Chemistry-Enabled Intercellular Enzymatic Labeling for Monitoring the Immune Effects of Cytotoxic T Lymphocytes In Vivo.

Monitoring the effector function of cytotoxic T lymphocytes (CTLs) in vivo remains a great challenge. Here, we develop a chemistry-enabled enzymatic labeling approach to evaluate the tumor-specific immune response of CTLs by precisely monitoring the interaction between CTLs and tumor cells. Staphylococcus aureus sortase A (SrtA) is linked to the CTL surface through bioconjugate chemistry and then catalyzes the transfer of fluorescent-labeled substrate, 5-Tamra-LPETG, to CTLs. Meanwhile, the tumor cells are specifically decorated with N-terminal glycine residues (G5 peptide) through the inherent glycolmetabolism of cathepsin B-specific cleavable triacetylated N-azidoacetyl-d-mannosamine (CB-Ac3ManNAz) and click chemistry. After the infiltration of engineered CTLs into the tumor tissues, the immune-synapse-mediated specific interaction of CTLs and tumor cells leads to the accurate fluorescent labeling of tumor cells through the SrtA-catalyzed 5-Tamra-LPETG transfer. Therefore, the immune effect of CTLs as well as the performance of immune drugs can be determined, providing a novel strategy for pushing ahead immunotherapy.

Two Key Descriptors for Designing Second Near-Infrared Dyes and Experimental Validation.

Second near-infrared (NIR-II) optical imaging technology has emerged as a powerful tool for diagnostic and image-guided surgery due to its higher imaging contrast. However, a general strategy for efficiently designing NIR-II organic molecules is still lacking, because NIR-II dyes are usually difficult to synthesize, which has impeded the rapid development of NIR-II bioprobes. Herein, based on the theoretical calculations on 62 multiaryl-pyrrole (MAP) systems with spectra ranging from the visible to the NIR-II region, a continuous red shift of the spectra toward the NIR-II region could be achieved by adjusting the type and site of substituents on the MAPs. Two descriptors (ΔEgs and µgs) were identified as exhibiting strong correlations with the maximum absorption/emission wavelengths, and the descriptors could be used to predict the emission spectrum in the NIR-II region only if ΔEgs ≤ 2.5 eV and µgs ≤ 22.55 D. The experimental absorption and emission spectra of ten MAPs fully confirmed the theoretical predictions, and biological imaging in vivo of newly designed MAP23-BBT showed high spatial resolution in the NIR-II region in deep tissue angiography. More importantly, both descriptors of ΔEgs and µgs have shown general applicability to most of the reported donor-acceptor-donor-type non-MAP NIR-II dyes. These results have broad implications for the efficient design of NIR-II dyes.

Hispidulin targets PTGS2 to improve cyclophosphamide-induced cystitis by suppressing NLRP3 inflammasome.

Interstitial cystitis (IC) is a chronic bladder inflammation. Inhibition of prostaglandin G/H synthase 2 (PTGS2) is the most common method for controlling inflammation-related diseases. This study aimed to analyze the effects of hispidulin on the PTGS2 and NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammation in experimental IC models. A binding activity between hispidulin and PTGS2 was measured using molecular docking. Human urothelial cells (SV-HUC-1) were stimulated by 2 ng/mL of interleukin (IL)-1ß for 24 h and cultured in a medium with different concentrations of hispidulin (2.5, 5, 10, 20 µM) for 24 h to observe the expressions of PTGS2 and NLRP3 protein. Cells overexpressing PTGS2 were established by PTGS2 cDNA transfection. In the IL-1ß-treated cells, the NLRP3 inflammasome was measured after 20 µM hispidulin treatment. In rats, animals were performed with three injections of 40 mg/kg cyclophosphamide (CYP) and orally treated with 50 mg/kg/day hispidulin or ibuprofen for 3 days. The bladder pain was measured using Von Frey filaments, and the bladder pathology was observed using hematoxylin and eosin (H&E) staining. The expressions of PTGS2 and NLRP3 inflammasome were also observed in the bladder tissues. A good binding activity was found between hispidulin and PTGS2 (score = - 8.9 kcal/mol). The levels of PTGS2 and NLRP3 inflammasome were decreased with the hispidulin dose increase in the IL-1ß-treated cells (p < 0.05). Cells overexpressing PTGS2 weakened the protective effects of hispidulin in the IL-1ß-treated cells (p < 0.01). In the CYP-treated rats, hispidulin treatment improved the bladder pain through decreasing the nociceptive score (p < 0.01) and suppressed the bladder inflammation through suppressing the expressions of PTGS2 and NLRP3 inflammasome in bladder tissues (p < 0.01). Additionally, the results of ibuprofen treatment were similar to the effects of hispidulin in the CYP-treated rats. This study demonstrates that hispidulin may be a new alternative drug for the IC treatment that binds PTGS2 to perform its functions.

