Predicting TCR sequences for unseen antigen epitopes using structural and sequence features.

T-cell receptor (TCR) recognition of antigens is fundamental to the adaptive immune response. With the expansion of experimental techniques, a substantial database of matched TCR-antigen pairs has emerged, presenting opportunities for computational prediction models. However, accurately forecasting the binding affinities of unseen antigen-TCR pairs remains a major challenge. Here, we present convolutional-self-attention TCR (CATCR), a novel framework tailored to enhance the prediction of epitope and TCR interactions. Our approach utilizes convolutional neural networks to extract peptide features from residue contact matrices, as generated by OpenFold, and a transformer to encode segment-based coded sequences. We introduce CATCR-D, a discriminator that can assess binding by analyzing the structural and sequence features of epitopes and CDR3-ß regions. Additionally, the framework comprises CATCR-G, a generative module designed for CDR3-ß sequences, which applies the pretrained encoder to deduce epitope characteristics and a transformer decoder for predicting matching CDR3-ß sequences. CATCR-D achieved an AUROC of 0.89 on previously unseen epitope-TCR pairs and outperformed four benchmark models by a margin of 17.4%. CATCR-G has demonstrated high precision, recall and F1 scores, surpassing 95% in bidirectional encoder representations from transformers score assessments. Our results indicate that CATCR is an effective tool for predicting unseen epitope-TCR interactions. Incorporating structural insights enhances our understanding of the general rules governing TCR-epitope recognition significantly. The ability to predict TCRs for novel epitopes using structural and sequence information is promising, and broadening the repository of experimental TCR-epitope data could further improve the precision of epitope-TCR binding predictions.

Thiacalix[4]arene-Protected Silver Nanoclusters Encapsulating Different Two-Electron Superatom Oligomers.

The subvalent silver kernel represents the nascent state of silver cluster formation, yet the growth mechanism has long been elusive. Herein, two silver nanoclusters (Ag30 and Ag34) coprotected by TC4A4- (H4TC4A = p-tert-butylthiacalix[4]arene) and TBPMT- (TBPMTH = 4-tert-butylbenzenemethanethiol) containing 6e and 4e silver kernels are synthesized and characterized. The trimer of the 2e superatom Ag14 kernel in Ag30 is built from a central Ag6 octahedron sandwiched by two orthogonally oriented Ag5 trigonal bipyramids through sharing vertexes, whereas a double-octahedral Ag10 kernel in Ag34 is a dimer of 2e superatoms. They manifest disparate polyhedron fusion growth patterns at the beginning of the silver cluster formation. Their excellent solution stabilities are contributed by the multisite and multidentate coordination fashion of TC4A4- and the special valence electron structures. This work demonstrates the precise control of silver kernel growth by the solvent strategy and lays a foundation for silver nanocluster application in photothermal conversion.

Solvent-Mediated Hetero/Homo-Phase Crystallization of Copper Nanoclusters and Superatomic Kernel-Related NIR Phosphorescence.

Atomically precise superatomic copper nanoclusters (Cu NCs) have been the subject of immense interest for their intriguing structures and diverse properties; nonetheless, the variable oxidation state of copper ions and complex solvation effects in wet synthesis systems pose significant challenges for comprehending their synthesis and crystallization mechanism. Herein, we present a solvent-mediated approach for the synthesis of two Cu NCs, namely, superatomic Cu26 and pure-Cu(I) Cu16. They initially formed as a hetero-phase and then separated as a homo-phase via modulating binary solvent composition. In situ UV/vis absorption and electrospray ionization mass spectra revealed that the solvent-mediated assembly was determined to be the underlying mechanism of hetero/homo-phase crystallization. Cu26 is a 2-electron superatom with a kernel-shell structure that includes a [Cu20Se12]4- shell and [Cu6]4+ kernel, containing two 1S jellium electrons. Conversely, Cu16 is a pure-Cu(I) Cu/Se nanocluster that features a [Cu16Se6]4+ core protected by extra dimercaptomaleonitrile ligands. Remarkably, Cu26 exhibits unique near-infrared phosphorescence (NIR PH) at 933 nm due to the presence of a superatomic kernel-related charge transfer state (3MM(Cu)CT). Overall, this work not only showcases the hetero/homo-phase crystallization of Cu NCs driven by a solvent-mediated assembly mechanism but also enables the rare occurrence of NIR PH within the 2-electron copper superatom family.

