Recent technological advances have expanded fluorescence (FL) imaging into the second near-infrared region (NIR-II; wavelength = 1000-1700 nm), providing high spatial resolution through deep tissues. However, bright and compact fluorophores are rare in this region, and sophisticated control over NIR-II probes has not been fully achieved yet. Herein, we report an enzyme-activatable NIR-II probe that exhibits FL upon matrix metalloprotease activity in tumor microenvironment. Bright and stable PbS/CdS/ZnS core/shell/shell quantum dots (QDs) were synthesized as a model NIR-II fluorophore, and activatable modulators were attached to exploit photoexcited electron transfer (PET) quenching. The quasi type-II QD band alignment allowed rapid and effective FL modulations with the compact surface ligand modulator that contains methylene blue PET quencher. The modulator was optimized to afford full enzyme accessibility and high activation signal surge upon the enzyme activity. Using a colon cancer mouse model, the probe demonstrated selective FL activation at tumor sites with 3-fold signal enhancement in 10 min. Optical phantom experiments confirmed the advantages of the NIR-II probe over conventional dyes in the first near-infrared region.
Non-cadmium-based highly bright and stable far-red- and near-infrared (NIR)-emitting Cu-doped InP/ZnS (core/shell) quantum dots were synthesized with precisely controlled doping steps and were employed for bioimaging probes.
The detection of colon cancer using endoscopy is widely used, but the interpretation of the diagnosis is based on the clinician's naked eye. This is subjective and can lead to false detection. Here we developed a rapid and accurate molecular fluorescence imaging technique using antibody-coated quantum dots (Ab-QDs) sprayed and washed simultaneously on colon tumor tissues inside live animals, subsequently excited and imaged by endoscopy. QDs were conjugated to matrix metalloproteinases (MMP) 9, MMP 14, or carcinoembryonic antigen (CEA) Abs with zwitterionic surface coating to reduce nonspecific bindings. The Ab-QD probes can diagnose tumors on sectioned mouse tissues, fresh mouse colons stained ex vivo and also in vivo as well as fresh human colon adenoma tissues in 30 min and can be imaged with a depth of 100 μm. The probes successfully detected not only cancers that are readily discernible by bare eyes but also hyperplasia and adenoma regions. Sum and cross signal operations provided postprocessed images that can show complementary information or regions of high priority. This multiplexed quantum dot, spray-and-wash, and endoscopy approach provides a significant advantage for detecting small or flat tumors that may be missed by conventional endoscopic examinations and bestows a strategy for the improvement of cancer diagnosis.
RNA interference (RNAi) is a mechanism in which small interfering RNA (siRNA) silences a target gene. Herein, we describe a DNA hydrogel capable of producing siRNA and interfering with protein expression. This RNAi-exhibiting gel (termed I-gel for interfering gel) consists of a plasmid carrying the gene transcribing siRNA against the target mRNA as part of the gel scaffold. The RNAi efficiency of the I-gel has been confirmed by green fluorescent protein (GFP) expression assay and RNA production quantification. The plasmid stability in the I-gel results in an 8-times higher transcription efficiency than that of the free plasmid. We further applied the I-gel to live cells and confirmed its effect in interfering with the GFP expression. The I-gel shows higher RNAi effect than plasmids in free form or complexed with Lipofectamine. This nanoscale hydrogel, which is able to produce RNA in a cell, provides a platform technology for efficient RNAi system.
A rapid and accurate molecular fluorescence imaging technique will greatly reduce cancer mortality by overcoming the detection limit of the naked eye in colonoscopy. Two imaging probes are reported that can be co-used for colonoscopic diagnosis: a fluorescent molecular probe, cresyl violet-glutamic acid derivative, that ratiometrically switches between two fluorescent colors in response to the enzyme activity of λ-glutamyltranspeptidase and an antibody quantum dot probe that is a conjugate of biocompatible AgInS 2 quantum dot with matrix metalloproteinase 14 antibodies. Validity of the probes is confirmed using human colon cancer cell lines, ex vivo mouse model tissues, and patient tumor colon tissues in which the tumor lesions are well-visualized in less than five minutes. Co-application of the two probes onto fresh colon tissues affords accurate visualization of carcinomas and also hyperplasia and adenoma regions. Fresh human colon adenoma tissues are also valuated, where the two probes show complementary diagnoses of cancer. Two-photon microscopy shows the time-dependent depth profiles of the two probes. Both rapidly permeate and populate most at 10-20 µm from the surface. Extensive toxicity studies are performed for the two probes at cellular level and also at the organ level using a small animal model.
