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Cytotoxic T lymphocytes (CTLs) are important immune cells, and their activation is a key step for cancer immunotherapy. Precise evaluation of CTL activity

Hydrogen sulfide (H

Emissive excimers, which are formed by planar polycyclic aromatic fluorophores (e.g., coumarin), enable high contrast tumor imaging. However, it is still challenging to "turn on" excimer fluorescence in physiological dilute solutions. The biocompatible CBT-Cys click condensation reaction enables both intra- and intermolecular aggregations of the as-loaded fluorophores on the probe molecules, which may promote the generation of emissive excimers in a synergistic manner. As a proof-of-concept, we herein design a fluorescence probe Cbz-Gly-Pro-Cys(StBu)-Lys(coumarin)-CBT (

Metastasis-induced high mortality of cancers urgently demands new approaches to simultaneously inhibit primary tumor metastasis and distant tumor growth. Herein, by rational design of a trident molecule Nap-Phe-Phe-Lys(SA-CPT)-Lys(SA-HCQ)-Tyr(H

This study was undertaken to report the swift, facile and convenient synthesis of novel hydrazones obtained by condensation reaction between 2-Amino-3-formylchromone and hydrazine derivatives. Various characterization techniques such as MALDI Mass, FTIR, 1HNMR and 13CNMR spectrum analysis was done to determine the chemical structure of these novel six hydrazones. Furthermore, UV-Vis and fluorescence spectra was studied to calculate λmax and εmax. These hydrazones are quite useful for their facile synthesis and chemical structure. Such hydrazones require separate clinical research to find their applications in biomedical fields.

The deep penetration, real-time monitoring ability, and high resolution of near-infrared (NIR) fluorescence imaging make it suitable for tumor diagnosis. However, the lack of specificity and selectivity restricts its further application. Here, for the first time, we applied a CBT-Cys click condensation reaction to synthesize an acidity-initiated molecular probe (AIM-Probe, Cys(StBu)-Lys(Cy 5.5)-EDA-PMA-CBT), which could self-assemble into nanoparticles (AIM-NP) with self-quenched fluorescence under glutathione (GSH) reduction. AIM-NP could accumulate in tumors after intravenous injection. Subsequently, the EDA-PMA part of AIM-Probe in AIM-NP is fractured by the unique subacid condition in the tumor microenvironment, and AIM-NP disassembles into a small AIM-cleaved molecule (PMA-CBT-Cys-Lys(Cy5.5)-EDA) along with fluorescence switching on. As a result, AIM-NP could switch on fluorescence at the tumor site, thereby achieving tumor-targeted imaging. To our knowledge, utilizing tumor acidity to initiate the disassembly of self-assembled nanoparticles through a CBT-Cys click condensation reaction has not been reported.

Urokinase-type plasminogen activator (uPA) is a cell-secreted serine protease and plays a significant role in numerous biological processes. Overexpression of uPA has been proved to be relevant to some malignant tumors as well as poor prognosis. However, bioluminescence (BL) probes for selectively sensing uPA activity have not been reported up to now. Herein, we designed a BL probe, GGR-AmLuc, to detect uPA in vitro and sense uPA both inside cells and in tumors. In vitro studies demonstrated that GGR-AmLuc was able to selectively detect uPA with a limit of detection (LOD) of 1.37 μg/L. Moreover, GGR-AmLuc was successfully applied to image uPA in living subjects with excellent sensitivity. We anticipate that probe GGR-AmLuc could be applied for highly sensitive diagnosis of cancers overexpressing uPA and provide guidance for cancer treatment in the near future.

Chemotherapy has remained an effective and predominant cancer treatment for the past decades, but is hampered by its low response rate and severe systemic toxicity. Combination chemotherapies are proposed to address these issues, yet their therapeutic outcomes are still far from satisfactory. Thus, it is urgent to develop novel strategies to promote tumor chemosensitivity while reducing toxic side effects of chemotherapeutics. Herein, employing a rationally designed peptide conjugate Nap-Phe-Phe-Lys(SA-AZD8055)-Tyr(H

Cancer cells frequently exhibit resistance to various molecular and nanoscale drugs, which inevitably affects the drugs' therapeutic outcomes. Overexpression of glutathione (GSH) has been observed in many cancer cells, and solid evidence has corroborated the resulting tumor resistance to a variety of anticancer therapies, suggesting that this biochemical characteristic of cancer cells can be developed as a potential target for cancer treatments. The single treatment of GSH-depleting agents can potentiate the responses of the cancer cells to different cell death stimuli; therefore, as an adjunctive strategy, GSH depletion is usually combined with mainstream cancer therapies for enhancing the therapeutic outcomes. Propelled by the rapid development of nanotechnology, GSH-depleting agents can be readily constructed into anticancer nanomedicines, which have shown a steep rise over the past decade. Here, we review the common GSH-depleting nanomedicines which have been widely applied in synergistic cancer treatments in recent years. Some current challenges and future perspectives for GSH depletion-based cancer therapies are also presented. With the understanding of the structure-property relationship and action mechanisms of these biomaterials, we hope that the GSH-depleting nanotechnology will be further developed to realize more effective disease treatments and even achieve successful clinical translations.

