Development of an FAP-Targeted PET Probe Based on a Novel Quinolinium Molecular Scaffold.

Fibroblast activation protein (FAP) has recently gained significant attention as a promising tumor biomarker for both diagnosis and therapeutic applications. A series of radiopharmaceuticals based on fibroblast activation protein inhibitors (FAPIs) have been developed and translated into the clinic. Though some of them such as radiolabeled FAPI-04 probes have achieved favorable in vivo imaging performance, further improvement is still highly desired for obtaining radiopharmaceuticals with a high theranostics potential. In this study, we innovatively designed an FAPI ligand SMIC-3002 by changing the core quinoline motif of FAPI-04 to the quinolinium scaffold. The engineered molecule was further radiolabeled with 68Ga to generate a positron emission tomography (PET) probe, [68Ga]Ga-SMIC-3002, which was then evaluated in vitro and in vivo. [68Ga]Ga-SMIC-3002 demonstrated high in vitro stability, nanomolar affinity for FAP (8 nM for protein, 23 nM for U87MG cells), and specific uptake in FAP-expressing tumors, with a tumor/muscle ratio of 19.1 and a tumor uptake of 1.48 ± 0.03 ID/g% at 0.5 h in U87MG tumor-bearing mice. In summary, the quinolinium scaffold can be successfully used for the development of the FAP-targeted tracer. [68Ga]Ga-SMIC-3002 not only shows high potential for clinical translation but also offers insights into designing a new generation of FAPI tracers.

Quinazoline-2,4(1 H,3 H)-dione Scaffold for development of a novel PARP-targeting PET probe for tumor imaging.

PURPOSE: Overexpression of Poly (ADP-ribose) polymerase (PARP) is associated with many diseases such as oncological diseases. Several PARP-targeting radiotracers have been developed to detect tumor in recent years. Two 18F labelled probes based on Olaparib and Rucaparib molecular scaffolds have been evaluated in clinical trials, but their slow hepatic clearance hinders their tumor imaging performance. Although a number of positron emission tomography (PET) probes with lower liver uptake have been designed, the tumor to background ratios remains to be low. Therefore, we designed a probe with low lipid-water partition coefficient to solve this problem. METHODS: A pyridine-containing quinazoline-2,4(1 H,3 H)-dione PARP-targeting group was rationally designed and used to conjugate with the chelator 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) to prepare the lead compound named as SMIC-2001 for radiolabeling. In vitro experiments, the lipid-water partition coefficient, stability, binding affinity, and cellular uptake of [68Ga]Ga-SMIC-2001 were determined. In vivo experiments, the U87MG xenograft models were used to evaluate its tumor imaging properties. RESULTS: [68Ga]Ga-SMIC-2001 showed a low Log D7.4 (-3.82 ± 0.06) and high affinity for PARP-1 (48.13 nM). In vivo study revealed that it exhibited a high tumor-to-background contrast in the U87MG xenograft models and mainly renal clearance. And the ratios of tumor to main organs were high except for the kidney (e.g. tumor to liver ratio reached 2.20 ± 0.51) at 60 min p.i. CONCLUSION: In summary, pyridine-containing quinazoline-2,4(1 H,3 H)-dione is a novel PARP-targeting molecular scaffold for imaging probe development, and [68Ga]Ga-SMIC-2001 is a highly promising PET probe capable of imaging tumors with PARP overexpression.

Nature Products Chlorophyll Derivatives for NIR-II Fluorescence Bioimaging and Plant-Imaging.

