NIR-II Fluorescence Imaging for the Detection and Resection of Cancerous Foci and Lymph Nodes in Early-Stage Orthotopic and Advanced-Stage Metastatic Ovarian Cancer Models
Tao PuYawei LiuYuetian PeiJing PengZehua WangMing DuQiyu LiuFangfang ZhongMingxing ZhangFuyou LiCongjian XuXiaoyan Zhang
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Abstract:
The high mortality rate of ovarian cancer can be primarily attributed to late diagnosis and early lymph node (LN) metastasis. The anatomically deep-located ovaries own intricate anatomical structures and lymphatic drainages that compromise the resolution and sensitivity of near-infrared first-window (NIR-I) fluorescence imaging. Reported NIR-II imaging studies of ovarian cancer focused on late-stage metastasis detection via the intraperitoneal xenograft model. However, given the significant improvement in patient survival associated with early-stage cancer detection, locating tumors that are restricted within the ovary is equally crucial. We obtained the polymer nanoparticles with bright near-infrared-II fluorescence (NIR-II NPs) by nanoprecipitation of DSPE-PEG, one of the ingredients of FDA-approved nanoparticle products, and benzobisthiadiazole, an organic NIR-II dye. The one-step synthesis and safe component lay the groundwork for its clinical translation. Benefiting from the NIR-II emission (∼1060 nm), NIR-II NPs enabled a high signal-to-noise (S/N) ratio (13.4) visualization of early-stage orthotopic ovarian tumors with NIR-II fluorescence imaging for the first time. Imaging with orthotopic xenograft allows a more accurate mimic of human ovarian cancer origin, thereby addressing the dilemma of translating existing nanoprobe preclinical research by providing the nano-bio interactions with early local tumor environments. After PEGylation, the desirable-sized probe (∼80 nm) exhibited high lymphophilicity and relatively extended circulation. NIR-II NPs maintained their accurate detection of orthotopic tumors, tumor-regional LNs, and minuscule (<1 mm) disseminated peritoneal metastases simultaneously (with S/N ratios all above 5) in mice with advanced-stage cancer in real time ∼36 h after systematic delivery. With NIR-II fluorescence guidance, we achieved accurate surgical staging in tumor-bearing mice and complete tumor removal comparable to clinical practice, which provides preclinical data for translating NIR-II fluorescence image-guided surgery.Keywords:
Fluorescence-lifetime imaging microscopy
Nanoprobe
Ovarian tumor
Hydrogen peroxide is a biologically important reactive oxygen species (ROS) and plays crucial roles in living organisms. Herein, a FRET-based ratiometric fluorescent probe has been developed for detecting H2O2in vitro and in vivo. In this nanoprobe, carbon dots serve as the energy donor and carrier for the H2O2 recognition element. This nanoprobe exhibits fast-response, low toxicity, high sensitivity (with a detection limit of 0.5 μM) and selectivity towards H2O2 over other reactive oxygen or nitrogen species. The nanoprobe has been successfully applied in the detection of H2O2 in live cells and in zebrafish larvae. By incubating the nanoprobe with zebrafishes, the nanoprobe can be absorbed by the fishes within 1 h and accumulates mainly in the abdominal region. Due to its small size (∼4 nm), the nanoprobe is gradually excreted by zebrafishes without long-term accumulation. Moreover, as the first ratiometric chemoprobe that can detect H2O2in vivo, the nanoprobe has been found capable of detecting and locating endogenous H2O2 in zebrafishes as a result of drug-induced oxidative damage. The successful detection of H2O2 by the nanoprobe in vivo may support its eventual use in clinical applications.
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Abstract Background: Excellent imaging performance and good biocompatibility of contrast agents are considered as prerequisites for accurate tumor diagnosis and treatment. Results: Herein, a novel imaging nanoprobe with actively targeting performance based on ultrasmall paramagnetic iron oxide (USPIO) was constructed by a facile cation exchange strategy followed by conjugation with transferrin (Tf). The stable gadolinium (Gd 3+ ) chelation endows the nanoparticles (NPs) with a low value of r 2 /r 1 (1.28) and relatively high r 1 value of 3.2 mM -1 s -1 , enabling their use in T 1 -weighted positive MR imaging. Conclusion: This constructed transferrin modified gadolinium-iron chelate nanoprobe, named as TUG, shows high biocompatibility within a given dose range. More importantly, compared with clinically used Gd-based small molecule contrast agents, the obtained TUG can be more engulfed by breast cancer cells, showing much enhanced T 1 -weighted positive MR imaging in either subcutaneous or in situ tumor models of breast cancer. This novel nanoprobe holds enormous promise to be utilized as a targeting contrast agent with high efficacy for T 1 -weighted positive MR imaging.