Fused-Ring Pyrrole-Based Near-Infrared Emissive Organic RTP Material for Persistent Afterglow Bioimaging.

Organic near-infrared room temperature phosphorescence (RTP) materials offer remarkable advantages in bioimaging due to their characteristic time scales and background noise elimination. However, developing near-infrared RTP materials for deep tissue imaging still faces challenges since the small band gap may increase the non-radiative decay, resulting in weak emission and short phosphorescence lifetime. In this study, fused-ring pyrrole-based structures were employed as the guest molecules for the construction of long wavelength emissive RTP materials. Compared to the decrease of the singlet energy level, the triplet energy level showed a more effectively decrease with the increase of the conjugation of the substituent groups. Moreover, the sufficient conjugation of fused ring structures in the guest molecule suppresses the non-radiative decay of triplet excitons. Therefore, a near-infrared RTP material (764 nm) was achieved for deep penetration bioimaging. Tumor cell membrane is used to coat RTP nanoparticles (NPs) to avoid decreasing the RTP performance compared to traditional coating by amphiphilic surfactants. RTP NPs with tumor-targeting properties show favorable phosphorescent properties, superior stability, and excellent biocompatibility. These NPs are applied for time-resolved luminescence imaging to eliminate background interference with excellent tissue penetration. This study provides a practical solution to prepare long-wavelength and long-lifetime organic RTP materials and their applications in bioimaging.

Monitoring the Cascade of Tumor-specific Immune Response in vivo via Chemoenzymatic Proximity Labeling.

Monitoring the highly dynamic and complex immune response remains a great challenge owing to the lack of reliable and specific approaches. Here, we develop a strategy to monitor the cascade of tumor immune response through the cooperation of pore-forming alginate gel with chemoenzymatic proximity-labeling. A macroporous gel containing tumor-associated antigens, adjuvants, and pro-inflammatory cytokines is utilized to recruit endogenous DCs and enhance their maturation in vivo. The mature DCs are then modified with GDP-fucose-fucosyltransferase (GDP-Fuc-Fuct) via the self-catalysis of fucosyltransferase (Fuct). Following the migration of the obtained Fuct-DCs to the draining lymph nodes (dLNs), the molecular recognition mediated interaction of DCs and T cells leads to the successful decoration of T cells with GDP-Fuc-azide through the Fuct catalyzed proximity-labeling. Therefore, the activated tumor-specific T cells in dLNs and tumors can be identified through bioorthogonal labeling, opening up a new avenue for studying the immune mechanism of tumors in situ.

Safety, Efficacy, and Biomarker Analyses of Dostarlimab in Patients with Endometrial Cancer: Interim Results of the Phase I GARNET Study.