The second near-infrared window (NIR-II, 1000-1700 nm) fluorescence imaging has attracted significant attention in research fields because of its unique advantages compared with conventional optical windows (400-900 nm). A variety of NIR-II fluorophores have been actively studied because they serve as a key component of fluorescence imaging. Among them, organic small molecule NIR-II fluorophores display outstanding imaging performance and many advantages, but types of small molecule NIR-II fluorophores with high biocompatibility are still quite limited. Novel molecular scaffolds based NIR-II dyes are highly desired. Herein, we hypothesized that chlorophyll is a new promising molecular platform for discovery NIR-II fluorophores. Thus, seven derivatives of derivatives were selected to characterize their optical properties. Interestingly, six chlorophyll derivatives displayed NIR-II fluorescence imaging capability. This characteristic allowed the successful NIR-II imaging of green leaves of various plants. Furthermore, most of these fluorophores showed capacity to monitor viscosity change because of their sensitive for viscosity. For demonstration of its biomedical applications, these probes were successfully used for NIR-II fluorescence-guided surgical resection of lymph nodes. In summary, chlorophylls are novel valuable tool molecules for NIR-II fluorescence imaging and have potential to expand their applications in biomedical field and plant science.

Fibroblast Activation Protein Targeting Probe with Gly-Pro Sequence for PET of Glioblastoma.

As an important cancer-associated fibroblast-specific biomarker, fibroblast activation protein (FAP) has become an attractive target for tumor diagnosis and treatment. However, most FAP-based radiotracers showed inadequate uptake and short retention in tumors. In this study, we designed and synthesized a novel FAP ligand (DOTA-GPFAPI-04) through assembling three functional moieties: a quinoline-based FAP inhibitor for specifically targeting FAP, a FAP substrate Gly-Pro as a linker for increasing the FAP protein interaction, and a 2,2',2″,2‴-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) chelator for radiolabeling with different radionuclides. The FAP targeting ability of DOTA-GPFAPI-04 was investigated by molecular docking studies. DOTA-GPFAPI-04 was then radiolabeled with 68Ga to give [68Ga]Ga-DOTA-GPFAPI-04 for positron emission tomography (PET) imaging of glioblastoma. [68Ga]Ga-DOTA-GPFAPI-04 exhibited a purity of >98% and high stability analyzed by radio-HPLC in saline and mouse serum. Cell uptake studies demonstrated the targeting specificity of the probe. Further in vivo pharmacokinetic studies in normal mice demonstrated the quick clearance of the probe. Moreover, compared with the widely studied [68Ga]Ga-FAPI-04, [68Ga]Ga-DOTA-GPFAPI-04 showed much higher U87MG tumor uptake values (4.467 ± 0.379 for [68Ga]Ga-DOTA-GPFAPI-04 and 1.267 ± 0.208% ID/g for [68Ga]Ga-FAPI-04 at 0.5 h post-injection, respectively). The area under the curve based on time-activity curve (TAC) analysis for tumor radioactivity in small animal models was 422.5 for [68Ga]Ga-DOTA-GPFAPI-04 and 98.14 for [68Ga]Ga-FAPI-04, respectively, demonstrating that the former had longer tumor retention time. The tumor-to-muscle (T/M) ratio for [68Ga]Ga-DOTA-GPFAPI-04 reached 9.15 in a U87MG xenograft animal model. PET imaging and blocking assays showed that [68Ga]Ga-DOTA-GPFAPI-04 had specific tumor uptake. In summary, this study demonstrates the successful synthesis and evaluation of a novel FAPI targeting probe, [68Ga]Ga-DOTA-GPFAPI-04, with a Gly-Pro sequence. It shows favorable in vivo glioblastoma imaging properties and relatively long tumor retention, highlighting DOTA-GPFAPI-04 as a promising molecular scaffold for developing FAP targeting tumor theranostic agents.

Biodegradable Silica-Based Nanotheranostics for Precise MRI/NIR-II Fluorescence Imaging and Self-Reinforcing Antitumor Therapy.