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Aim: To monitor cells in vivo or to detect the sentinel lymph node, we developed a PET/MRI silica nanoprobe with an enhanced near-infrared fluorescence signal. Methods: We developed enhanced near-infrared fluorescent (NIRF) magnetic silica nanoparticles, MNP-SiO2(NIR797), that encapsulate NIRF dye in the silica. We applied this probe to visualizing cells in the deep tissue of mice using NIRF imaging. After labeling with a radioisotope, 68Ga, on the surface of MNP-SiO2(NIR797), we injected it into the forepaw of mice to visualize the sentinel lymph node. Results: This encapsulated nanoprobe showed enhancement of fluorescent intensity and stability compared with the nanoprobe, which had the same dyes on the surface of the silica nanoparticles. We also obtained multimodal in vivo imaging of 68Ga-{MNP-SiO2(NIR797)} applied to sentinel lymph node detection of mice using PET/MRI/NIRF images. Conclusion: This multimodal nanoprobe with enhanced fluorescence may provide a useful tool for imaging diagnostics and cell tracking.
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Bioimaging is widely used in various fields of modern medicine. Fluorescence imaging has the advantages of high sensitivity, high selectivity, noninvasiveness, in situ imaging, and so on. However, one-photon (OP) fluorescence imaging has problems, such as low tissue penetration depth and low spatiotemporal resolution. These disadvantages can be solved by two-photon (TP) fluorescence imaging. However, TP imaging still uses fluorescence intensity as a signal. The complexity of organisms will inevitably affect the change of fluorescence intensity, cause false-positive signals, and affect the accuracy of the results obtained. Fluorescence lifetime imaging (FLIM) is different from other kinds of fluorescence imaging, which is an intrinsic property of the material and independent of the material concentration and fluorescence intensity. FLIM can effectively avoid the fluctuation of TP imaging based on fluorescence intensity and the interference of autofluorescence. Therefore, based on silica-coated gold nanoclusters (AuNCs@SiO2) combined with nucleic acid probes, the dual-mode nanoprobe platform was constructed for TP and FLIM imaging of intracellular endogenous miRNA-21 for the first time. First, the dual-mode nanoprobe used a dual fluorescence quencher of BHQ2 and graphene oxide (GO), which has a high signal-to-noise ratio and anti-interference. Second, the dual-mode nanoprobe can detect miR-21 with high sensitivity and selectivity in vitro, with a detection limit of 0.91 nM. Finally, the dual-mode nanoprobes performed satisfactory TP fluorescence imaging (330.0 μm penetration depth) and FLIM (τave = 50.0 ns) of endogenous miR-21 in living cells and tissues. The dual-mode platforms have promising applications in miRNA-based early detection and therapy and hold much promise for improving clinical efficacy.
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Cu2+ is closely related to the occurrence and development of Wilson's disease (WD), and quantitative detection of various copper indicators (especially liver Cu2 and urinary Cu2+) is the key step for the early diagnosis of WD in the clinic. However, the clinic Cu2+ detection approach was mainly based on testing the liver tissue through combined invasive liver biopsy and the ICP-MS method, which is painful for the patient and limited in determining WD status in real-time. Herein, we rationally designed a type of Cu2+-activated nanoprobe based on nanogapped gold nanoparticles (AuNNP) and poly(N-isopropylacrylamide) (PNIPAM) to simultaneously quantify the liver Cu2+ content and urinary Cu2+ in WD by photoacoustic (PA) imaging and ratiometric surface-enhanced Raman scattering (SERS), respectively. In the nanoprobe, one Raman molecule of 2-naphthylthiol (NAT) was placed in the nanogap of AuNNP. PNIPAM and the other Raman molecule mercaptobenzonitrile (MBN) were coated on the AuNNP surface, named AuNNP-NAT@MBN/PNIPAM. Cu2+ can efficiently coordinate with the chelator PNIPAM and lead to aggregation of the nanoprobe, resulting in the absorption red-shift and increased PA performance of the nanoprobe in the NIR-II window. Meanwhile, the SERS signal at 2223 cm–1 of MBN is amplified, while the SERS signal at 1378 cm–1 of NAT remains stable, generating a ratiometric SERS I2223/I1378 signal. Both NIR-II PA1250 nm and SERS I2223/I1378 signals of the nanoprobe show a linear relationship with the concentration of Cu2+. The nanoprobe was successfully applied for in vivo quantitative detection of liver Cu2+ of WD mice through NIR-II PA imaging and accurate quantification of urinary Cu2+ of WD patients by ratiometric SERS. We anticipate that the activatable nanoprobe might be applied for assisting an early, precise diagnosis of WD in the clinic in the future.