PURPOSE: This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an analysis of tumor biomarkers as prognostic indicators. PATIENTS AND METHODS: A total of 153 patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) and 161 patients with mismatch repair proficient (MMRp)/microsatellite stable (MSS) EC were enrolled and dosed. Patients received 500 mg dostarlimab every 3 weeks for four cycles, then 1,000 mg every 6 weeks until progression. Primary endpoints were objective response rate (ORR) and duration of response (DOR). RESULTS: A total of 143 patients with dMMR/MSI-H EC and 156 patients with MMRp/MSS EC were evaluated for efficacy. ORR was 45.5% (n = 65) and 15.4% (n = 24) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. Median DOR for dMMR/MSI-H EC was not met (median follow-up, 27.6 months); median DOR for MMRp/MSS EC was 19.4 months. The ORRs by combined positive score (CPS) ≥1 status were 54.9% and 21.7% for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORRs by high tumor mutational burden (≥10 mutations/Mb) were 47.8% (43/90) and 45.5% (5/11) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORR in TP53mut or POLεmut molecular subgroups was 18.1% (17/94) and 40.0% (2/5), respectively. The safety profile of dostarlimab was consistent with previous reports. CONCLUSIONS: Dostarlimab demonstrated durable antitumor activity and safety in patients with dMMR/MSI-H EC. Biomarkers associated with EC may identify patients likely to respond to dostarlimab. See related commentary by Jangra and Dhani, p. 4521.

A plain language summary of results from the GARNET study of dostarlimab in patients with endometrial cancer.

WHAT IS THIS SUMMARY ABOUT?: Dostarlimab, also known by the brand name JEMPERLI, is a medicine that can be used to treat certain types of endometrial cancer. GARNET is an ongoing phase 1 clinical study that is testing the safety and side effects of dostarlimab and the best way to administer it to patients. The results presented in this summary are from a time point in the middle of the study. WHAT WERE THE RESULTS?: The results from the GARNET study published in 2022 showed how well dostarlimab worked for people participating in the study. Dostarlimab was found to reduce the size of tumors in patients with certain types of endometrial cancer. The patients treated with dostarlimab had side effects that could be managed and few severe side effects. WHAT DO THE RESULTS MEAN?: The results of the GARNET study led to dostarlimab being approved to treat patients with certain types of endometrial cancer. For patients with advanced-stage endometrial cancer, or endometrial cancer that has come back after chemotherapy (recurrent), there are few treatment options. The results suggest that dostarlimab may provide long-term benefits for these patients.

Enhanced Proliferation of Visualizable Mesenchymal Stem Cell-Platelet Hybrid Cell for Versatile Intracerebral Hemorrhage Treatment.

The intrinsic features and functions of platelets and mesenchymal stem cells (MSCs) indicate their great potential in the treatment of intracerebral hemorrhage (ICH). However, neither of them can completely overcome ICH because of the stealth process and the complex pathology of ICH. Here, we fabricate hybrid cells for versatile and highly efficient ICH therapy by fusing MSCs with platelets and loading with lysophosphatidic acid-modified PbS quantum dots (LPA-QDs). The obtained LPA-QDs@FCs (FCs = fusion cells) not only inherit the capabilities of both platelets and MSCs but also exhibit clearly enhanced proliferation activated by LPA. After systemic administration, many proliferating LPA-QDs@FCs rapidly accumulate in ICH areas for responding to the vascular damage and inflammation and then efficiently prevent both the primary and secondary injuries of ICH but with no obvious side effects. Moreover, the treatment process can be tracked by near-infrared II fluorescence imaging with highly spatiotemporal resolution, providing a promising solution for ICH therapy.

Constructing Hypoxia-Tolerant and Host Tumor-Enriched Aggregation-Induced Emission Photosensitizer for Suppressing Malignant Tumors Relapse and Metastasis.

Photodynamic immunotherapy is a promising treatment strategy that destroys primary tumors and inhibits the metastasis and relapse of distant tumors. As reactive oxygen species are an intermediary for triggering immune responses, photosensitizers (PSs) that can actively target and efficiently trigger oxidative stress are urgently required. Herein, pyrrolo[3,2-b]pyrrole as an electronic donor is introduced in acceptor-donor-acceptor skeleton PSs (TP-IS1 and TP-IS2) with aggregation-induced emission properties and high absorptivity. Meanwhile, pyrrolo[3,2-b]pyrrole derivatives innovatively prove their ability of type I photoreaction, indicating their promising hypoxia-tolerant advantages. Moreover, M1 macrophages depicting an ultrafast delivery through the cell-to-cell tunneling nanotube pathway emerge to construct TP-IS1@M1 by coating the photosensitizer TP-IS1. Under low concentration of TP-IS1@M1, an effective immune response of TP-IS1@M1 is demonstrated by releasing damage-associated molecular patterns, maturating dendritic cells, and vanishing the distant tumor. These findings reveal insights into developing hypoxia-tolerant PSs and an efficient delivery method with unprecedented performance against tumor metastasis.

