the first dual-locked afterglow probe but also proposes a new design way toward dual-locked probes via reactive oxygen species transfer processes.

Molecular radio afterglow probes for cancer radiodynamic theranostics.

X-ray-induced afterglow and radiodynamic therapy tackle the tissue penetration issue of optical imaging and phototherapy. However, inorganic nanophosphors used in this therapy have their radio afterglow dynamic function as always on, limiting the detection specificity and treatment efficacy. Here we report organic luminophores (IDPAs) with near-infrared afterglow and 1O2 production after X-ray irradiation for cancer theranostics. The in vivo radio afterglow of IDPAs is >25.0 times brighter than reported inorganic nanophosphors, whereas the radiodynamic production of 1O2 is >5.7 times higher than commercially available radio sensitizers. The modular structure of IDPAs permits the development of a smart molecular probe that only triggers its radio afterglow dynamic function in the presence of a cancer biomarker. Thus, the probe enables the ultrasensitive detection of a diminutive tumour (0.64 mm) with superb contrast (tumour-to-background ratio of 234) and tumour-specific radiotherapy for brain tumour with molecular precision at low dosage. Our work reveals the molecular guidelines towards organic radio afterglow agents and highlights new opportunities for cancer radio theranostics.

Eosinophil-Activating Semiconducting Polymer Nanoparticles for Cancer Photo-Immunotherapy.

Eosinophils are important immune effector cells that affect T cell-mediated antitumor immunity. However, the low frequency and restrained activity of eosinophils restricted the outcome of cancer immunotherapies. We herein report an eosinophil-activating semiconducting polymer nanoparticle (SPNe) to improve photodynamic tumor immunogenicity, modulate eosinophil chemotaxis, and reinvigorate T-cell immunity for activated cancer photo-immunotherapy. SPNe comprises an amphiphilic semiconducting polymer and a dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin via a 1O2-cleavable thioketal linker. Upon localized NIR photoirradiation, SPNe generates 1O2 to elicit immunogenic cell death of tumors and induce specific activation of sitagliptin. The subsequent inhibition of DPP4 increases intratumoral CCL11 levels to promote eosinophil chemotaxis and activation. SPNe-mediated photo-immunotherapy synergized with immune checkpoint blockade greatly promotes tumor infiltration and activation of both eosinophils and T cells, effectively inhibiting tumor growth and metastasis. Thus, this study presents a generic polymeric nanoplatform to modulate specific immune cells for precision cancer immunotherapy.

A Tandem-Locked Chemiluminescent Probe for Imaging of Tumor-Associated Macrophage Polarization.

Tumor-associated macrophages (TAMs) play a role in both pro- and anti-tumor functions; and the targeted polarization from M2 to M1 TAMs has become an effective therapy option. Although detection of M1 TAMs is imperative to assess cancer immunotherapeutic efficacy, existing optical probes suffer from shallow tissue penetration depth and poor specificity toward M1 TAMs. Herein, we report a tandem-locked NIR chemiluminescent (CL) probe for specific detection of M1 TAMs. Through a combined molecular engineering approach via both atomic alternation and introduction of electron-withdrawing groups, near-infrared (NIR) chemiluminophores are screened out to possess record-long emission (over 800 nm), record-high CL quantum yield (2.7 % einstein/mol), and prolonged half-life (7.7 h). Based on an ideal chemiluminophore, the tandem-locked probe (DPDGN) is developed to only activate CL signal in the presence of both tumour (γ-glutamyl transpeptidase) and M1 macrophage biomarkers (nitric oxide). Such a tandem-lock design ensures its high specificity towards M1 macrophages in the tumor microenvironment over those in normal tissues or peripheral blood. Thus, DPDGN permits noninvasive imaging and tracking of M1 TAM in the tumor of living mice during R837 treatment, showing a good correlation with ex vivo methods. This study not only reports a new molecular approach towards highly efficient chemiluminophores but also reveals the first tandem-locked CL probes for enhanced imaging specificity.

Dynamic large strain measurement under high-temperature environment using a modified FBG sensor and plasma surface treatment.