Multi-modality cancer diagnosis techniques based on the second near-infrared window fluorescence (NIR-II FL, 1000-1700 nm) imaging have become the focus of research attention. For such multimodality probes, how to take advantage of the tumor microenvironments (TME) characteristics to better image diseases and combine efficient therapeutics to achieve theranostics is still a big challenge. Herein, a novel TME-activated nanosystem (FMSN-MnO2 -BCQ) employing degradable silica-based nanoplatform is designed, adjusting the ratio of intratumoral hydrogen peroxide (H2 O2 )/glutathione (GSH) for magnetic resonance imaging (MRI)/NIR-II FL imaging and self-reinforcing chemodynamic therapy (CDT). Innovative bovine serum albumin (BSA)-modified fusiform-like mesoporous silica nanoparticles (FMSN) is fabricated as a carrier for NIR-II small molecule (CQ4T) and MRI reporter MnO2 . Remarkably, the BSA modification helped to achieve the dual-functions of high biocompatibility and enhance NIR-II fluorescence. The FMSN-MnO2 -BCQ with FMSN framework featuring a stepwise degradability in tumor interior released MnO2 and BCQ nanoparticles. Through the specific degradation of MnO2 by the TME, the produced Mn2+ ions are effectively exerted Fenton-like activity to generate hydroxyl radical (•OH) from endogenous H2 O2 to eradicate tumor cells. More importantly, the GSH depletion due to the synergistic effect of tetrasulfide bond and MnO2 in turn induced the oxidative cytotoxicity for self-reinforcing CDT.

Mitochondria-targeted delocalized lipophilic cation complexed with human serum albumin for tumor cell imaging and treatment.

Small molecule 5BMF is a novel mitochondria-targeted delocalized lipophilic cation (DLC) with good anti-tumor activity and fluorescence emission suitable for bioimaging. In this study, human serum albumin (HSA) complexed with 5BMF (5BMF@HSA) has been developed to further improve its solubility (from 1.61 to 5.41 mg/mL), and the fluorescent intensity of 5BMF@HSA was improved over 2 times. Nearly 10-fold 5BMF was released from 5BMF@HSA complex in acidic condition when compared with neutral/basic environment. Intracellular distribution of 5BMF was altered by HSA as its signals were observed in lysosomes where free 5BMF barely localized. Both 5BMF@HSA and 5BMF showed selective toxicity toward tumor cells in µM and nM range and effectively inhibited tumor growth in mice model. In summary, 5BMF@HSA shows improved solubility in aqueous buffer and enhanced fluorescence emission, and maintains tumor inhibition capability. It is a promising protein complex for tumor cell imaging and tumor treatment.

Hierarchically Nanostructured Hybrid Platform for Tumor Delineation and Image-Guided Surgery via NIR-II Fluorescence and PET Bimodal Imaging.

Bimodal imaging with fluorescence in the second near infrared window (NIR-II) and positron emission tomography (PET) has important significance for tumor diagnosis and management because of complementary advantages. It remains challenging to develop NIR-II/PET bimodal probes with high fluorescent brightness. Herein, bioinspired nanomaterials (melanin dot, mesoporous silica nanoparticle, and supported lipid bilayer), NIR-II dye CH-4T, and PET radionuclide 64 Cu are integrated into a hybrid NIR-II/PET bimodal nanoprobe. The resultant nanoprobe exhibits attractive properties such as highly uniform tunable size, effective payload encapsulation, high stability, dispersibility, and biocompatibility. Interestingly, the incorporation of CH-4T into the nanoparticle leads to 4.27-fold fluorescence enhancement, resulting in brighter NIR-II imaging for phantoms in vitro and in situ. Benefiting from the fluorescence enhancement, NIR-II imaging with the nanoprobe is carried out to precisely delineate and resect tumors. Additionally, the nanoprobe is successfully applied in tumor PET imaging, showing the accumulation of the nanoprobe in a tumor with a clear contrast from 2 to 24 h postinjection. Overall, this hierarchically nanostructured platform is able to dramatically enhance fluorescent brightness of NIR-II dye, detect tumors with NIR-II/PET imaging, and guide intraoperative resection. The NIR-II/PET bimodal nanoprobe has high potential for sensitive preoperative tumor diagnosis and precise intraoperative image-guided surgery.

Molecular Targeted NIR-II Probe for Image-Guided Brain Tumor Surgery.