An acceptor-shielding strategy of photosensitizers for enhancing the generation efficiency of type I reactive oxygen species and the related photodynamic immunotherapy.

Developing efficient photosensitizers (PSs) that can generate type I reactive oxygen species (ROS) under illumination is considered an effective way to improve photodynamic therapy (PDT) outcomes due to the hypoxic nature of the tumor environment, but also is very challenging. Herein, a new PS of the multiarylpyrrole (MAP) derivative with a typical donor-acceptor structure was synthesized to efficiently generate type I ROS by using an acceptor-shielding strategy in their aggregated state. The enhanced generation mechanism of type I ROS originated from its ultralong triplet lifetime and the narrow singlet-triplet energy gap of the MAP. More importantly, type I ROS can transform protumoral M2 macrophages (M2) into antitumoral M1 macrophages (M1), which showed synergistic immunotherapy in in vivo experiments. Therefore, introducing shielding groups into acceptors provides general guidance for developing efficient PSs in the aggregation state for clinical PDT.

Long noncoding RNA ZFPM2-AS1 regulates renal cell carcinoma progression via miR-130a-3p/ESCO2.

Previous studies reported that long noncoding RNA (lncRNA) ZFPM2-AS1 is upregulated in renal cell carcinoma (RCC). However, the biological role of lncRNA ZFPM2-AS1 in RCC has not been explored. In this study, we investigated the role of lncRNA ZFPM2-AS1 in the progression of RCC. Quantitative real-time polymerase chain reaction was used for gene expression analysis, and functional assays including Cell Counting Kit-8 assay, flow cytometry-based apoptosis assay and transwell migration assays were performed to examine the malignant phenotypes. The functional interaction between ZFPM2-AS1 or miR-130A-3P and their targets was detected by dual-luciferase reporter assay. We found that the expressions of ZFPM2-AS1 and ESCO2 were upregulated in RCC tissues and cells, whereas miR-130a-3p was downregulated. The expression level of ZFPM2-AS1 is significantly associated with advanced TNM, distant metastasis, lymphatic metastasis, and a poor overall survival in RCC patients. Silencing ZFPM2-AS1 in RCC cells suppressed cell proliferation, invasion, and migration, and induced cell apoptosis. ZFPM2-AS1 interacted with miR-130A-3P and negatively regulated its expression in RCC cells. We further showed that ESCO2 was a downstream target of miR-130a-3p. Both miR-130a-3p inhibitor and ESCO2 overexpression could rescue the inhibitory effects of ZFPM2-AS1 knockdown in RCC cells. Together, our study demonstrates that ZFPM2-AS1 plays an oncogenic role in RCC progression via the miR-130a-3p/ESCO2 axis.

Mitochondrial targeted AIEgen phototheranostics for bypassing immune barrier via encumbering mitochondria functions.

Photodynamic therapy combined with immunogenic cell death has been proposed to overcome the unsolvable problems of single therapy, such as high levels of tumor recurrence and treatment resistance of tumors. Previous works on this theme have mostly concentrated on endoplasmic reticulum (ER)-stressed damage-associated molecular patterns (DAMPs), ignoring the secretion and function of mitochondria-related DAMPs. Herein, our work reports two intersystem crossing photosensitizers based on well-designed multiarylpyrrole structures and draws valuable attention to mitochondria-related DAMP-TFAM (mitochondrial transcription factor) when cancer cells are under forceful oxidative stress. The tumors vanished, and immunogenic experiments were applied to illuminate the advantages of double treatment. Our discovery of new mitochondria-related DAMPs compensates for the lack of ER-stressed DAMPs and offers an innovative target for immunity therapy.

Unprecedented Application of Covalent Organic Frameworks for Polymerization Catalysis: Rh/TPB-DMTP-COF in Polymerization of Phenylacetylene and Its Functional Derivatives.

