Abstract
The limited signal of long-wavelength near-infrared-II (NIR-II, 900–1880 nm) fluorophores and the strong background caused by the diffused photons make high-contrast fluorescence imaging in ...vivo with deep tissue disturbed still challenging. Here, we develop NIR-II fluorescent small molecules with aggregation-induced emission properties, high brightness, and maximal emission beyond 1200 nm by enhancing electron-donating ability and reducing the donor-acceptor (D-A) distance, to complement the scarce bright long-wavelength emissive organic dyes. The convincing single-crystal evidence of D-A-D molecular structure reveals the strong inhibition of the π-π stacking with ultralong molecular packing distance exceeding 8 Å. The delicately-designed nanofluorophores with bright fluorescent signals extending to 1900 nm match the background-suppressed imaging window, enabling the signal-to-background ratio of the tissue image to reach over 100 with the tissue thickness of ~4–6 mm. In addition, the intraluminal lesions with strong negatively stained can be identified with almost zero background. This method can provide new avenues for future long-wavelength NIR-II molecular design and biomedical imaging of deep and highly scattering tissues.
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with the worst prognosis. Radiotherapy (RT) is one of the core modalities for the disease; however, the ionizing radiation of RT has ...severe side effects. The consistent development direction of RT is to achieve better therapeutic effect with lower radiation dose. Studies have demonstrated that synergistic effects can be achieved by combining RT with non-ionizing radiation therapies such as light and magnetic therapy, thereby achieving the goal of dose reduction and efficacy enhancement. In this study, we applied FeCo NPs with magneto thermal function and phototherapeutic agent IR-780 to construct an ionizing and non-ionizing radiation synergistic nanoparticle (INS NPs). INS NPs are first subjected to morphology, size, colloidal stability, loading capacity, and photothermal conversion tests. Subsequently, the cell inhibitory and cellular internalization were evaluated using cell lines in vitro. Following comprehensive assessment of the NPs' in vivo biocompatibility, tumor-bearing mouse model was established to evaluate their distribution, targeted delivery, and anti-tumor effects in vivo. INS NPs have a saturation magnetization exceeding 72 emu/g, a hydrodynamic particle size of approximately 40 nm, a negatively charged surface, and good colloidal stability and encapsulation properties. INS NPs maintain the spectral characteristics of IR-780 at 808 nm. Under laser irradiation, the maximum temperature was 92 degreesC, INS NPs also achieved the effective heat temperature in vivo. Both in vivo and in vitro tests have proven that INS NPs have good biocompatibility. INS NPs remained effective for more than a week after one injection in vivo, and can also be guided and accumulated in tumors through permanent magnets. Later, the results exhibited that under low-dose RT and laser irradiation, the combined intervention group showed significant synergetic effects, and the ROS production rate was much higher than that of the RT and phototherapy-treated groups. In the mice model, 60% of the tumors were completely eradicated. INS NPs effectively overcome many shortcomings of RT for TNBC and provide experimental basis for the development of novel clinical treatment methods for TNBC.
Abstract
Bright anti-Stokes fluorescence (ASF) in the first near-infrared spectral region (NIR-I, 800 nm–900 nm) under the excitation of a 915 nm continuous wave (CW) laser, is observed in ...Indocyanine Green (ICG), a dye approved by the Food and Drug Administration for clinical use. The dependence of fluorescence intensity on excitation light power and temperature, together with fluorescence lifetime measurement, establish this ASF to be originated from absorption from a thermally excited vibrational level (hot-band absorption), as shown in our experiments, which is stronger than the upconversion fluorescence from widely-used rare-earth ion doped nanoparticles. To test the utility of this ASF NIR-I probe for advanced bioimaging, we successively apply it for biothermal sensing, cerebral blood vessel tomography and blood stream velocimetry. Moreover, in combination with L1057 nanoparticles, which absorb the ASF of ICG and emit beyond 1100 nm, these two probes generate multi-mode images in two fluorescent channels under the excitation of a single 915 nm CW laser. One channel is used to monitor two overlapping organs, urinary system & blood vessel of a live mouse, while the other shows urinary system only. Using in intraoperative real-time monitoring, such multi-mode imaging method can be beneficial for visual guiding in anatomy of the urinary system to avoid any accidental injury to the surrounding blood vessels during surgery.