The quantum yield (Q) of the "cold light" of firefly bioluminescence (BL) is remarkably high due to its nonradiative decay is extremely minimized. Thus, an artificial firefly represents the new generation of biomimetic "cold light" source with highest energy utilization. However, to manufacture a firefly-biomimetic "cold light" in vitro, one has to overcome several challenges including realization of the firefly BL cycle by incorporating the two important enzymes (i.e., firefly luciferase (Fluc) and luciferin-regenerating enzyme (LRE)) in one system. Here in this work, using self-prepared Fluc, LRE, and the main substrates, we realized the firefly BL cycle both in vitro and in cells. Moreover, using combinational analyses of HPLC and nESI-CID-MS/MS, we identified the main chemicals in the metabolic pathways underlying the firefly BL cycle. Using theoretical simulations, we revealed an optimum chemical route which balances the reaction cycle to achieve the highest BL intensity with the least chemical supplies. We anticipate that this pioneering study of the firefly cycle would provide industry with the opportunity to design tunable, economical, biomimetic "cold light" device in near future.

Salt-inducible kinase 2 (SIK2) is a promising target for ovarian cancer therapy due to its critical role in tumorigenesis and progression. Currently available SIK2 inhibitors have shown remarkable therapeutic effects on ovarian cancers in preclinical studies. However, direct administration of the SIK2 inhibitors may bring significant off-target effect, limiting their clinical applications. In this work, by rational design of a hydrogelator Nap-Phe-Phe-Glu-Glu-Leu-Tyr-Arg-Thr-Gln-Ser-Ser-Ser-Asn-Leu-OH (Nap-S) to coassemble a SIK2 inhibitor HG-9-91-01 (HG), a SIK2-responsive supramolecular hydrogel (Gel Nap-S+HG) for local administration and SIK2-responsive release of HG is reported to efficiently suppress ovarian cancer metastasis. Under the activation of SIK2 overexpressed in ovarian cancers, Nap-S in the hydrogel is phosphorylated to yield hydrophilic Nap-Phe-Phe-Glu-Glu-Leu-Tyr-Arg-Thr-Gln-Ser(H

Polymeric carbon nitrides (CN), due to their unique physicochemical properties, versatile surface functionalization, ultra-high surface area, and good biocompatibility, have attracted considerable interest in diverse biomedical applications, such as biosensors, drug delivery, bioimaging, and theranostics. In this review, the recent advances in bioimaging of CN-based nanomaterials are summarized according to the imaging modalities, including optical (fluorescence and Raman) imaging, magnetic resonance imaging (MRI), photoacoustic imaging (PAI), computed tomography (CT), and multimodal imaging. The pros and cons of CN bioimaging are comprehensively analyzed and compared with those in previous reports. In the end, the prospects and challenges of their future bioimaging applications are outlooked.

To track an intact biological process inside cells, continuous showing of the assembly/disassembly process is needed and fluorescence is advantageous in characterizing these processes. However, using fluorescence "on/off" to observe a sequential assembly/disassembly process in living cells has not been reported. Herein, we rationally designed a probe PEA-NBD-Yp and employed its fluorescence "on/off" to trace tandem assembly/disassembly of nanofibers in living HeLa cells. In vitro experiments validated that PEA-NBD-Yp could be efficiently dephosphorylated by ALP to yield PEA-NBD-Y, which self-assembled into nanofibers with the NBD fluorescence "on". Also, the PEA-NBD-Y nanofiber was disassembled by GSH, accompanied by fluorescence "off". Living cell imaging (together with ALP-inhibition or GSH-blocking) experiments sequentially showed the self-assembling nanofibers on the cell outer membrane with fluorescence "on" (On1), translocated inside cells (On2), and disassembled by GSH with fluorescence "off" (Off2). We anticipate that our strategy of one probe conferring temporal "on/off" fluorescence signals might provide people with a new tool to deeply understand a biological event in living cells in the near future.