Covalent organic frameworks (COFs) are applied widely in organic catalysis; however, no precedent has been reported in polymerization catalysis. Herein, we report the new application of COFs for polymerization catalysis. Different amounts of homogeneous Rh catalyst are incorporated into the COF via post-treatment to give a series of TPB-DMTP-COF-X wt % Rh (b-e) containing varying amounts of Rh from 2.74 to 11.38 wt %. In contrast to the known Rh catalysts, TPB-DMTP-COF-X wt % Rh (b-e) display an uncommon synergistic effect and exceptional steric confinement effect of nanochannels. Therefore, they possess the advantages of both homogeneous catalysts in high activity and selectivity and heterogeneous catalysts in stability and recyclability with extremely high activity up to 1.3 × 107 g·molRh-1·h-1 and cis-selectivity up to 99% and can be readily recycled and reused five times in the polymerization of phenylacetylene and its derivatives, affording cis-transoidal polyphenylacetylene and its derivatives having helical structures, aggregation-induced emission properties, or fluorescence properties with narrow molecular weight distributions.

Evinacumab in Patients with Refractory Hypercholesterolemia.

BACKGROUND: Patients with refractory hypercholesterolemia, who have high low-density lipoprotein (LDL) cholesterol levels despite treatment with lipid-lowering therapies at maximum tolerated doses, have an increased risk of atherosclerosis. In such patients, the efficacy and safety of subcutaneous and intravenous evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, are not known. METHODS: In this double-blind, placebo-controlled, phase 2 trial, we enrolled patients with or without heterozygous familial hypercholesterolemia who had refractory hypercholesterolemia, with a screening LDL cholesterol level of 70 mg per deciliter or higher with atherosclerosis or of 100 mg per deciliter or higher without atherosclerosis. Patients were randomly assigned to receive subcutaneous or intravenous evinacumab or placebo. The primary end point was the percent change from baseline in the LDL cholesterol level at week 16 with evinacumab as compared with placebo. RESULTS: In total, 272 patients were randomly assigned to the following groups: subcutaneous evinacumab at a dose of 450 mg weekly (40 patients), 300 mg weekly (43 patients), or 300 mg every 2 weeks (39 patients) or placebo (41 patients); or intravenous evinacumab at a dose of 15 mg per kilogram of body weight every 4 weeks (39 patients) or 5 mg per kilogram every 4 weeks (36 patients) or placebo (34 patients). At week 16, the differences in the least-squares mean change from baseline in the LDL cholesterol level between the groups assigned to receive subcutaneous evinacumab at a dose of 450 mg weekly, 300 mg weekly, and 300 mg every 2 weeks and the placebo group were -56.0, -52.9, and -38.5 percentage points, respectively (P<0.001 for all comparisons). The differences between the groups assigned to receive intravenous evinacumab at a dose of 15 mg per kilogram and 5 mg per kilogram and the placebo group were -50.5 percentage points (P<0.001) and -24.2 percentage points, respectively. The incidence of serious adverse events during the treatment period ranged from 3 to 16% across trial groups. CONCLUSIONS: In patients with refractory hypercholesterolemia, the use of evinacumab significantly reduced the LDL cholesterol level, by more than 50% at the maximum dose. (Funded by Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03175367.).

Functional Isocyanide-Based Polymers.