Optical imaging strategies for improving delineation of glioblastoma (GBM) is highly desired for guiding surgeons to distinguish cancerous tissue from healthy and precious brain tissue. Fluorescence imaging (FLI) in the second near-infrared window (NIR-II) outperforms traditional NIR-I imaging with better tissue penetration, higher spatial and temporal resolution, and less auto fluorescence and scattering. Because of high expression in GBM and many other tumors, urokinase Plasminogen Activator Receptor (uPAR) is an attractive and well proven target for FLI. Herein we aim to combine the benefit of a NIR-II fluorophore with a high affinity uPAR targeting small peptide. A targeted NIR-II fluorescent probe was developed by conjugating an in-house synthesized NIR-II fluorophore, CH1055, and a uPAR targeting peptide, AE105. To characterize the in vivo distribution and targeting properties, a dynamic imaging was performed in orthotopic GBM bearing nude mice ( n = 8). Additionally, fluorescence guided surgery of orthotopic GBM was performed in living animals. CH1055-4Glu-AE105 was easily synthesized with >75% yield and >98% HPLC evaluated purity. The retention time of the probe on analytical HPLC was 15.9 min and the product was verified by mass spectrometry. Dynamic imaging demonstrated that the uPAR targeting probe visualized orthotopic GBM through the intact skull with a tumor-to-background ratio (TBR) of 2.7 peaking at 96 h. Further, the orthotopic GBM was successfully resected in small animals guided by the NIR-II FLI. By using a small uPAR targeting NIR-II probe, FLI allows us to specifically image and detect GBM. A real-time imaging setup further renders FLI guided tumor resection, and the probe developed in this work is a promising candidate for clinical translation.

Multifunctional biomedical imaging in physiological and pathological conditions using a NIR-II probe.

Compared with imaging in the visible (400 - 650 nm) and near-infrared window I (NIR-I, 650 - 900 nm) regions, imaging in near-infrared window II (NIR-II, 1,000-1,700 nm) is a highly promising in vivo imaging modality with improved resolution and deeper tissue penetration. In this work, a small molecule NIR-II dye,5,5'-(1H,5H-benzo[1,2-c:4,5-c'] bis[1,2,5]thiadiazole)-4,8-diyl)bis(N,N-bis(4-(3-((tert-butyldimethylsilyl)oxy)propyl)phenyl) thiophen-2-amine), has been successfully encapsulated into phospholipid vesicles to prepare a probe CQS1000. Then this novel NIR-II probe has been studied for in vivo multifunctional biological imaging. Our results indicate that the NIR-II vesicle CQS1000 can noninvasively and dynamically visualize and monitor many physiological and pathological conditions of circulatory systems, including lymphatic drainage and routing, angiogenesis of tumor and vascular deformity such as arterial thrombus formation and ischemia with high spatial and temporal resolution. More importantly, by virtue of the favorable half-life of blood circulation of CQS1000, NIR-II imaging is capable of aiding us to accomplish precise resection of tumor such as osteosarcoma, and to accelerate the process of lymph nodes dissection to complete sentinel lymph node biopsy for better decision-making during the tumor surgery. Overall, CQS1000 is a highly promising NIR-II probe for multifunctional biomedical imaging in physiological and pathological conditions, surpassing traditional NIR-I imaging modality and pathologic assessments for clinical diagnosis and treatment.

A small-molecule dye for NIR-II imaging.

Fluorescent imaging of biological systems in the second near-infrared window (NIR-II) can probe tissue at centimetre depths and achieve micrometre-scale resolution at depths of millimetres. Unfortunately, all current NIR-II fluorophores are excreted slowly and are largely retained within the reticuloendothelial system, making clinical translation nearly impossible. Here, we report a rapidly excreted NIR-II fluorophore (∼90% excreted through the kidneys within 24 h) based on a synthetic 970-Da organic molecule (CH1055). The fluorophore outperformed indocyanine green (ICG)-a clinically approved NIR-I dye-in resolving mouse lymphatic vasculature and sentinel lymphatic mapping near a tumour. High levels of uptake of PEGylated-CH1055 dye were observed in brain tumours in mice, suggesting that the dye was detected at a depth of ∼4 mm. The CH1055 dye also allowed targeted molecular imaging of tumours in vivo when conjugated with anti-EGFR Affibody. Moreover, a superior tumour-to-background signal ratio allowed precise image-guided tumour-removal surgery.