Chiral Ligand-Concentration Mediating Asymmetric Transformations of Silver Nanoclusters: NIR-II Circularly Polarized Phosphorescence Lighting.

Near infrared (NIR) emitter with circularly polarized phosphorescence (CPP), known as NIR CPP, has emerged as a key part in the research of cutting-edge luminescent materials. However, it remains a challenge to obtain nanoclusters with NIR CPP activity. Here, we propose an asymmetric transformation approach to efficiently synthesize two pairs of chiral silver nanoclusters (R/S-Ag29 and R/S-Ag16) using an achiral Ag10 nanocluster as starting material in the presence of different concentration chiral inducer (R/S)-1,1'-binaphthyl-2,2'-diyl hydrogenphosphate (R/S-BNP). R/S-Ag29, formed in the low-concentration R/S-BNP, exhibits a unique kernel-shell structure consisting of a distorted Ag13 icosahedron and an integrated cage-like organometallic shell with a C3 symmetry, and possesses a superatomic 6-electron configuration (1S2|1P4). By contrast, R/S-Ag16, formed in the high-concentration R/S-BNP, features a sandwich-like pentagram with AgI-pure kernel. Profiting from the hierarchically chiral structures and superatomic kernel-dominated phosphorescence, R/S-Ag29 exhibits infrequent CPP activity in the second near-infrared (975 nm) region, being the first instance of NIR-II CPP observed among CPL-active metal nanoclusters. This study presents a new approach to reduce the difficulty of de novo synthesis for chiral silver nanomaterials, and facilitates the design of CPP-active superatomic nanoclusters in NIR region.

Eight-Electron Superatomic Cu31 Nanocluster with Chiral Kernel and NIR-II Emission.

Owing to the inherent instability caused by the low Cu(I)/Cu(0) half-cell reduction potential, Cu(0)-containing copper nanoclusters are quite uncommon in comparison to their Ag and Au congeners. Here, a novel eight-electron superatomic copper nanocluster [Cu31(4-MeO-PhC≡C)21(dppe)3](ClO4)2 (Cu31, dppe = 1,2-bis(diphenylphosphino)ethane) is presented with total structural characterization. The structural determination reveals that Cu31 features an inherent chiral metal core arising from the helical arrangement of two sets of three Cu2 units encircling the icosahedral Cu13 core, which is further shielded by 4-MeO-PhC≡C- and dppe ligands. Cu31 is the first copper nanocluster carrying eight free electrons, which is further corroborated by electrospray ionization mass spectrometry, X-ray photoelectron spectroscopy and density functional theory calculations. Interestingly, Cu31 demonstrates the first near-infrared (750-950 nm, NIR-I) window absorption and the second near-infrared (1000-1700 nm, NIR-II) window emission, which is exceptional in the copper nanocluster family and endows it with great potential in biological applications. Of note, the 4-methoxy groups providing close contacts with neighboring clusters are crucial for the cluster formation and crystallization, while 2-methoxyphenylacetylene leads only to copper hydride clusters, Cu6H or Cu32H14. This research not only showcases a new member of copper superatoms but also exemplifies that copper nanoclusters, which are nonluminous in the visible range may emit luminescence in the deep NIR region.

Highly Effective Hybrid Copper(I) Iodide Cluster Emitter with Negative Thermal Quenched Phosphorescence for X-Ray Imaging.