Research interest in the isocyanide-based reaction can be traced back to 1921 when the Passerini reaction was first reported. However, most of these research efforts did not lead to important progress in the synthesis of isocyanide-based polymers (IBPs). The major challenge resides in the lack of highly efficient polymerization methods, which limits large-scale preparation and applications. Modern organic chemistry provides efficient access to develop functional IBPs on the basis of isocyanide chemistry. However, it is still challenging to prepare the IBPs with small molecular isocyanide reaction. Our investigations into catalyst exploration and polymerization methodology have prompted the synthesis of a series of IBPs. Two classes of isocyanide monomers can be used for the construction of IBPs. The first class includes monomers with a single isocyanide. Novel catalysts for the synthetic chemistry of isocyanide allow the introduction of functional pendants into the linear polymer chains. This molecular functionalization endows the polymers with an array of new functional properties. For example, the incorporation of a chromophore on the polymeric side chain provides novel functional properties, such as aggregation-induced emission and optical activity. Diisocyanide monomers can be also utilized for the construction of heterocyclic, spiro-heterocyclic, and bispiro-heterocyclic polymers in the polymeric backbones. A new concept of "multi-component spiropolymerization" has been developed for the preparation of spiropolymers using the catalysis-free one-pot reaction. Proper structural design allows for the preparation of a heterocyclic polymeric chain with natural bioactivity and biological compatibility, generating new IBPs with biofunctionalities.In this Account, we discuss progress mainly made in our lab and related fields for the design of isocyanide monomers, exploration of new catalysts, and optimization of reaction conditions. The subsequent section discusses the characteristic properties and applications of selected examples of these functional polymers, mainly focusing on their optical applications. We have investigated the UV-sensitive IBPs that could potentially be used for lithography applications. One-pot highly efficient polymerization of diisocyanides and CO2 under mild conditions can provide a new method for realizing the reuse of CO2 and reducing the greenhouse effect. Through a combination of structural modifications, IBPs bearing dimethylbenzene moieties exhibit characteristics of black materials that can be potentially utilized as pyroelectric sensors, thermal detectors, and optical instruments. Most recently, our group synthesized a spiro-heterocyclic IBP with clusterization-triggered emission properties that can be used to discriminate cancer cells from normal cells and provides a new method for the treatment of cancer. The studies reviewed in this Account suggest that polymerization with isocyanide chemistry can be implemented in diverse functional macromolecules and materials.

Efficacy and Safety of Alirocumab in Adults With Homozygous Familial Hypercholesterolemia: The ODYSSEY HoFH Trial.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is characterized by extremely elevated low-density lipoprotein-cholesterol (LDL-C) levels and early onset atherosclerotic cardiovascular disease despite treatment with conventional lipid-lowering treatment. OBJECTIVES: This study was designed to assess LDL-C reduction with the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in adult patients with HoFH. METHODS: This randomized, double-blind, placebo-controlled, parallel-group, phase 3 study evaluated efficacy and safety of alirocumab 150 mg every 2 weeks. The primary endpoint was percent reduction from baseline in LDL-C versus placebo after 12 weeks of treatment. RESULTS: Patients (N = 69) were randomized 2:1 to alirocumab or placebo. At baseline, background lipid-lowering treatment included 67 patients receiving statin (59 patients on high-intensity statin); 50 patients on ezetimibe; 10 patients on lomitapide; and 10 patients undergoing apheresis. Mean baseline LDL-C was 259.6 mg/dl in the placebo group and 295.0 mg/dl in the alirocumab group. At week 12, the least squares mean difference in LDL-C percent change from baseline was -35.6% (alirocumab [-26.9%] vs. placebo [8.6%]; p < 0.0001). Reductions (least squares mean difference) in other atherogenic lipids at week 12 were: apolipoprotein B, -29.8%; non-high-density lipoprotein cholesterol, -32.9%; total cholesterol, -26.5%; and lipoprotein(a), -28.4% (all p < 0.0001). No serious adverse events, permanent treatment discontinuations, or deaths due to treatment-emergent adverse events were reported during the double-blind treatment period. CONCLUSIONS: In the largest randomized controlled interventional trial in HoFH patients to date, alirocumab resulted in significant and clinically meaningful reductions in LDL-C at week 12. Alirocumab was generally well tolerated, with a safety profile comparable to that of placebo. (Study in Participants With Homozygous Familial Hypercholesterolemia [HoFH] [ODYSSEY HoFH] NCT03156621.).

MDM2-Associated Clusterization-Triggered Emission and Apoptosis Induction Effectuated by a Theranostic Spiropolymer.

Heteroatom-containing spiropolymers were constructed in a facile manner by a catalyst-free multicomponent spiropolymerization route. P1a2b as the most potent of these spiropolymers, demonstrates cluster-triggered emission resulting from strong interactions with the MDM2 protein. By preventing the anti-apoptotic p53/MDM2 interaction, P1a2b triggers apoptosis in cancerous cells, while demonstrating a good biocompatibility and non-toxicity in non-cancerous cells. The combined results from solution and cell-based cluster-triggered emission studies, docking, protein expression experiments and cytotoxicity data strongly support the MDM2-binding hypothesis and indicate a potential application as a fluorescent cancer marker as well as therapeutic for this spiropolymer.