Studies towards the synthesis of medermycin via Dötz benzannulation.

The C-arylglycosides are available in enantiomerically pure form via the Dötz benzannulation reaction between Fischer alkenyl chromium carbene complexes and alkynes; it also could be converted to a precursor of medermycin by O-carbamate directed ipso bromination and nitrile substitution in good overall yields.

Real time monitoring peripheral nerve function with ICG and BDA-ICG by NIR-II fluorescence imaging.

Neuroanatomical tract tracers are important for studying axoplasmic transport and the complex interconnections of the nervous system. Though traditional fluorescent tracers are widely used, they have several prominent drawbacks when imaging, including low resolutions and low tissue penetrations and inability to be supervised dynamically within a long peripheral nerve during the long term. Here, we explored the potential of ICG as a neural tracer for axoplasmic transport and for the first time demonstrated that ICG could be used to detect transport function within peripheral nerve by near-infrared region II (NIR-II) imaging. On basis of this finding, a novel bi-directional neural tracer biotinylated dextran amine-indocyanine green (BDA-ICG) was prepared and characterized with better long-term stability and higher nerve-to-background ratio than ICG in vivo, and successfully imaged the injured peripheral nerve from the healthy one within 24 h. Our results show that BDA-ICG are promising neural tracers and clinically available dyes with NIR-II emission tail characteristics as ICG.

Development of a Novel 18F-Labeled Probe for PET Imaging of Estrogen Receptor ß.

Estrogen receptor beta (ERß) is an important ER subtype that plays crucial roles in many physiological and pathological disorders. Herein, we developed the probe [18F]PVBO for in vivo ERß targeted PET imaging and obtained promising results. The nonradioactive PVBO showed a 12.5-fold stronger binding affinity to ERß than to ERα in vitro. In vitro assays revealed the specific uptake of [18F]PVBO by DU145 cells. The uptake of [18F]PVBO by DU145 xenografts increased during the 120 min dynamic scanning, with a maximum uptake of 2.80 ± 0.30% ID/g. Based on time activity curves (TACs), the injection of [18F]PVBO with unlabeled PVBO or ERB-041 resulted in a significant signal reduction with the tumor/muscle (T/M) ratio <1 at 30, 60, 75, and 120 min post-injection (p < 0.05). [18F]PVBO demonstrates the feasibility of noninvasively imaging ERß-positive tumors by small-animal PET and provides a new strategy for visualizing ERß in vivo.

Clinically Translatable Solid-State Dye for NIR-II Imaging of Medical Devices.

Medical devices are commonly implanted underneath the skin, but how to real-time noninvasively monitor their migration, integrity, and biodegradation in human body is still a formidable challenge. Here, the study demonstrates that benzyl violet 4B (BV-4B), a main component in the FDA-approved surgical suture, is found to produce fluorescence signal in the first near-infrared window (NIR-I, 700-900 nm) in polar solutions, whereas BV-4B self-assembles into highly crystalline aggregates upon a formation of ultrasmall nanodots and can emit strong fluorescence in the second near-infrared window (NIR-II, 1000-1700 nm) with a dramatic bathochromic shift in the absorption spectrum of ≈200 nm. Intriguingly, BV-4B-involved suture knots underneath the skin can be facilely monitored during the whole degradation process in vivo, and the rupture of the customized BV-4B-coated silicone catheter is noninvasively diagnosed by NIR-II imaging. Furthermore, BV-4B suspended in embolization glue achieves hybrid fluorescence-guided surgery (hybrid FGS) for arteriovenous malformation. As a proof-of-concept study, the solid-state BV-4B is successfully used for NIR-II imaging of surgical sutures in operations of patients. Overall, as a clinically translatable solid-state dye, BV-4B can be applied for in vivo monitoring the fate of medical devices by NIR-II imaging.

Liver injury long-term monitoring and fluorescent image-guided tumor surgery using self-assembly amphiphilic donor-acceptor NIR-II dyes.