Pathological stimuli-responsive self-assembly of peptide nanofibers enables selective accumulation of imaging agent cargos in the stimuli-rich regions of interest. It provides enhanced imaging signals, biocompatibility, and tumor/disease accessibility and retention, thereby promoting smart, precise, and sensitive tumor/disease imaging both in vitro and in vivo. Considering the remarkable significance and recent encouraging breakthroughs of self-assembled peptide nanofibers in tumor/disease diagnosis, this reivew is herein proposed. We emphasize the recent advances particularly in the past three years, and provide an outlook in this field.

Owing to their superior loading capacity and biocompatibility, imaging agent-conjugated (or encapsulated) peptide-based supramolecular hydrogels are capable of imaging in vivo biological events with enhanced signals. Notably, by rational design of the hydrogelators, the hydrogelation process can "smartly" occur on the pathological site (or region of interest), rendering precise and sensitive bioimaging of the disease (or event) in vivo. Considering their importance in disease diagnosis, herein, we provide a review on the recent advances in peptide-based supramolecular hydrogels for bioimaging applications. Besides, we provide an outlook on the challenges (or chances) for these types of biomaterials in the field of bioimaging.

Alkaline phosphatase (ALP) and γ-glutamyltranspeptidase (GGT) are regarded as two important biomarkers in several human cancers. There are many probes for ALP or GGT detection but no probe was reported to sense the activity of both ALP and GGT

MicroRNAs, as one kind of significant biomarkers, play indispensable roles in the diagnosis and treatment of cancers. Yet, owing to low expression and high sequence homology, high sensitivity and specificity for microRNA detection are greatly challenging. Herein, a sensitive sensing platform with high specificity was developed for microRNA-27a (miRNA-27a) based on the miRNA-27a-triggered chemical etching of gold nanorods to a smaller size, which was accompanied by a significant blue shift and a large decrease of intensity in the localized surface plasmon resonance (LSPR) scattering and remarkable color variability from red to green. When combined with strand displacement reactions as well as liposome signal amplification and transduction, the proposed bioassay presented high selectivity toward miRNA-27a in a dynamic range from 100 fM to 3 pM and a low limit of detection of 16.5 fM (3σ/

Today, tumor therapy and its therapeutic efficiency evaluation are conducted separately, and current imaging techniques cannot evaluate tumor-therapeutic effects in real time. Therefore, it is of great importance to develop highly efficient theranostic strategies which are able to evaluate their tumor-therapeutic effects in real time. In this work, by rational design of a small molecular near-infrared probe Cys(StBu)-Asp-Glu-Val-Asp-Lys(Cypate)-CBT (Cy-CBT) and using a CBT-Cys click condensation reaction, we facilely prepare an intelligent nanoparticle Cy-CBT-NP which is able to evaluate its photothermal therapy (PTT) efficiency on tumors by fluorescence "Turn-On". Fluorescence of Cy-CBT-NP is quenched and photothermal responsive. Upon caspase 3 (Casp3) cleavage of its DEVD substrates, Cy-CBT-NP disassembles to turn the fluorescence "On", which in turn evaluates the PTT efficiency of the nanoparticle on cells and tumors in real time. We envision that our smart strategy could be applied for PTT and real-time evaluation of the therapeutic efficiency of solid tumors in the near future.

Developing suitable molecular tools for monitoring SO2 and its derivatives in living organisms is attractive due to their importance for human health. Herein, the first near-infrared fluorescent probe Mito-HN with aggregation-induced emission enhancement (AIEE) characteristics for ratiometric sensing of SO2 derivatives in vitro, in cells, and in zebrafish was designed and synthesized. By connecting the electron-donating naphthopyran and electron-withdrawing hemicyanine via the alkenyl group, this probe displays a near-infrared fluorescence emission and notable solid-state luminescence with AIEE features. Based on the specific 1,4-addition reaction of HSO3−/SO32− with the CC double bond of Mito-HN, this probe can specifically sense HSO3− in real time with an excellent near-infrared ratiometric fluorescence effect, a low detection limit of 0.17 μM, and a fast response time of less than 30 s. Cell imaging and zebrafish imaging results demonstrate that Mito-HN can ratiometrically not only sense endogenous SO2 derivatives in mitochondria but also monitor SO2 in living organisms. We anticipate that Mito-HN could be applied for the diagnosis of SO2-related diseases in the future.