A Freezing-Induced Turn-On Imaging Modality for Real-Time Monitoring of Cancer Cells in Cryosurgery.

Cryosurgery has attracted much attention for the treatment of tumors owing to its clear advantages. However, determining the volume of frozen tissues in real-time remains a challenge, which greatly lowers the therapeutic efficacy of cryosurgery and hinders its broad application for the treatment of cancers. Herein, we report a freezing-induced turn-on strategy for the selective real-time imaging of frozen cancer cells. As a type of aggregation-induced emission (AIE) fluorogen, TABD-Py molecules interact specifically with ice crystals and form aggregates at the ice/water interface. Consequently, bright fluorescent emission appears upon freezing. TABD-Py molecules are enriched mostly in the cancer cells and exhibit high biocompatibility as well as low cytotoxicity; therefore, a freezing-induced turn-on imaging modality for cryosurgery is developed, which will certainly maximize the therapeutic efficacy of cryosurgery in treating tumors.

Triphenylquinoline (TPQ)-Based Dual-State Emissive Probe for Cell Imaging in Multicellular Tumor Spheroids.

Insufficient intratumoral penetration and limited stroma distribution of the imaging probes or theranostics can lead to a poor-quality diagnosis or therapeutic resistance. Multicellular tumor spheroids can recapitulate the physiological environment of tumor tissues with the extracellular matrix and is thus a better in vitro tumor model to evaluate the imaging performance and barrier penetration capability of advanced cancer imaging probes. In this Article, we designed and synthesized a series of quinoline-based fluorophores with strong emissions in both solution and solid states. The quinoline core can be constructed via a one-pot iron-catalysis reaction. Optical properties and single crystal structures of these quinoline derivatives were tuned by varying the substitutes at the 6-position of the quinoline core. The twisted intramolecular charge transfer effect can enhance the fluorescent efficiency, resulting in the high quantum yield of TPQ-TPA in both solution (70%) and solid (48%) states (TPQ, triphenylquinoline; TPA, triphenylamine). In addition, TPQ-TPA exhibited a good biocompatibility and can deeply penetrate into 3D tumor spheroids within 12 h. The results indicated that quinoline can be a new fluorescent scaffold, and the employment of quinoline-based probes will provide a new platform for biological applications.

Application of a Novel "Turn-on" Fluorescent Material to the Detection of Aluminum Ion in Blood Serum.

A novel "turn-on" fluorescent bioprobe, 1,2,3,4,5-penta(4-carboxyphenyl)pyrrole sodium salt (PPPNa), with aggregation-enhanced emission characteristics was synthesized for the in situ quantitative detection of Al3+ in serum. It exhibited a high selectivity to Al3+ in both simulated serum and fetal calf serum with no interferences from other metal ions or serum components observed and no isolation required. A weak interaction between PPPNa and serum albumin was found, which caused no interference, but enhanced fluorescence response of PPPNa to Al3+ and improved detection sensitivity. The limit of detection was determined to be 1.50 µmol/L Al3+ in phosphate-buffered saline solution containing 33 µg/mL bovine serum albumin (BSA) and decreased to 0.98 µmol/L as BSA concentration increased to 100 µg/mL. The fluorescence "turn-on" mechanism of the PPPNa probe to detect Al3+ was proposed. A bidentate complex is formed between the carboxy group of PPPNa and Al3+, causing the photoluminescence (PL) emission enhancement by aggregation. BSA chains further strengthen the stacking compactness of the aggregates of PPPNa and Al3+ and consequently enhance the PL emission of PPPNa by further promoting the restriction of intramolecular rotation of the phenyl ring. Its application to the in situ Al3+ was successfully demonstrated with HeLa cells and NIH 3T3 cells. The low cytotoxicity and highly selective response of PPPNa to Al3+ endow its great potentials to in vivo detecting and imaging of Al3+ as well as an absorbent of Al3+.