The low efficiency triplet emission of hybrid copper(I) iodide clusters is a critical obstacle to their further practical optoelectronic application. Herein, we present an efficient hybrid copper(I) iodide cluster emitter (DBA)4 Cu4 I4 , where the cooperation of excited state structure reorganization and the metallophilicity interaction enables ultra-bright triplet yellow-orange emission with a photoluminescence quantum yield over 94.9 %, and the phonon-assisted de-trapping process of exciton induces the negative thermal quenching effect at 80-300 K. We also investigate the potential of this emitter for X-ray imaging. The (DBA)4 Cu4 I4 wafer demonstrates a light yield higher than 104  photons MeV-1 and a high spatial resolution of ≈5.0 lp mm-1 , showing great potential in practical X-ray imaging applications. Our new copper(I) iodide cluster emitter can serve as a model for investigating the thermodynamic mechanism of photoluminescence in hybrid copper(I) halide phosphorescence materials.

Sulfide Boosting Near-Unity Photoluminescence Quantum Yield of Silver Nanocluster.

Silver nanoclusters have emerged as promising candidates for optoelectronic applications, but their room-temperature photoluminescence quantum yield (PLQY) is far from ideal to access cutting-edge device performance. Herein, two supertetrahedral silver nanoclusters with high PLQY in non-degassed solution at room temperature were constructed by interiorly supporting the core with multiple VO43- and E2- anions as structure-directing agents and exteriorly protecting the core with a rigid ligand shell of PhC≡C- and Ph2PE2- (E = S, Ag64-S; E = Se, Ag64-Se). Both clusters have similar outer Ag58 tetrahedral cages and [Ag6E4@(VO4)4] cores, forming a pair of comparable clusters to decrypt the origin of such a high PLQY, particularly in Ag64-S, where the PLQY reached up to 97%. The stronger suppression effect of inner sulfides for nonradiative decay is critical to boost the PLQY to near unity. Transient absorption spectroscopy is employed to confirm the phosphorescence nature. The quadruple-capping assembly mechanism involving Ag7 secondary building units on a Ag36 truncated tetrahedron was also established by collision-induced dissociation studies. This work not only provides a strategy of core engineering for the controlled syntheses of silver nanoclusters with high PLQY but also deciphers the origin of a near-unity PLQY, which lays a foundation for fabricating highly phosphorescent silver nanoclusters in the future.

Fine Tuning of Multiphoton AIE Emission Behavior, Organelle Targeting, and Fluorescence Lifetime Imaging of Terpyridine Derivatives by Alkyl Chain Engineering.

In this work, a series of multiphoton terpyridine agents (ZA, ZA-Mex, and ZA-Hex) for fluorescence lifetime imaging microscopy (FLIM) are designed and synthesized. The results from photophysical property research reveal that ZA-Hex, as an N-hexylated terpyridine salt, has stronger three-photon aggregation-induced emission (AIE) properties compared to ZA-Mex due to enhanced intramolecular charge transfer (ICT) performance. All three terpyridine derivatives possess suitable fluorescence intensities and stable fluorescence lifetimes under different pH conditions (pH = 4.0-8.0), thereby performing multiphoton fluorescence lifetime imaging. For biological imaging applications, it is found that ZA shows good lipid droplet (LD) turn-on fluorescence performance, and ZA-Hex could easily accumulate in mitochondria with high specificity. This is the first report of terpyridine salts as three-photon AIE probes used for multiphoton FLIM imaging.

Real-Time Fluorescent Monitoring of Kinetically Controlled Supramolecular Self-Assembly of Atom-Precise Cu8 Nanocluster.

