Magnetic resonance imaging with upconversion nanoprobes capable of crossing the blood-cerebrospinal fluid barrier.

The central nervous system (CNS) maintains homeostasis with its surrounding environment by restricting the ingress of large hydrophilic molecules, immune cells, pathogens, and other external harmful substances to the brain. This function relies heavily on the blood-cerebrospinal fluid (B-CSF) and blood-brain barrier (BBB). Although considerable research has examined the structure and function of the BBB, the B-CSF barrier has received little attention. Therapies for disorders associated with the central nervous system have the potential to benefit from targeting the B-CSF barrier to enhance medication penetration into the brain. In this study, we synthesized a nanoprobe ANG-PEG-UCNP capable of crossing the B-CSF barrier with high targeting specificity using a hydrocephalus model for noninvasive magnetic resonance ventriculography to understand the mechanism by which the CSF barrier may be crossed and identify therapeutic targets of CNS diseases. This magnetic resonance nanoprobe ANG-PEG-UCNP holds promising potential as a safe and effective means for accurately defining the ventricular anatomy and correctly locating sites of CSF obstruction.

Uncovering the Metabolic Origin of Aspartate for Tumor Growth Using an Integrated Molecular Deactivator.

Reprogrammed glucose metabolism is vital for cancer cells, but aspartate, an intermediate metabolic product, is the limiting factor for cancer cell proliferation. However, due to the complexity of metabolic pathways, it remains unclear whether glucose is the primary source of endogenous aspartate. Here, we report the design of an innovative molecular deactivator, based on a multifunctional upconversion nanoprobe, to explore the link between glucose and aspartate. This molecular deactivator mainly works in the acidic, hypoxic tumor microenvironment and deactivates multiple types of glucose transporters on cancer cell membranes upon illumination at 980 nm. Cancer cell proliferation in vivo is strongly inhibited by blocking glucose transporters. Our experimental data confirm that the cellular synthesis of aspartate for tumor growth is glucose-dependent. This work also demonstrates the untapped potential of molecularly engineered upconversion nanoprobes for discovering hidden metabolic pathways and improving therapeutic efficacy of conventional antitumor drugs.

Multicolor Upconversion Nanoprobes Based on a Dual Luminescence Resonance Energy Transfer Assay for Simultaneous Detection and Bioimaging of [Ca2+ ]i and pHi in Living Cells.

Intracellular [Ca2+ ]i and pHi have a close relationship, and their abnormal levels can result in cell dysfunction and accompanying diseases. Thus, simultaneous determination of [Ca2+ ]i and pHi can more accurately investigate complex biological processes in an integrated platform. Herein, multicolor upconversion nanoparticles (UCNPs) were prepared with the advantages of no spectral overlapping, single NIR excitation wavelengths, and greater tissue penetration depth. The upconversion nanoprobes were easily prepared by the attachment of two fluorescent dyes, Fluo-4 and SNARF-4F. Based on the dual luminescence resonance energy transfer (LRET) process, the blue and green fluorescence of the UCNPs were specially quenched and selectively recovered after the detachment and/or absorbance change of the attached fluorescent dyes, enabling dual detection. Importantly, the developed nanoprobe could successfully be applied for the detection of [Ca2+ ]i and pHi change in adenosine triphosphate (ATP) and ethylene glycol tetraacetic acid (EGTA) stimulation in living cells.

Dye-sensitized lanthanide-doped upconversion nanoprobe for enhanced sensitive detection of Fe3+ in human serum and tap water.

Iron ion (Fe3+) detection is crucial for human health since it plays a crucial role in many physiological activities. In this work, a novel Schiff-base functionalized cyanine derivative (CyPy) was synthesized, which was successfully assembled on the surface of upconversion nanoparticles (UCNPs) through an amphiphilic polymer encapsulation method. In the as-designed nanoprobe, CyPy, a recognizer of Fe3+, is served as energy donor and ß-NaYF4:Yb,Er upconversion nanoparticles are adopted as energy acceptor. As a result, a 93-fold enhancement of upconversion luminescence is achieved. The efficient energy transfer from CyPy to ß-NaYF4:Yb,Er endows the nanoprobe a high sensitivity for Fe3+ in water with a low detection limit of 0.21 µM. Moreover, the nanoprobe has been successfully applied for Fe3+ determination in human serum and tap water samples with recovery ranges of 95 %-105 % and 97 %-106 %, respectively. Moreover, their relative standard deviations are all below 3.72 %. This work provides a sensitive and efficient methodology for Fe3+ detection in clinical and environmental testing.

NIR-excited imaging and in vivo visualization of ß-galactosidase activity using a pyranonitrile-modified upconversion nanoprobe.

ß-galactosidase (ß-gal) is a diagnostic biomarker of primary ovarian cancers. The development of effective fluorescent probes for investigating the activity of ß-gal will be beneficial to cancer diagnosis. Herein, a near-infrared (NIR) excited ratiometric nanoprobe (DCM-ß-gal-UCNPs) by assembling pyranonitrile dye (DCM-ß-gal) on the surface of upconversion nanophosphors (UCNPs) was designed for the evaluation of ß-gal activity in vivo. Upon the interaction with ß-gal, a marked decrease of upconversion luminescence (UCL) signal in the green channel was observed owing to the luminescence resonance energy transfer from the UCNPs to pyranonitrile chromophore, whereas the NIR UCL emission at 800 nm was almost no influence. Thus, the ß-gal activity could be quantitatively detected by the UCL intensity ratio of UCL543 nm/UCL800 nm with the limit of detection of 3.1 × 10-4 U/mL. Moreover, DCM-ß-gal-UCNPs was effectively applied for monitoring ß-gal fluctuation in living cells and zebrafish by a ratiometric UCL signal excited by 980 nm laser. We envision that nanoprobe DCM-ß-gal-UCNPs might be used as a potential bioimaging tool to disclose more biological information of ß-gal in ß-gal-associated diseases in the future.