Near-infrared(NIR) lights are powerful tools to conduct deep-tissue imaging since NIR-I wavelengths hold less photon absorption and NIR-II wavelengths serve low photon scattering in the biological ...tissues compared with visible lights. Two-photon fluorescence lifetime microscopy(2PFLM) can utilize NIR-II excitation and NIR-I emission at the same time with the assistance of a well-designed fluorescent agent. Aggregation induced emission(AIE) dyes are famous for unique optical properties and could serve a large two-photon absorption(2PA) cross-section as aggregated dots. Herein, we report two-photon fluorescence lifetime microscopic imaging with NIR-II excitation and NIR-I emission using a novel deep-red AIE dye. The AIE-gens held a 2PA cross-section as large as 1.61×10
4
GM at 1040 nm. Prepared AIE dots had a two-photon fluorescence peak at 790 nm and a stable lifetime of 2.2 ns under the excitation of 1040 nm femtosecond laser. The brain vessels of a living mouse were vividly reconstructed with the two-photon fluorescence lifetime information obtained by our home-made 2PFLM system. Abundant vessels as small as 3.17 µm were still observed with a nice signal-background ratio at the depth of 750 µm. Our work will inspire more insight into the improvement of the working wavelength of fluorescent agents and traditional 2PFLM.
Hot-band absorption (HBA)-induced anti-Stokes fluorescence (ASF) with longer-wavelength excitation is one effective pathway to deep penetration and low autofluorescence in intravital fluorescence ...imaging, raising demands for fluorophores with broad spectra, high absorption, and strong emission. However, typical fluorescent dyes display some emission quenching when their concentration is increased in order to obtain brighter fluorescence. In this work, the HBA-induced ASF of aggregation-induced emission (AIE) dots is reported. BPN-BBTD dots were synthesized and confirmed with a fluorescence enhancement and a considerable ASF intensity. In addition, the mechanism of ASF and the HBA process of BPN-BBTD dots were carefully validated and discussed. To obtain the full advantages of the long-wavelength excitation and the short fluorescence lifetime in deep-tissue bioimaging, a large-depth ASF confocal microscopic imaging of in vivo cerebral vasculature was conducted under the excitation of a 980 nm continuous wave laser after intravenous injection of BPN-BBTD dots. Meanwhile, the 3D structure of the cerebrovascular network was successfully reconstructed.
Theranostic agents with fluorescence in the second near-infrared (NIR-II) window, especially in its long-wavelength region, and NIR-II-excitable photothermal effect is promising but challenging in ...tumor diagnosis and therapy. Here, we report a simple but effective strategy to develop semiconducting polymer nanoparticles-based theranostic agents (PBQ
NPs) and demonstrate their applications for long-wavelength NIR-II fluorescence imaging beyond 1400 nm and photothermal therapy (PTT) of tumors upon excitation at 1064 nm. Both experimental results and theory calculations show that the brightness and photothermal performance of PBQ
NPs can be simultaneously improved by simply increasing the repeating unit number of semiconducting polymers. For example, PBQ45 NPs have 5-fold higher brightness than PBQ5 NPs and 6.7-fold higher photothermal effect (based on PCE × ε) than PBQ3 NPs, and exhibit promising applications in long-wavelength NIR-II fluorescence abdomen imaging, image-guided tumor resection, and image-guided PTT. This study demonstrates the effectiveness and importance of repeating unit numbers in regulating the theranostic performance, which has not received enough attention before.
Display omitted
•Drug nanocarriers were prepared by dual supramolecular self-assembly.•pH and GSH-responsive programmed nanocarriers were designed for PDT.•The nanocarriers showed enhanced ...photodynamic therapy on orthotopic hepatoma.
Supramolecular self-assembly has been extensively adopted as a promising strategy to fabricate nanoassemblies as drug carriers for cancer treatment. In this research, glutathione (GSH) activatable photosensitizer (PS)-conjugated nanoassemblies are fabricated by dual supramolecular self-assembly. Poly(ethylene glycol)-block-polylysine with pendant benzimidazole (PEG-b-PLys(BM)) is synthesized as the guest molecule of α-CD and β-CD. Chlorin e6 (Ce6) is loaded to the nanocarriers by the formation of polyrotaxanes between Ce6 conjugated α-CD (α-CD-SS-Ce6) and PEG block of PEG-b-PLys(BM). The Ce6 conjugated nanocarriers are then capped by (2-hydroxypropyl)-β-cyclodextrin (β-CD-HP) due to the host–guest interaction between β-CD-HP and benzimidazole (BM) to form supramolecular nanocarriers (BM-Ce6 NPs). BM-Ce6 NPs are negatively charged in physiological environment. However, because of the removal of β-CD-HP upon the protonation of BM, the surface charge of BM-Ce6 NPs can be converted to positive in acidic tumour microenvironment, which could lead to enhanced cellular internalization. Furthermore, Ce6 can be effectively released and activated in intracellular reductive environment, resulting in stronger reactive oxygen species (ROS) generation capability. The photodynamic therapeutic efficacy of BM-Ce6 NPs is evaluated on subcutaneous and orthotopic hepatoma model on nude mice. This research provides an innovative approach to fabricate drug nanocarriers by dual supramolecular self-assembly.