Kinetically stable and long-lived intermediates are crucial in monitoring the progress and understanding of supramolecular self-assembly of diverse aggregated structures with collective functions. Herein, the complex dynamics of an atomically precise CuI nanocluster [Cu8 (t BuC6 H4 S)8 (PPh3 )4 ] (Cu8a) is systematically investigated. Remarkably, by monitoring the aggregation-induced emission (AIE) and electron microscopy of the kinetically stable intermediates in real time, the directed self-assembly (DSA) process of Cu8a is deduced. The polymorphism and different emission properties of Cu NCs aggregates were successfully captured, allowing the structure-optical property relationship to be established. More importantly, the utilization of a mathematical "permutation and combination" ideology by introducing a heterogeneous luminescent agent of a carbon dot (CD) to Cu8a aggregates enriches the "visualization" fluorescence window, which offers great potential in real time application for optical sensing of materials.

Ag22 Nanoclusters with Thermally Activated Delayed Fluorescence Protected by Ag/Cyanurate/Phosphine Metallamacrocyclic Monolayers through In-Situ Ligand Transesterification.

The composition of protection monolayer exerts great influence on the molecular and electronic structures of atomically precise monolayer protected metal nanoclusters. Four isostructural Ag/cyanurate/phosphine metallamacrocyclic monolayer protected Ag22 nanoclusters are synthesized by kinetically controlled in-situ ligand formation-driven strategy. These eight-electron superatomic silver nanoclusters feature an unprecedented interfacial bonding structure with diverse E-Ag (E=O/N/P/Ag) interactions between the Ag13 core and metallamacrocyclic monolayer, and displays thermally activated delayed fluorescence (TADF), benefiting from their distinct donor-acceptor type electronic structures. This work not only unmasks a new core-shell interface involving cyanurate ligand but also underlines the significance of high-electron-affinity N-heterocyclic ligand in synthesizing TADF metal nanoclusters. This is the first mixed valence Ag0/I nanocluster with TADF characteristic.

Functional Platinum(II) Complexes with Four-Photon Absorption Activity, Lysosome Specificity, and Precise Cancer Therapy.

Multiphoton materials are in special demand in the field of photodynamic therapy and multiphoton fluorescence imaging. However, rational design methodology for these brands of materials is still nascent. This is despite transition-metal complexes favoring optimized nonlinear-optical (NLO) activity and heavy-atom-effected phosphorescent emission. Here, three four-photon absorption (4PA) platinum(II) complexes (Pt1-Pt3) are achieved by the incorporation of varied functionalized C^N^C ligands with high yields. Pt1-Pt3 exhibit triplet metal-to-ligand charge-transfer transitions at ∼460 nm, which are verified multiple times by transient absorption spectra, time-dependent density functional theory calculations, and low-temperature emission spectra. Further, Pt1-Pt3 undergo 4PA. Notably, one of the complexes, Pt2, has maximum 4PA cross-sectional values of up to 15.2 × 10-82 cm8 s3 photon-3 under excitation of a 1600 nm femtosecond laser (near-IR II window). The 4PA cross sections vary when Pt2 is binding to lecithin and when it displays its lysosome-specific targeting behavior. On the basis of the excellent 4PA property of Pt2, we believe that those 4PA platinum(II) complexes have great potential applications in cancer theranostics.

Activated Type I and Type II Process for Two-Photon Promoted ROS Generation: The Coordinated Zn Matters.

The construction of novel classes of photosensitizers for efficient reactive oxygen species (ROS) generation is of great interest, yet it is a challenge. In this work, a bis(terpyridine)zinc(II) complex (namely, ZnL1) with two-photon absorption activity as an efficient ROS photogenerator was synthesized. Benefiting from the coordinated Zn, the decreased singlet-triplet energy gap favors the intersystem crossing process facilitating the singlet oxygen (1O2) generation via energy transfer. In addition, it makes the superoxide radical (O2·-) generation easier. This is an extremely rare study on two-photon excited ROS generation by activating type I and type II processes based on a cheaper and bioaccessible Zn complex.

Suppression of NF-κB signal pathway by NLRC3-like protein in stony coral Acropora aculeus under heat stress.