A highly selective and sensitive upconversion nanoprobe for monitoring hydroxyl radicals in living cells and the liver.

Excessive reactive oxygen species (ROS) would attack living cells and cause a series of oxidative stress related diseases, such as liver damage. Hydroxyl radicals (·OH) are currently known as one of the most toxic and harmful free radicals to organisms. Therefore, studies involving hydroxyl radicals have become important research topics in the fields of biology, biochemistry, and biomedicine. In addition, imaging of analytes using upconversion nanoparticles (UCNPs) possesses significant advantages over that using general fluorescent dyes or nanoparticles due to its high spatial resolution, reduced photodamage, and deep tissue penetration properties. Herein, we designed a highly selective and sensitive hydroxyl radical nanoprobe based on the luminescence resonance energy transfer between upconversion nanoparticles and methylene blue (MB). The concentration of ·OH could be determined by the fluorescence recovery of the UCNPs due to the oxidative damage of MB. Using this nanoprobe, the ·OH in living cells or in liver tissues could be monitored with high sensitivity and selectivity.

Cyanine-modified near-infrared upconversion nanoprobe for ratiometric sensing of N2H4 in living cells.

Although being as an important chemical material in industry, hydrazine (N2H4) is highly toxic to the humans and animals. The development of sensitive methods for the detection of hydrazine is meaningful. Herein, we develop a new organic-inorganic hybrid nanoprobe for the detection of N2H4 based on luminescent resonance energy transfer (LRET) process. The nanoprobe contains N2H4-responsive NIR cyanine dye (CQM1) and α-cyclodextrin (CD) anchored on the surface of lanthanide-doped upconversion nanophosphors (UCNPs). In the presence of hydrazine, the hybrid materials (CQM1-UCNPs) showed the a large ratiometric luminescent signal change with high sensitivity and selectivity. More importantly, by taking advantage of ratiometric Upconversion luminescent (UCL) signal and the features of NIR emission/excitation, the nanoprobe was successfully applied for visualization of hydrazine in living cells for the first time.

FRET-Based Upconversion Nanoprobe Sensitized by Nd3+ for the Ratiometric Detection of Hydrogen Peroxide in Vivo.

The exorbitant level of hydrogen peroxide is closely related to many human diseases. The development of novel probes for H2O2 detection will be beneficial to disease diagnosis. In this study, a novel Nd3+-sensitized upconversion nanoprobe based on Förster resonance energy transfer was first developed for sensing H2O2. This nanosystem was made of core-shell upconversion nanoparticles (emission at 540 and 660 nm), dicyanomethylene-4 H-pyran (DCM)-H2O2, and poly acrylic acid (PAA)-octylamine. Obviously, upconversion nanoparticles (UCNPs) doped with Nd3+ acted as an energy donor, and DCM-H2O2, transferring to DCM-OH with the reaction of H2O2, acted as an energy acceptor. The ratiometric upconversion luminescence (540 nm/660 nm) signal could be utilized to visualize the H2O2 level, and the LOD of the nanoprobe for H2O2 was quantified to be 0.168 µM. Meanwhile, owing to the dope of Nd3+, the nanoprobe would not induce the overheating effect in biological samples and could possess deeper tissue penetration depth, compared with the UCNPs excited by 980 nm light during bioimaging. The nanoprobe could also play an important role in detecting the exogenous and endogenous H2O2 in living cells with ratiometric UCL (upconversion luminescence) imaging. Furthermore, our nanoprobe could function in detecting the H2O2 in a tumor-bearing mouse model. Therefore, this novel nanoprobe along with the ratiometric method for responding and bioimaging H2O2 could serve as a new model that promotes the emergence of novel probes for H2O2 detection.

Optical/MRI dual-modality imaging of M1 macrophage polarization in atherosclerotic plaque with MARCO-targeted upconversion luminescence probe.

Pro-inflammatory M1 macrophage is identified as a prominent component initializing the progress of vulnerable atherosclerotic plaque. Here, we constructed anti-MARCO NaGdF4:Yb,Er@NaGdF4 upconversion nanoparticles (UCNPs) by conjugating polyclonal MARCO antibody to the surface of NaGdF4:Yb,Er@NaGdF4via condensation reaction. UCNPs displayed highly mono-dispersion with average sizes of 26.7 ±â€¯0.8 nm and favorable biocompatibility. In vivo upconversion optical imaging revealed that distinctive fluorescence signal could be observed in the regions of carotid artery 10 min post-injection, reached peak value at 1 h and decreased back to baseline at 24 h post-injection. The carotid artery wall demonstrated high signal intensity on T1-weighted MR images after anti-MARCO UCNPs injection, as determined by 7.0T MRI. Immunofluorescence staining of tissue section of carotid artery revealed that MARCO was highly abundant in shoulder regions of plaque. Anti-MARCO UCNPs is a promising optical/MRI dual-modality imaging probe which can non-invasively reflect M1 phenotype macrophages behavior in vivo.