Large strain measurement under high-temperature environment has been a hot but difficult research issue in the fields of measurement and metrology. However, conventional resistive strain gauges are susceptible to electromagnetic interference at high temperature, and typical fiber sensors will be invalid under high-temperature environment or fall off under large strain conditions. In this paper, aiming to achieve effective and precision measurement of large strain under high-temperature environment, a systematic scheme combining a well-designed encapsulation of a fiber Bragg grating (FBG) sensor and a special surface treatment method using plasma is presented. The encapsulation protects the sensor from damage while achieving partial thermal isolation and avoiding shear stress and creep, resulting in higher accuracy. And the plasma surface treatment provides a new bonding solution which can greatly improve the bonding strength and coupling efficiency without damaging the surface structure of the object under test. Suitable adhesive and temperature compensation method are also carefully analyzed. Consequently, large strain measurement up to 1500 µÉ› under high-temperature (1000°C) environment is experimentally achieved in a cost-effective way.

Highly Bright Near-Infrared Chemiluminescent Probes for Cancer Imaging and Laparotomy.

Near-infrared (NIR) chemiluminescence imaging holds potential for sensitive imaging of cancer due to its low background; however, few NIR chemiluminophores are available, which share the drawback of low chemiluminescence quantum yields (ΦCL ). Herein, we report the synthesis of NIR chemiluminophores for cancer imaging and laparotomy. Molecular engineering of the electron-withdrawing group at the para-position of the phenol-dioxetane leads to a highly bright NIR chemiluminophore (DPT), showing the ΦCL (4.6×10-2  Einstein mol-1 ) that is 3 to 5-fold higher than existing NIR chemiluminophores. By caging the phenol group of DPT with a cathepsin B (CatB) responsive moiety, an activatable chemiluminescence probe (DPTCB ) is developed for real-time turn-on detection of deeply buried tumor tissues in living mice. Due to its high brightness, DPTCB permits accurate chemiluminescence-guided laparotomy.

Near-Infrared Photodynamic Chemiluminescent Probes for Cancer Therapy and Metastasis Detection.

There is growing interest in the development of chemiluminescence (CL) probes for phototheranostics because of their minimized tissue autofluorescence. However, due to a lack of near-infrared (NIR)-absorbing chemiluminophores, current probes for NIR CL-guided phototherapy are based on nanoparticles made up of multiple components. We report bright unimolecular chemiluminophores with NIR absorptions and emissions, long CL half-lives and ideal photodynamic efficiency. One luminophore is modified into an activatable probe, DBPOL , with a turn-on CL signal and photodynamic activity that are specific to a cancer biomarker. The highly sensitive DBPOL allows CL-guided photodynamic therapy which completely inhibits tumor growth and lung metastasis in mouse models, and can be applied for noninvasive monitoring of lung metastasis. We provide molecular guidelines for NIR-absorbing CL probes for imaging-guided phototherapy.

Polymeric STING Pro-agonists for Tumor-Specific Sonodynamic Immunotherapy.

The efficacy of combination immunotherapy has been limited by tumor specificity and immune-related adverse events (irAEs). Herein, we report the development of polymeric STING pro-agonists (PSPA), whose sono-immunotherapeutic efficacy is activated by sono-irradiation and elevated glutathione (GSH) within the tumor microenvironment (TME). PSPA is composed of sonosensitizers (semiconducting polymer) and STING agonists (MSA-2) via the GSH-activatable linkers. Under sono-irradiation, PSPA serves as a sonosensitizer to generate 1 O2 and induce immunogenic cell death (ICD) of malignant tumor cells. Furthermore, MSA-2 is released specifically in tumor microenvironment with highly expressed GSH, minimizing off-target side effects. The activation of the STING pathway elevates the interferon-ß level and synergizes with SDT to enhance the anti-tumor response. Therefore, this work proposes a universal approach for spatiotemporal regulation of cancer sono-immunotherapy.

A Polymeric Extracellular Matrix Nanoremodeler for Activatable Cancer Photo-Immunotherapy.