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We report a new type of dual modal nanoprobe to combine optical and magnetic resonance bioimaging. A simple reverse microemulsion method and coating process was introduced to synthesize silica-coated Gd2(CO3)3:Tb nanoparticles, and the particles, with an average diameter of 16 nm, can be dispersed in water. As in vitro cell imaging of the nanoprobe shows, the nanoprobe accomplishes delivery to gastric SGC7901 cancer cells successfully in a short time, as well as NCI-H460 lung cancer cells. Furthermore, it presents no evidence of cell toxicity or adverse affect on kidney cell growth under high dose, which makes the nanoprobe's optical bioimaging modality available. The possibility of using the nanoprobe for magnetic resonance imaging is also demonstrated, and the nanoprobe displays a clear T1-weighted effect and could potentially serve as a bimodal T1-positive contrast agent. Therefore, the new nanoprobe formed from carbonate nanoprobe doped with rare earth ions provides the dual modality of optical and magnetic resonance imaging.
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A BSTRACT Ovarian tumors are a common form of neoplasia in women and it accounts for about 30% of female genital cancers. A coexistence of ovarian tumors with the same histogenetic origin such as germ cell or epithelial or sex cord stromal, but different histologic subtype is relatively common, whereas a synchronous occurrence of tumors with different histogenetic origin is rare. We report a case of 58-year-old woman with the synchronous presentation of adult granulosa cell tumor with fibroma (ovarian tumors with the same origin (sex cord stromal) but different histologic type) in one ovary and Brenner tumor (epithelial origin) in other ovary. Our patient presented with postmenopausal bleeding and was diagnosed with this rare combination of ovarian tumors on histopathology supplemented with immunohistochemistry. On extensive literary search, there is only a single report of mixed ovarian tumor composed of Brenner tumor and adult-type granulosa cell tumor. Our case is different from the above-mentioned report as although, in our patient both tumors coexisted, but in contralateral ovaries.
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Biological fluorescence imaging technologies have attracted a lot of attention and have been widely used in biomedical fields. Compared with other technologies, fluorescence imaging has a lower cost, higher sensitivity, and easier operation. However, due to the disadvantages of one-photon (OP) fluorescence imaging, such as low spatial and poor temporal resolution and poor tissue permeability depth, the application of OP fluorescence imaging has some limitations. Though two-photon (TP) fluorescence imaging can well overcome these shortcomings of OP, the single-mode imaging remains deficient. Therefore, dual-mode imaging combined with TP imaging and magnetic resonance imaging (MRI) can make up for the deficiency well, which make dual-mode imaging for the early diagnosis of diseases more accurate. Hence, a dual-mode nanoprobe TP-CQDs@MnO2 was designed for probing the fluorescence/MR dual-mode imaging strategy of intracellular H+ by using TP-CQDs (two photon-carbon quantum dots) and MnO2 nanosheets. The MnO2 nanosheets treated as fluorescence quenching agents of TP-CQDs exhibited a supersensitive response to H+, which made the fluorescence signals turn "off" to "on" for TP fluorescence imaging, in the meantime, large amounts of Mn2+ were generated for MRI. A dual-mode nanoprobe TP-CQDs@MnO2 can monitor intracellular wide pH (4.0–8.0), and the fluorescence intensity of TP-CQDs@MnO2 has recovered up to more than six times and the corresponding results of MRI were satisfactory. TP fluorescence imaging of cells and tissues showed higher detection sensitivity and deeper tissue penetration (240.0 μm) than OP. The dual-mode imaging platform hold great promise for pH-related early diagnosis and treatment, which has great potential to improve clinical efficacy.
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