Yolk-shell structured Au nanorods@mesoporous silica for gas bubble driven drug release upon near-infrared light irradiation.

Drug release systems co-encapusulated with ammonium bicarbonate (ABC) could facilitate drug release upon acidic or thermal stimulations to improve therapeutic effect. However, it is not easy to control drug release rate, owing to relative stable temperature and acidic condition in living body. Besides, the additional loaded ABC reduces drug loading capacity. Herein, a near-infrared light triggered rapid drug release system with high loading capacity was developed by loading ABC and doxorubicin into yolk-shell structured Au nanorods@mesoporous silica. Gas bubbles were generated from the thermolysis of ABC utilizing photothermal effect of Au nanorods to extrude drug molecules. The mesoporous silica shell was finally destroyed along with growing bubbles, resulting in burst drug release. The photothermal therapeutic effect of Au nanorods also contributed in tumor treatment. The excellent therapeutic effect was demonstrated in cancer cells and tumor-bearing mice, which provides a new reference to achieve controllable rapid drug release in cancer medicine.

Hollow Silica Nanoparticles Penetrate the Peripheral Nerve and Enhance the Nerve Blockade from Tetrodotoxin.

The efficacy of tetrodotoxin (TTX), a very potent local anesthetic, is limited by its poor penetration through barriers to axonal surfaces. To address this issue, we encapsulated TTX in hollow silica nanoparticles (TTX-HSN) and injected them at the sciatic nerve in rats. TTX-HSN achieved an increased frequency of successful blocks, prolonged the duration of the block, and decreased the toxicity compared to free TTX. In animals injected with fluorescently labeled HSN, the imaging of frozen sections of nerve demonstrated that HSN could penetrate into nerve and that the penetrating ability of silica nanoparticles was highly size-dependent. These results demonstrated that HSN could deliver TTX into the nerve, enhancing efficacy while improving safety.

Enhanced Precision of Nanoparticle Phototargeting in Vivo at a Safe Irradiance.

A large proportion of the payload delivered by nanoparticulate therapies is deposited not in the desired target destination but in off-target locations such as the liver and spleen. Here, we demonstrate that phototargeting can improve the specific targeting of nanoparticles to tumors. The combination of efficient triplet-triplet annihilation upconversion (TTA-UC) and Förster resonance energy transfer (FRET) processes allowed in vivo phototargeting at a safe irradiance (200 mW/cm(2)) over a short period (5 min) using green light.

Efficient Triplet-Triplet Annihilation-Based Upconversion for Nanoparticle Phototargeting.

High-efficiency upconverted light would be a desirable stimulus for triggered drug delivery. Here we present a general strategy to achieve photoreactions based on triplet-triplet annihilation upconversion (TTA-UC) and Förster resonance energy transfer (FRET). We designed PLA-PEG micellar nanoparticles containing in their cores hydrophobic photosensitizer and annihilator molecules which, when stimulated with green light, would undergo TTA-UC. The upconverted energy was then transferred by FRET to a hydrophobic photocleavable group (DEACM), also in the core. The DEACM was bonded to (and thus inactivated) the cell-binding peptide cyclo-(RGDfK), which was bound to the PLA-PEG chain. Cleavage of DEACM by FRET reactivated the PLA-PEG-bound peptide and allowed it to move from the particle core to the surface. TTA-UC followed by FRET allowed photocontrolled binding of cell adhesion with green light LED irradiation at low irradiance for short periods. These are attractive properties in phototriggered systems.

A general strategy for biocompatible, high-effective upconversion nanocapsules based on triplet-triplet annihilation.

A general strategy for constructing high-effective upconversion nanocapsules based on triplet-triplet annihilation (TTA) was developed by loading both sensitizer and annihilator into BSA-dextran stabilized oil droplets. This strategy can maintain high translational mobility of the chromophores, avoid luminescence quenching of chromophore by aggregation, and decrease the O2-induced quenching of TTA-based upconversion emission. Pt(II)-tetraphenyl-tetrabenzoporphyrin (PtTPBP) and BODIPY dyes (BDP-G and BDP-Y with the maximal fluorescence emission at 528 and 546 nm, respectively) were chosen as sensitizer/annihilator couples to fabricate green and yellow upconversion luminescent emissive nanocapsules, named UCNC-G and UCNC-Y, respectively. In water under the atmospheric environment, interestingly, UCNC-G and UCNC-Y exhibit intense upconversion luminescence (UCL) emission (λex = 635 nm) with the quantum efficiencies (ΦUCL) of 1.7% and 4.8%, respectively, whereas very weak UCL emission (ΦUCL < 0.1%) was observed for the corresponding previous reported SiO2-coating nanosystems because of aggregation-induced fluorescence quenching of annihilators. Furthermore, application of theses upconversion nanocapsules for high-contrast UCL bioimaging in vivo of living mice without removing the skin was demonstrated under 635-nm excitation with low power density of 12.5 mW cm(-2).

A cyanine-modified nanosystem for in vivo upconversion luminescence bioimaging of methylmercury.

Methylmercury (MeHg(+)) is a strong liposoluble ion, which can be accumulated in the organs of animals and can cause prenatal nervous system and visceral damage. Therefore, the efficient and sensitive monitoring of MeHg(+) in organisms is of great importance. Upconversion luminescence (UCL) detection based on rare-earth upconversion nanophosphors (UCNPs) as probes has been proved to exhibit a large anti-Stokes shift, no autofluorescence from biological samples, a remarkably deep penetration depth, and no photobleaching. In this study, a hydrophobic heptamethine cyanine dye (hCy7) modified by two long alkyl moieties and amphiphilic polymer (P-PEG)-modified nanophosphors (hCy7-UCNPs) was fabricated as a highly sensitive water-soluble probe for UCL monitoring and bioimaging of MeHg(+). Further application of hCy7-UCNPs for sensing MeHg(+) was confirmed by an optical titration experiment and upconversion luminescence live cell imaging. Using the ratiometric upconversion luminescence as a detection signal, which provides a built-in correction for environmental effects, the detection limit of MeHg(+) for this nanosystem was as low as 0.18 ppb. Importantly, the hCy7-UCNPs nanosystem was shown to be capable of monitoring MeHg(+)ex vivo and in vivo by upconversion luminescence bioimaging.