Cancer immunotherapy has shown tremendous potential to train the intrinsic immune system against malignancy in the clinic. However, the extracellular matrix (ECM) in tumor microenvironment is a formidable barrier that not only restricts the penetration of therapeutic drugs but also prevents the infiltration of antitumor immune cells. We herein report a semiconducting polymer-based ECM nanoremodeler (SPNcb) to combine photodynamic antitumor activity with cancer-specific inhibition of collagen-crosslinking enzymes (lysyl oxidase (LOX) family) for activatable cancer photo-immunotherapy. SPNcb is self-assembled from an amphiphilic semiconducting polymer conjugated with a LOX inhibitor (ß-aminopropionitrile, BAPN) via a cancer biomarker (cathepsin B, CatB)-cleavable segment. BAPN can be exclusively activated to inhibit LOX activity in the presence of the tumor-overexpressed CatB, thus blocking collagen crosslinking and decreasing ECM stiffness. Such an ECM nanoremodeler synergizes immunogenic phototherapy and checkpoint blockade immunotherapy to improve the tumor infiltration of cytotoxic T cells, inhibiting tumor growth and metastasis.

High speed surface defects detection of mirrors based on ultrafast single-pixel imaging.

High speed surface defects detection of mirrors is of great significance, for detecting the quality of the mirrors on-site, and ultimately for monitoring the operating states of laser systems. The speeds of conventional proposals are relatively low as they utilize mechanically scanning methods or two-dimensional charge-coupled devices. Here, we propose a high speed surface detection method based on ultrafast single-pixel imaging, which consists of a spatial Fourier optical module for frequency-space mapping and a dispersive Fourier transform module for frequency-time mapping. An optical grating is utilized to map the wideband spectrum of dissipative soliton into the spatial domain under far-field diffraction, where the mirror is inspected. Dispersive Fourier transform is used to map the surface-defects-coded spectral information into the temporal domain, then recorded by a high speed single-pixel detector. The detection system permits continuous single-shot spectra measurement with a frame rate equivalent to the pulse repetition rate (8.4 MHz). We extract amplitude defects by demodulating light intensity, and obtain phase defects by demodulating the interference spectrum with a Mach-Zehnder interferometer structure. Experimental results show that the damaged mirror with a two-dimensional width of 10 × 13 mm can be obtained with a spatial resolution of 90 µm. The obtained phase accuracy after Hilbert transformation is 0.00217 rad, corresponding to a depth resolution of 51 nm. This scheme can find promising applications for surface defects detection of large aperture mirrors, and real-time monitoring of laser systems with high energy.

Dynamic phase retrieval method for ultrafast and precise vibration sensing based on time stretching.

We demonstrate a method for retrieving the phase information from single-shot interference spectra obtained by dispersive Fourier transform, through which the error accumulation during phase retrieval is restrained. A Mach-Zehnder interferometer is proposed for vibration sensing with high speed. We find that relative phase trends at different time delays can be precisely retrieved to improve the signal-to-noise ratio when the time interval jitter between pulses within two arms is less than four times the pulse width. The verification experiment achieves a phase resolution of 5.3 mrad and a high-speed refresh frame rate of 51.8 MHz. Numerical simulations and experiments show that the method is effective for phase demodulation of dynamic interference spectra, and provides a reliable strategy for high-speed, precision sensing.

Chemiluminescent Probes with Long-Lasting High Brightness for In Vivo Imaging of Neutrophils.

Real-time optical imaging of immune cells can contribute to understanding their pathophysiological roles, which still remains challenging. Current sensitive chemiluminophores have issues of short half-lives and low brightness, limiting their ability for in vivo longitudinal monitoring of immunological processes. To tackle these issues, we report benzoazole-phenoxyl-dioxetane (BAPD)-based chemiluminophores with intramolecular hydrogen bonding for in vivo imaging of neutrophils. Compared with the classical counterpart, chemiluminescence half-lives and brightness of BAPDs in the aqueous solution are increased by ∼ 33- and 8.2-fold, respectively. Based on the BAPD scaffold, a neutrophil elastase-responsive chemiluminescent probe is developed for real-time imaging of neutrophils in peritonitis and psoriasis mouse models. Our study provides an intramolecular hydrogen bonding molecular design for improving the performance of chemiluminophores in advanced imaging applications.