Molecular fluorophores with the second near‐infrared (NIR‐II) emission hold great potential for deep‐tissue bioimaging owing to their excellent biocompatibility and high resolution. Recently, ...J‐aggregates are used to construct long‐wavelength NIR‐II emitters as their optical bands show remarkable red shifts upon forming water‐dispersible nano‐aggregates. However, their wide applications in the NIR‐II fluorescence imaging are impeded by the limited varieties of J‐type backbone and serious fluorescence quenching. Herein, a bright benzocthiophene (BT) J‐aggregate fluorophore (BT6) with anti‐quenching effect is reported for highly efficient NIR‐II bioimaging and phototheranostics. The BT fluorophores are manipulated to have Stokes shift over 400 nm and aggregation‐induced emission (AIE) property for conquering the self‐quenching issue of the J‐type fluorophores. Upon forming BT6 assemblies in an aqueous environment, the absorption over 800 nm and NIR‐II emission over 1000 nm are boosted for more than 41 and 26 folds, respectively. In vivo visualization of the whole‐body blood vessel and imaging‐guided phototherapy results verify that BT6 NPs are excellent agent for NIR‐II fluorescence imaging and cancer phototheranostics. This work develops a strategy to construct bright NIR‐II J‐aggregates with precisely manipulated anti‐quenching properties for highly efficient biomedical applications.
A bright benzocthiophene J‐aggregate with anti‐quenching property is developed. The J‐type nanoparticles (NPs) are featured with large Stokes shift of 402 nm. After forming aggregates in aqueous milieu, the second near‐infrared (NIR‐II) fluorescence intensity is enhanced ≈26 folds due to aggregation‐induced emission (AIE) effect. The bright J‐type AIE NPs are used to conduct whole‐body blood vessel NIR‐II fluorescence imaging and cancer phototheranostics.
Superb reliability and biocompatibility equip aggregation‐induced emission (AIE) dots with tremendous potential for fluorescence bioimaging. However, there is still a chronic lack of design ...instructions of excretable and bright AIE emitters. Here, a kind of PEGylated AIE (OTPA‐BBT) dots with strong absorption and extremely high second near‐infrared region (NIR‐II) PLQY of 13.6% is designed, and a long‐aliphatic‐chain design blueprint contributing to their excretion from an animal's body is proposed. Assisted by the OTPA‐BBT dots with bright fluorescence beyond 1100 nm and even 1500 nm (NIR‐IIb), large‐depth cerebral vasculature (beyond 600 µm) as well as real‐time blood flow are monitored through a thinned skull, and noninvasive NIR‐IIb imaging with rich high‐spatial‐frequency information gives a precise presentation of gastrointestinal tract in marmosets. Importantly, after intravenous or oral administration, the definite excretion of OTPA‐BBT dots from the body is demonstrated, which provides influential evidence of biosafety.
The long aliphatic chains of aggregation‐induced emission (AIE)‐gens are conducive to the excretion of AIE dots from an animal's body. The deep micro cerebrovasculature in marmosets is visualized through the thinned skull. Non‐invasive and high‐spatial‐frequency near‐infrared‐IIb imaging is utilized in non‐human primates. It is believed this work provides crucial ideas to advance the development of biosafe AIE dots and future nanomedicine.
Uterine diseases seriously threaten the physical and mental health of women. The main principle, when clinicians adopt examinations, is to achieve efficient diagnosis without negative effect on the ...physical function including fertility. Hysterography in near-infrared (NIR) IIb window (1500–1700 nm) presents perceptibly enhanced signal to background ratio (SBR) and higher penetration capability compared with those beyond 1000 nm and 1300 nm, but lays down high requirements for the biosafety of fluorophores at the same time. Assisted by the biologically excretable aggregation-induced emission (AIE) dots, non-invasive NIR-IIb fluorescence hysterography visualized typical Y-shaped uteruses, real-time uterine peristalsis or the uterine lesions (mimetic disease statuses in clinic) in mouse models. Significantly, after intrauterine perfusion, the reproductive capacity was unimpaired via fertility assessment and histological analysis. This work could inspire some new ideas for non-invasive clinical diagnosis of uterine diseases and effectively promote the clinical translation of AIE dots.
Display omitted
•Bright aggregation-induced emission dots over 1500 nm benefit deep penetration.•Novel dots show no obvious effect on fertility post intravenous or uterine perfusion.•Near-infrared-IIb fluorescence imaging enables non-invasive hysterography in vivo.•Fluorescence hysterography assists uterine rupture detection and repair surgery.•High-definition visualization allows for evaluating uterine obstruction and relief.
PDF