Heat stress is the most common factor for coral bleaching, which has increased both in frequency and severity due to global warming. In the present study, the stony coral Acropora aculeus was subjected to acute heat stress and entire transcriptomes were sequenced via the next generation sequencing platform. Four paired-end libraries were constructed and sequenced in two groups, including a control and a heat stress group. A total of 120,319,751 paired-end reads with lengths of 2 × 100 bp were assembled and 55,021 coral-derived genes were obtained. After read mapping and abundance estimation, 9110 differentially expressed genes were obtained in the comparison between the control and heat stress group, including 4465 significantly upregulated and 4645 significantly downregulated genes. Twenty-three GO terms in the Biological Process category were overrepresented for significantly upregulated genes, and divided into six groups according to their relationship. These three groups were related to the NF-κB signal pathway, and the remaining three groups were relevant for pathogen response, immunocyte activation and protein ubiquitination. Forty-three common genes were found in four GO terms, which were directly related to the NF-κB signal pathway. These included 2 NACHT, LRR, PYD domains-containing protein, 5 nucleotide-binding oligomerization domain-containing protein, 29 NLRC3-like protein, 4 NLRC5-like protein, and 3 uncharacterized protein. For significantly downregulated genes, 27 overrepresented GO terms were found in the Biological Process category, which were relevant to protein ubiquitination and ATP metabolism. Our results indicate that heat stress suppressed the immune response level via the NLRC3-like protein, the fine-tuning of protein turnover activity, and ATP metabolism. This might disrupt the balance of coral-zooxanthellae symbiosis and result in the bleaching of the coral A. aculeus.

Arylgold nanoclusters: Phenyl-stabilized Au44 with thermal-controlled NIR single/dual-channel phosphorescence.

Arylation of gold holds paramount importance in the domain of organometallic chemistry; however, the exploration of arylgold nanoclusters remains in its infancy primarily due to the synthetic challenge. Here, we present a facile and effective arylation strategy to directly synthesize two arylgold nanoclusters (Au44a and Au44b), by using tetraarylborates, capable of transferring aryl fragments to metal centers. X-ray crystallography reveals that both Au44 nanoclusters contain an Au44 kernel co-protected by six aryl groups, two tetrahydrothiophene, and 16 alkynyl-ether ligands, the latter is generated in situ through Williamson ether reaction during the assembly processes. Notably, Au44 nanoclusters exhibit near-infrared (NIR) phosphorescence (λmax = 958 nm) and microsecond radiative relaxation at ambient condition, which is a thermal-controlled single/dual-channel phosphorescent emission revealed by temperature-dependent NIR, time-resolved emission, and femtosecond/nanosecond transition absorption spectra. This work represents a breakthrough in using aryl as protective ligands for the construction of gold nanoclusters, which is poised to have a transformative impact on organometallic nanoclusters.

Biomimetic crystallization for long-pursued -COOH-functionalized gold nanocluster with near-infrared phosphorescence.

As an interdisciplinary product, water-soluble gold nanoclusters (AuNCs) stabilized by ligands containing carboxyl (-COOH) group have garnered significant attention from synthetic chemists and biologists due to their immense potential for biomedical applications. However, revealing the crystallographic structures of -COOH-functionalized AuNCs remains a bottleneck. Herein, we successfully applied the salting-out method to obtain a series of high-quality single crystals of -COOH-functionalized Au25 nanoclusters and revealed their crystallographic structures. Particularly, K3Au25(2-Hmna)9(mna)6]- (Au25a) protected by 2-mercaptonicotinic acid features an unprecedented tetrameric Au4(SRS)3(SRS,N)2 staple motifs surrounding the icosahedral Au13 kernel, breaking the traditional perception on the structure of Au25(SR)18. Au25a exhibits a distinct near-infrared emission at 970 nm with long lifetime of 8690 ns, which have been studied by transient absorption spectroscopy and time-dependent density functional theory. This work compensates for the research gap in the experimental structure of -COOH-functionalized AuNCs and opens up a new avenue to explore their structure-property correlations.

Survival benefits of primary tumor surgery for synchronous brain metastases: A SEER-based population study with propensity-matched comparative analysis.