A Dual-Locked Activatable Phototheranostic Probe for Biomarker-Regulated Photodynamic and Photothermal Cancer Therapy.

Activatable phototheranostics holds promise for precision cancer treatment owing to the "turn-on" signals and therapeutic effects. However, most activatable phototheranostic probes only possess photodynamic therapy (PDT) or photothermal therapy (PTT), which suffer from poor therapeutic efficacy due to deficient cellular oxygen and complex tumor microenvironment. We herein report a dual-locked activatable phototheranostic probe that activates near-infrared fluorescence (NIRF) signals in tumor, triggers PDT in response to a tumor-periphery biomarker, and switches from PDT to PTT upon detecting a tumor-core-hypoxia biomarker. This PDT-PTT auto-regulated probe exhibits complete tumor ablation under the photoirradiation of a single laser source by producing cytotoxic singlet oxygen at the tumor periphery and generating hyperthermia at tumor-core where is too hypoxic for PDT. This dual-locked probe represents a promising molecular design approach toward precise cancer phototheranostics.

Molecular Chemiluminescent Probes with a Very Long Near-Infrared Emission Wavelength for in†Vivo Imaging.

Chemiluminescence imaging is imperative for diagnostics and imaging due to its intrinsically high sensitivity. To improve in vivo detection of biomarkers, chemiluminophores that simultaneously possess near-infrared (NIR) emission and modular structures amenable to construction of activatable probes are highly desired; however, these are rare. Herein, we report two chemiluminophores with record long NIR emission (>750 nm) via integration of dicyanomethylene-4H-benzothiopyran or dicyanomethylene-4H-benzoselenopyran with dioxetane unit. Caging of the chemiluminophores with different cleavable moieties produces NIR chemiluminescence probes (NCPs) that only produce signals upon reaction with reactive oxygen species or enzymes, for example, ß-galactosidase, with a tissue-penetration depth of up to 2 cm. Thus, this study provides NIR chemiluminescence molecular scaffolds applicable for in vivo turn-on imaging of versatile biomarkers in deep tissues.

Simple Method to Supply Organic Nanoparticles with Excitation-Wavelength-Dependent Photoluminescence.

Organic fluorescent nanoparticles (FNPs) have become increasingly prevalent in a variety of applications but the creation of organic FNPs using a simple procedure and that possess diverse morphology, multicolor luminescence, and high brightness has been challenging. Herein, a facile strategy to prepare this class of organic FNPs is established by way of preformed organic nanoparticles themselves. It was found that as long as the nanoparticles contained aromatic/heterocyclic rings in their base unit and regardless of morphologies (e.g., small-molecule micelles, polymeric micelles, reverse micelles, solid microspheres, and vesicles), simple UV irradiation can result in the particles exhibiting excitation-wavelength-dependent photoluminescence with considerable quantum yields (∼8.3-16.7% for tested particles). Upon initial investigation of the mechanism, the photoluminescence behavior was attributed to a polycyclic aromatic hydrocarbon (PAH) process. Furthermore, the application of the synthesized organic FNPs in cancer cell imaging is demonstrated as just one of the many potential applications. The straightforward method to supply preformed organic nanoparticles with photoluminescence would be attractive for scientists in both academia and industry.

A Renal-Clearable Macromolecular Reporter for Near-Infrared Fluorescence Imaging of Bladder Cancer.

Bladder cancer (BC) is a prevalent disease with high morbidity and mortality; however, in vivo optical imaging of BC remains challenging because of the lack of cancer-specific optical agents with high renal clearance. Herein, a macromolecular reporter (CyP1) was synthesized for real-time near-infrared fluorescence (NIRF) imaging and urinalysis of BC in living mice. Because of the high renal clearance (ca. 94 % of the injection dosage at 24 h post-injection) and its cancer biomarker (APN=aminopeptidase N) specificity, CyP1 can be efficiently transported to the bladder and specially turn on its NIRF signal to report the detection of BC in living mice. Moreover, CyP1 can be used for optical urinalysis, permitting the ex vivo tracking of tumor progression for therapeutic evaluation and easy translation of CyP2 as an in vitro diagnostic assay. This study not only provides new opportunities for non-invasive diagnosis of BC, but also reveals useful guidelines for the development of molecular reporters for the detection of bladder diseases.