Real-time monitoring of liver dysfunction represents a significant unmet demand in clinical and preclinical research. The second near-infrared window (NIR-II, 1000-1700 nm) fluorescent imaging is an attractive method for biomedical imaging and may be a promising approach for liver dysfunction monitoring. Herein, we designed and synthesized a small-molecule NIR-II dye TQT 1009 with an asymmetric donor-acceptor (D-A) core. By introducing four kinds of polyethylene glycol (PEG) with different length and molecular weights (nK, n = 0.5, 2, 5, 10) to TQT1009, the dye was self-assembled into different nanoparticles named as TQP nK with regulated size and controllable circulation lifetime in vivo. In general, TQP nK showed a super high contrast ratio for blood vessels, bones, intestines, lymph, and tumor imaging. The best-selected probe, TQP 10K, exhibited ultralong in vivo circulation time (>96 h) which was suitable for long-term quantitative monitoring of liver and vessel function at a single dose, implying the excellent prospects compared with ICG, which was quickly eliminated in blood within a few minutes. Meanwhile, TQP 10K also achieved NIR-II surgical navigation of tumor in an extended time window (>7 d). Overall, our results demonstrate the self-assembly PEGylated amphiphilic TQP nK provide a new probe design strategy for liver function monitoring and image-guided tumor surgery in a prolonged time window.

Organic single molecule based nano-platform for NIR-II imaging and chemo-photothermal synergistic treatment of tumor.

Integrating multiple functionalities of near-infrared second window fluorescence imaging (NIR-Ⅱ FLI), chemotherapy, and photothermal treatment (PTT) into a single molecule is desirable but still a highly challenging task. Herein, inspired by the results that hyperthermia can enhance the cytotoxicity of some alkylating agents, we designed and synthesized the novel compound NM. By introducing nitrogen mustard's active moiety bis(2-chlorethyl)amino into Donor-Acceptor-Donor (D-A-D) electronic structure, the unimolecular system not only behaviored as a chemotherapeutic agent but also exhibited good PTT and NIR-Ⅱ FLI abilities. The hydrophobic agent NM was encapsulated by DSPE-PEG2000 to generate the nano-platform NM-NPs. The current study on in vitro and in vivo experiments indicated that NM-NPs make vessels visualize clearly in the NIR-II zone and achieve complete tumor elimination through chemo-photothermal synergistic treatment. Overall, this study provides a new innovative strategy for developing superior, versatile phototheranostics for cancer theranostics.

A Small-Molecule Based Organic Nanoparticle for Photothermal Therapy and Near-Infrared-IIb Imaging.

Near-infrared window IIb (NIR-IIb, 1500-1700 nm) fluorescence imaging demonstrates attractive properties including low scattering, low absorption, and deep tissue penetration, and photothermal therapy (PTT) is also a promising modality for cancer treatment. However, until now, there is no report on theranostic systems based on small organic molecules combining fluorescence imaging in the NIR-IIb and PTT, highlighting the challenge and strong need for development of such agents. Herein, we report a novel small molecule NIR-IIb dye IT-TQF with a D-A-D structure, which exhibited high fluorescence intensity in the NIR-IIb window. To further translate IT-TQF into an effective theranostic agent, IT-TQF was encapsulated into DSPE-PEG2000 to construct IT-TQF NPs. The physical and photochemical properties of the nanoprobe were investigated in vitro, and the in vivo NIR-IIb imaging and PTT performance were evaluated in normal, subcutaneous, orthotopic, and metastatic tumor mice models. IT-TQF NP-based NIR-IIb imaging demonstrated high spatial resolution and high tissue penetration depth, and small normal blood vessels (55.3 µm) were successfully imaged in the NIR-IIb window. Subcutaneous, orthotopic, and metastatic tumors were all clearly delineated. A high tumor signal-to-background ratio (SBR) of 9.42 was achieved for orthotopic osteosarcoma models, and the erosions of bone tissue caused by tumor cells were precisely visualized. Moreover, NIR-II image-guided surgery was successfully performed to completely remove the orthotopic tumor. Importantly, IT-TQF NPs displayed high PTT efficacy (photothermal conversion efficiency: 47%) for effective treatment of tumor mice. In conclusion, IT-TQF NPs are a novel and promising phototheranostic agent in the NIR-IIb window, and the nanoprobe has high potential for a broad range of biomedical applications.