BACKGROUND: Evidence about the prognostic value of primary tumor surgery (PTS) in patients with brain metastatic malignancies is ambiguous and controversial. This study assessed the survival benefits of primary tumor surgery in patients with brain metastases (BMs). METHODS: Adults patients with BMs that originated from lung, breast, kidney, skin, colon, and liver diagnosed between 2010 and 2018 were derived from the Surveillance, Epidemiology, and End Results database (SEER). Propensity score matching (PSM) was used to balance the bias between patients with or without PTS. Then the prognostic value of PTS was estimated by Kaplan-Meier analysis and Cox proportional hazard regression models. RESULTS: A total of 32,760 patients with BMs secondary to non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), breast cancer, renal cancer, melanoma, colorectal cancer, and liver cancer were identified from the database. After PSM at 1:1 ratio, PTS appeared to significantly prolong cause-specific survival (CSS) time for patients with BMs secondary to NSCLC, breast cancer, renal cancer, and colorectal cancer (hazard ratio [HR] = 0.60 [0.53-0.68], 0.56 [0.43-0.73], 0.47 [0.37-0.60], and 0.59 [0.37-0.95], respectively, all p < 0.05). Patients with earlier T and N classifications, no extracranial metastasis, and cancer-specific subtypes (adenocarcinoma in NSCLC, hormone receptor-negative breast cancer) may derive more survival benefits from PTS when suffering from BMs. CONCLUSION: This population-based study supported PTS could provide survival benefits for patients with BMs secondary to NSCLC, breast cancer, renal cancer, and colorectal cancer. More emphasis should be put on PTS of selected patients with BMs.

CoSe2 nanoparticles anchored on CoNC carbon nanoplates as bifunctional electrocatalyst for flexible rechargeable Zn-air batteries.

A flexible solid rechargeable Zn-air battery for advanced energy conversion and storage has extensive applications in portable electric sources, wildlife rescue and flexible wearable systems. Herein, the CoSe2 nanoparticles anchored on cobalt-embedded N-doping carbon nanoplates (CoSe2/CoNC) is developed as a highly active bifunctional catalyst via pyrolysis and selenization of bimetallic zeolitic imidazolate frameworks containing Zn and Co. The introduction of inactive Zn generates strong electrochemically active surface areas due to the synergistic effect between CoSe2 nanoparticles and CoNC matrix. Further, CoSe2/CoNC exhibits prominent Zn-air battery performance and even outperforms the commercially available noble-metal catalysts. Notably, a high-rate flexible Zn-air battery enabled by an alkaline composite polyacrylic acid-carboxymethyl cellulose electrolyte delivers the open-circuit potential of 1.51 V. The battery offers high wearability and performs very well under various conditions, such as soaking, drilling and sewing.

In vivo evaluation of integrin αvß6-targeting peptide in NSCLC and brain metastasis.

Introduction: Integrin αvß6, which is upregulated in malignancies and remains absent or weak in normal tissue, is a promising target in molecular imaging therapeutics. In vivo imaging of integrin αvß6 could therefore be valuable for early tumor detection and intraoperative guidance. Methods: In this study, integrin αvß6-targeting probe G2-SFLAP3 was labeled with near-infrared (NIR) dye Cy5.5 or radioisotope 68Ga. The resulting probes were evaluated in integrin αvß6-positive A549 and αvß6-negative H1703 xenograft mice models. Results: The cellar uptake of G2-SFLAP3-Cy5.5 was consistent with the expression of integrin αvß6. Both subcutaneous and brain metastatic A549 tumors could be clearly visualized by NIR fluorescent imaging of G2-SFLAP3-Cy5.5. A549 tumors demonstrated the highest G2-SFLAP3-Cy5.5 accumulation at 4h post-injection (p.i.) and remain detectable at 84h p.i. The fluorescent signal of G2-SFLAP3-Cy5.5 was significantly reduced in H1703 and A549-blocking groups. Consistently, small-animal PET imaging showed tumor-specific accumulation of 68Ga-DOTA-G2-SFLAP3. Discussion: G2-SFLAP3 represents a promising agent for noninvasive imaging of non-small cell lung cancer (NSCLC) and brain metastases.