Photoactivatable Organic Semiconducting Pro-nanoenzymes.

Therapeutic enzymes hold great promise for cancer therapy; however, in vivo remote control of enzymatic activity to improve their therapeutic specificity remains challenging. This study reports the development of an organic semiconducting pro-nanoenzyme (OSPE) with a photoactivatable feature for metastasis-inhibited cancer therapy. Upon near-infrared (NIR) light irradiation, this pro-nanoenzyme not only generates cytotoxic singlet oxygen (1O2) for photodynamic therapy (PDT), but also triggers a spontaneous cascade reaction to induce the degradation of ribonucleic acid (RNA) specifically in tumor microenvironment. More importantly, OSPE-mediated RNA degradation is found to downregulate the expression of metastasis-related proteins, contributing to the inhibition of metastasis after treatment. Such a photoactivated and cancer-specific synergistic therapeutic action of OSPE enables complete inhibition of tumor growth and lung metastasis in mouse xenograft model, which is not possible for the counterpart PDT nanoagent. Thus, our study proposes a phototherapeutic-proenzyme approach toward complete-remission cancer therapy.

Lipoic acid based core cross-linked micelles for multivalent platforms: design, synthesis and application in bio-imaging and drug delivery.

Natural lipoic acid derived small-molecule amphiphiles self-assemble into micelles in water. The presence of numerous disulfides accumulated in the core makes the micelles readily cross-linked to achieve the establishment of core cross-linked micelles (CCMs). Thanks to the inherent biocompatibility, the resulting lipoic acid based CCMs (LA-CCMs) are good multivalent platforms for biomedical applications.

Use of the Wilkinson catalyst for the ortho-C-H heteroarylation of aromatic amines: facile access to highly extended π-conjugated heteroacenes for organic semiconductors.

An unprecedented catalytic system composed of the Wilkinson catalyst [Rh(PPh3)3Cl] and CF3COOH enabled the highly regioselective cross-coupling of aromatic amines with a variety of heteroarenes through dual C-H bond cleavage. This protocol provided a facile and rapid route from readily available substrates to (2-aminophenyl)heteroaryl compounds, which may be conveniently transformed into highly extended π-conjugated heteroacenes. The experimental studies and calculations showed that thianaphtheno[3,2-b]indoles have large HOMO-LUMO energy gaps and low-lying HOMO levels, and could therefore potentially be high-performance organic semiconductors. Herein we report the first use of a rhodium(I) catalyst for oxidative C-H/C-H coupling reactions. The current innovative catalyst system is much less expensive than [RhCp*Cl2]2/AgSbF6 and could open the door for the application of this approach to other types of C-H activation processes.

Near-Infrared Chemiluminescence Imaging of Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) has a high prevalence but is poorly managed for cancer patients due to the lack of reliable and sensitive diagnostic techniques. Molecular optical imaging can provide a noninvasive way for real-time monitoring of CIPN; However, this is not reported, likely due to the absence of optical probes capable of imaging deep into the spinal canal and possessing sufficient sensitivity for minimal dosage through local injection into the dorsal root ganglia. Herein, a near-infrared (NIR) chemiluminophore (MPBD) with a chemiluminescence quantum yield higher than other reported probes is synthesized and a NIR activatable chemiluminescent probe (CalCL) is developed for in vivo imaging of CIPN. CalCL is constructed by caging MPBD with calpain-cleavable peptide moiety while conjugating polyethylene glycol chain to endow water solubility. Due to the deep-tissue penetration of chemiluminescence and specific turn-on response of CalCL toward calpain (a hallmark of CIPN), it allows for sensitive detection of paclitaxel-mediated CIPN in living mice, which is unattainable by fluorescence imaging. This study thus not only develops a highly efficient chemiluminescent probe, but also presents the first optical imaging approach toward high-throughput screening of neurotoxic drugs.