Acceptor engineering for NIR-II dyes with high photochemical and biomedical performance.

It is highly important and challenging to develop donor-acceptor-donor structured small-molecule second near-infrared window (NIR-II) dyes with excellent properties such as water-solubility and chem/photostability. Here, we discovery an electron acceptor, 6,7-di(thiophen-2-yl)-[1,2,5]thiadiazolo[3,4-g]quinoxaline (TQT) with highest stability in alkaline conditions, compared with conventional NIR-II building block benzobisthiadiazole (BBT) and 6,7-diphenyl-[1,2,5] thiadiazolo[3,4-g]quinoxaline (PTQ). The sulfonated hydrophilic dye, FT-TQT, is further synthesized with 2.13-fold increased quantum yield than its counterpart FT-BBT with BBT as acceptor. FT-TQT complexed with FBS is also prepared and displays a 16-fold increase in fluorescence intensity compared to FT-TQT alone. It demonstrates real-time cerebral and tumor vessel imaging capability with µm-scale resolution. Dynamic monitoring of tumor vascular disruption after drug treatment is achieved by NIR-II fluorescent imaging. Overall, TQT is an efficient electron acceptor for designing innovative NIR-II dyes. The acceptor engineering strategy provides a promising approach to design next generation of NIR-II fluorophores which open new biomedical applications.

A phosphorescent probe for in vivo imaging in the second near-infrared window.

In the second near-infrared spectral window (NIR-II; with wavelengths of 1,000-1,700 nm), in vivo fluorescence imaging can take advantage of reduced tissue autofluorescence and lower light absorption and scattering by tissue. Here, we report the development and in vivo application of a NIR-II phosphorescent probe that has lifetimes of hundreds of microseconds and a Stokes shift of 430 nm. The probe is made of glutathione-capped copper-indium-selenium nanotubes, and in acidic environments (pH 5.5-6.5) switches from displaying fluorescence to phosphorescence. In xenograft models of osteosarcoma and breast cancer, intravenous or intratumoral injections of the probe enabled phosphorescence imaging at signal-to-background ratios, spatial resolutions and sensitivities higher than NIR-II fluorescence imaging with polymer-stabilized copper-indium-sulfide nanorods. Phosphorescence imaging may offer superior imaging performance for a range of biomedical uses.

J-aggregates albumin-based NIR-II fluorescent dye nanoparticles for cancer phototheranostics.

Phototheranostics, relying on energy conversions of fluorophores upon excitation, integrating diagnostic fluorescence imaging and photo-driven therapy, represents a promising strategy for cancer precision medicine. Compared with the first near-infrared biological window (NIR-I), fluorophores imaged in the second window (NIR-II, 1000-1700 â€‹nm) exhibit a higher temporal and spatial resolution and tissue penetration depth. Polymethine cyanine-based dye IR1061 is a typical NIR-II small-molecule organic fluorophore, but its low water solubility and short circulation time limiting its biological applications. Therefore, human serum albumin (HSA) nanoparticles with great biocompatibility and biosafety were employed to fabricate hydrophobic IR1061, which exhibited red-shifted absorption band as typical for J-aggregates. Moreover, IR1061@HSA nanoparticles can be successfully used for NIR-II imaging to noninvasively visualize the tumor vascular networks, as well as real-time intraoperative image-guided tumor resection. Interestingly, benefiting from the high photothermal conversion efficiency brought by J-aggregates, IR1061@HSA nanoparticles were also explored for photothermal therapy (PTT) and cause efficient thermal ablation of tumors. Overall, IR1061@HSA, as a novel J-aggregates albumin-based NIR II dye nanoparticle with high biocompatibility, provides an integrated versatile platform for cancer phototheranostics with promising clinical translation prospects.