The aggregation of superparamagnetic iron oxide (SPIO) nanoparticles (NPs) can greatly enhance magnetic resonance imaging (MRI) T2-weighted imaging and near-infrared (NIR) absorption in experiments. In this study, an Ac-Arg-Val-Arg-Arg-Cys(StBu)-Lys-CBT probe was designed and coupled with monodispersed carboxyl-decorated SPIO NPs to form SPIO@1NPs, which use it for intracellular self-aggregation. In vitro experiments showed that the self-aggregation of SPIO@1NPs was induced by a condensation reaction mediated by the enzyme furin in furin-overexpressing tumor cells. Moreover, the NPs in the aggregated state showed significantly higher MR r2 values and photothermal conversion efficiency than the NPs in the monodisperse state. Then, the in vivo SPIO@1NP self-aggregation in tumors can facilitate accurate MRI T2 imaging-guided photothermal therapy for effectively killing cancer cells. We believe that this basic technique, based on tumor-specific enzyme-instructed intracellular self-aggregation of NPs, could be useful for the rational synthesis of other inorganic NPs for use in the fields of tumor diagnosis and treatment.

Multifunctional nanomaterials with targeted imaging and chemotherapy have high demand with great challenge. Herein, we rationally aimed to design multifunctional drug delivery systems by RGD-modified chitosan (CH)-coated nanoneedles (NDs) of gadolinium arsenate (RGD-CH-Gd-AsNDs). These NDs have multifunctionality for imaging and targeted therapy. NDs on intravenous administration demonstrated significant accumulation of As ions/species in tumor tissues, which was monitored by the change in T1-weighted magnetic resonance (MR) imaging. Moreover, NDs were well opsonized in cells with high specificity, subsequently inducing apoptosis to the HepG2 cells. Consequent to this, the in vivo results demonstrated biosafety, enhanced tumor targeting, and tumor regression in a subcutaneously transplanted xenograft model in nude mice. These RGD-CH-Gd-AsNDs have great potential, and we anticipate that they could serve as a novel platform for real-time T1-weighted MR diagnosis and chemotherapy.

Cathepsin B (CTSB) is a lysosomal protease, and several human cancers are reported highly expressing CTSB. Many optical methods have been developed for CTSB detection but not a bioluminescence (BL) probe. Herein, a CTSB-specific bioluminescence probe Val-Cit-AL was rationally designed for selectively sensing CTSB activity in vitro with a 67-fold "Turn-On" of BL intensity and an excellent limit of detection. Inhibitory experiments indicated that Val-Cit-AL is capable of sensing CTSB activity in living cells and tumors. We anticipate that Val-Cit-AL might be applied to diagnose CTSB-related diseases in rodent models or evaluate CTSB roles in more biological processes in the near future.

Positron-emission tomography (PET) is routinely used in the clinic for tumor imaging with ultrahigh sensitivity, but tumor-targeted PET imaging probes are quite few. In this work, we rationally designed a furin-responsive radiotracer Acetyl-Arg-Val-Arg-Arg-Cys(StBu)-Lys(DOTA-68Ga)-CBT (CBT-68Ga) and demonstrated that coinjection of the radiotracer with its cold analogue CBT-Ga instructed the formation of 68Ga nanoparticles in furin-overexpressing MDA-MB-468 cancer cells, which significantly enhanced microPET imaging of the tumor in vivo. In vitro results showed that CBT-Ga subjected to furin-initiated CBT-Cys condensation reaction and self-assembly to form the nanoparticles CBT-Ga-NPs with an average diameter of 258.3 nm. In vivo microPET imaging results indicate that the mice coinjected with CBT-68Ga and CBT-Ga, which warrants 68Ga nanoparticle formation in their MDA-MB-468 tumors, had a tumor/liver ratio 9.1-fold of that of the mice only injected with CBT-68Ga. We envisioned that, by replacing the RVRR substrate of CBT-68Ga with other enzyme-specific ones and using the strategy of intracellular nanoparticle formation, a series of radioactive probes could be developed for more sensitive and precise tumor microPET imaging in the near future.

Background: Nowadays, magnetic resonance imaging (MRI) is routinely applied in clinical diagnosis. However, using one contrast agent (CA) to simultaneously enhance the T1 and T2 MR contrast at low and high magnetic fields respectively has not been reported. Methods: Herein, we investigated the MR property of a γ-glutamyl transpeptidase (GGT)-instructed, intracellular formed gadolinium nanoparticle (DOTA-Gd-CBT-NP) at low and high magnetic fields. Results: Experimental results showed that DOTA-Gd-CBT-NP possesses a low r2/r1 ratio 0.91 which enables it to enhance T1 MR imaging of liver tumor at 1.0 T, and a high r2/r1 ratio 11.8 which renders the nanoparticle to largely enhance T2 MR imaging of liver tumor at 9.4 T. Conclusion: We expect that our GGT-responsive Gd-nanoparticle could be applied for simultaneous T1 and T2 MRI diagnosis of early liver cancer in clinic at respective low and high magnetic fields when the 9.4 T MR machine is clinically available in the future.