Treatments for brain metastases from EGFR/ALK-negative/unselected NSCLC: A network meta-analysis.

More clinical evidence is needed regarding the relative priority of treatments for brain metastases (BMs) from EGFR/ALK-negative/unselected non-small cell lung cancer (NSCLC). PubMed, EMBASE, Web of Science, Cochrane Library, and ClinicalTrials.gov databases were searched. Overall survival (OS), central nervous system progression-free survival (CNS-PFS), and objective response rate (ORR) were selected for Bayesian network meta-analyses. We included 25 eligible randomized control trials (RCTs) involving 3,054 patients, investigating nine kinds of treatments for newly diagnosed BMs and seven kinds of treatments for previously treated BMs. For newly diagnosed BMs, adding chemotherapy, EGFR-TKIs, and other innovative systemic agents (temozolomide, nitroglycerin, endostar, enzastaurin, and veliparib) to radiotherapy did not significantly prolong OS than radiotherapy alone; whereas radiotherapy + nitroglycerin showed significantly better CNS-PFS and ORR. Surgery could significantly prolong OS (hazard ratios [HR]: 0.52, 95% credible intervals: 0.41-0.67) and CNS-PFS (HR: 0.32, 95% confidence interval: 0.18-0.59) compared with radiotherapy alone. For previously treated BMs, pembrolizumab + chemotherapy, nivolumab + ipilimumab, and cemiplimab significantly prolonged OS than chemotherapy alone. Pembrolizumab + chemotherapy also showed better CNS-PFS and ORR than chemotherapy. In summary, immune checkpoint inhibitor (ICI)-based therapies, especially ICI-combined therapies, showed promising efficacies for previously treated BMs from EGFR/ALK-negative/unselected NSCLC. The value of surgery should also be emphasized. The result should be further confirmed by RCTs.

Preclinical assessment of IRDye800CW-labeled gastrin-releasing peptide receptor-targeting peptide for near infrared-II imaging of brain malignancies.

We aimed to develop a new biocompatible gastrin-releasing peptide receptor (GRPR) targeted optical probe, IRDye800-RM26, for fluorescence image-guided surgery (FGS) of brain malignancies in near-infrared window II (NIR-II) imaging. We developed a novel GRPR targeting probe using a nine-amino-acid bombesin antagonist analog RM26 combined with IRDye800CW, and explored the fluorescent probe according to optical properties. Fluorescence imaging characterization in NIR-I/II region was performed in vitro and in vivo. Following simulated NIR-II image-guided surgery, we obtained time-fluorescent intensity curves and time-signal and background ratio curves. Further, we used histological sections of brain from tumor-beating mice model to compare imaging specificity between 5-aminolevulinic acid (5-ALA) and IRDye800-RM26, and evaluated biodistribution and biocompatibility. IRDye800-RM26 had broad emission ranging from 800 to 1200 nm, showing considerable fluorescent intensity in NIR-II region. High-resolution NIR-II imaging of IRDye800-RM26 can enhance the advantages of NIR-I imaging. Dynamic and real time fluorescence imaging in NIR-II region showed that the probe can be used to treat brain malignancies in mice between 12 and 24 h post injection. Its specificity in targeting glioblastoma was superior to 5-ALA. Biodistribution analysis indicated IRDye800-RM26 excretion in the kidney and liver. Histological and blood test analyses did not reveal acute severe toxicities in mice treated with effective dose (40 µg) of the probe for NIR-II imaging. Because of the considerable fluorescent intensity in NIR-II region and high spatial resolution, biocompatible and excretable IRDye800-RM26 holds great potentials for FGS, and is essential for translation into human use.