Abstract:Intravital imaging has provided molecular, cellular and anatomical insight into the study of tumor. Early detection and treatment of gastrointestinal (GI) diseases can be enhanced with specific molecular markers and endoscopic imaging modalities. We present a wide-field multichannel fluorescence endoscope to screen GI tract for colon cancer using multiple molecular probes targeting matrix metalloproteinases (MMP) conjugated with quantum dots (QD) in AOM/DSS mouse model. MMP9 and MMP14 antibody (Ab)-QD conjugates demonstrate specific binding to colonic adenoma. The average target-to-background (T/B) ratios are 2.10 ± 0.28 and 1.78 ± 0.18 for MMP14 Ab-QD and MMP9 Ab-QD, respectively. The overlap between the two molecular probes is 67.7 ± 8.4%. The presence of false negative indicates that even more number of targeting could increase the sensitivity of overall detection given heterogeneous molecular expression in tumors. Our approach indicates potential for the screening of small or flat lesions that are precancerous. References and links1. G. Oh, E. Chung, and S. H. Yun, "Optical fibers for high-resolution in vivo microendoscopic fluorescence imaging," Opt. Fiber Technol. 19(6), 760-771 (2013). 2. J. C. van Rijn, J. B. Reitsma, J. Stoker, P. M. Bossuyt, S. J. van Deventer, and E. Dekker, "Polyp miss rate determined by tandem colonoscopy: a systematic review," Am. J. Gastroenterol. 101(2), 343-350 (2006). 3. C. A. Munroe, P. Lee, A. Copland, K. K. Wu, T. Kaltenbach, R. M. Soetikno, and S. Friedland, "A tandem colonoscopy study of adenoma miss rates during endoscopic training: a venture into uncharted territory," Gastrointest. Endosc. 75(3), 561-567 (2012 Rat, P. Roignot, J. Faivre, P. Laurent-Puig, and F. Piard, "Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers," Int.
PbS/CdS core/shell quantum dots (QDs) that emit at the second near‐infrared (NIR‐II, 1000–1700 nm) window are synthesized. The PbS seed size and CdS shell thicknesses are carefully controlled to produce bright and narrow fluorescence that are suitable for multiplexing. A polymer encapsulation yields polymer‐encapsulated NIR‐II QDs (PQDs), which provides the QDs with long‐term fluorescence stability over a week in biological media. Exploiting the simple bioconjugation capability of PQDs, folic acids are conjugated to PQDs that can efficiently label folate receptor overexpressing cell lines. The PQDs afford multiplexed and nearly real‐time longitudinal whole‐body in vivo imaging. Two NIR‐II QD probes are prepared: folic acid‐conjugated PQDs (FA‐PQDs) emitting at 1280 nm and unconjugated PQDs emitting at 1080 nm. The two PQDs are engineered to have compact and similar hydrodynamic sizes. A mixture of the folic acid‐conjugated PQD and unconjugated PQDs is injected intravenously into a tumor‐xenografted mouse, and the signals from them are monitored. This NIR‐II whole‐body imaging with the two PQDs provides precise evaluation of the active ligand‐assisted tumor‐targeting capability of the FA‐PQD probe because the hydrodynamic size control of the two PQDs effectively eliminates effects from the size‐dependent accumulations by permeations and retentions in tumors.
In spite of recent developments in mass spectrometry imaging techniques, high-resolution multiplex protein bioimaging techniques are required to unveil the complex inter-and intracellular biomolecular interactions for accurate understanding of life phenomena and disease mechanisms. Herein, we report multiplex protein imaging with secondary ion mass spectrometry (SIMS) using metal oxide nanoparticle (MONP)conjugated antibodies with <300 nm spatial resolution in the low ion dose without ion beam damage because of the high secondary ion yields of the MONPs, which can provide simultaneous imaging of several proteins, especially from cell membranes. We applied our new imaging technique for the study of hippocampal tissue samples from control and Alzheimer's disease (AD) model mice; the proximity of protein clusters in the hippocampus CA1 region showed intriguing dependence on aging and AD progress, suggesting that protein cluster proximity may be helpful for understanding pathological pathways in the microscopic cellular level.
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