Blue-emissive upconversion nanoparticles for low-power-excited bioimaging in vivo.

Water-soluble upconversion luminescent (UCL) nanoparticles based on triplet-triplet annihilation (TTA) were successfully prepared by coloading sensitizer (octaethylporphyrin Pd complex) and annihilator (9,10-diphenylanthracene) into silica nanoparticles. The upconversion luminescence quantum yield of the nanoparticles can be as high as 4.5% in aqueous solution. As determined by continuous kinetic scan, the nanoparticles have excellent photostability. Such TTA-based upconversion nanoparticles show low cytotoxicity and were successfully used to label living cells with very high signal-to-noise ratio. UCL imaging with the nanoparticles as probe is capable of completely eliminating background fluorescence from either endogenous fluorophores of biological sample or the colabeled fluorescent probe. In particular, such blue-emissive upconversion nanoparticles were successfully applied in lymph node imaging in vivo of living mouse with excellent signal-to-noise ratio (>25), upon low-power density excitation of continuous-wave 532 laser (8.5 mW cm(-2)). Such high-contrast and low-power excited bioimaging in vivo with a blue-emissive upconversion nanoparticle as probe may extend the arsenal of currently available luminescent bioimaging in vitro and in vivo.

NIR-light-induced deformation of cross-linked liquid-crystal polymers using upconversion nanophosphors.

When upconversion nanophosphors were incorporated into an azotolane-containing cross-linked liquid-crystal polymer film, the resulting composite film generated fast bending upon exposure to continuous-wave near-IR light at 980 nm. This occurs because the upconversion luminescence of the nanophosphors leads to trans-cis photoisomerization of the azotolane units and an alignment change of the mesogens. The bent film completely reverted to the initial flat state after the light source was removed.

Sub-10 nm hexagonal lanthanide-doped NaLuF4 upconversion nanocrystals for sensitive bioimaging in vivo.

By thermal decomposition in the presence only of oleylamine, sub-10 nm hexagonal NaLuF(4)-based nanocrystals codoped with Gd(3+), Yb(3+), and Er(3+) (or Tm(3+)) have been successfully synthesized. Sub-10 nm ß-NaLuF(4): 24 mol % Gd(3+), 20 mol % Yb(3+), 1 mol % Tm(3+) nanocrystals display bright upconversion luminescence (UCL) with a quantum yield of 0.47 ± 0.06% under continuous-wave excitation at 980 nm. Furthermore, through the use of ß-NaLuF(4):Gd(3+),Yb(3+),Tm(3+) nanocrystals as a luminescent label, the detection limit of <50 nanocrystal-labeled cells was achieved for whole-body photoluminescent imaging of a small animal (mouse), and high-contrast UCL imaging of a whole-body black mouse with a penetration depth of ~2 cm was achieved.

3,3,4,4,5,5-Hexafluoro-1-(2-methoxyphenyl)-2-[5-(4-methoxyphenyl)-2-methyl-3-thienyl]cyclopent-1-ene: a photochromic compound.

The photochromic title compound, C(24)H(18)F(6)O(2)S, has thienyl and aryl substituents on the C=C double bond of the shallow half-chair-shaped cyclopentene ring. The planes of the two substituent rings are inclined to that of the cyclopentene ring, with dihedral angles between the mean plane of the cyclopentene ring and those of the phenylene and thienyl rings of 51.2 (1) and 51.3 (1) degrees, respectively. The molecule adopts an antiparallel conformation, with a distance between the two photoreactive C atoms of 3.717 (2) A.

1-[5-(3-Chloro-phen-yl)-2-methyl-3-thi-en-yl]-3,3,4,4,5,5-hexa-fluoro-2-(2-methoxy-phen-yl)-cyclo-pent-1-ene.

The title compound, C(23)H(15)ClF(6)OS, has thienyl and phenyl-ene substituents on the double-bond C atoms of the envelope-shaped cyclo-pentenyl ring. The aromatic systems are aligned at 55.3 (4) (thien-yl) and 60.8 (7)° (phenyl-ene) with respect to the planar C-C=C-C portion of the main central cyclo-pentenyl ring.

Synthesis, crystal structure and optoelectronic properties of a new unsymmetrical photochromic diarylethene.

A new unsymmetrical photochromic diarylethene, 1-(2-methyl-5-phenyl-3-thienyl)-2-[2-methyl-5-(3-trifluoromethylphenyl)-3-thienyl]perfluorocyclopentene (1a), was synthesized and its structure was determined by single-crystal X-ray diffraction analysis. Its optical and electrochemical properties, including photochromic reactivity both in solution and in the solid state (PMMA film and the single-crystalline phase), fluorescence and electrochemical properties were investigated in detail. The compound showed excellent photochromism even in the single-crystalline phase by photo-irradiation. In acetonitrile, the open-ring isomer of diarylethene 1 exhibited relatively strong fluorescence at 470 nm when excited at 300 nm, and its emission intensity decreased along with the photochromism upon irradiation with 313 nm light. Its closed-ring isomer showed almost no fluorescence. The electrochemical properties of diarylethene were investigated by performing cyclic voltammetry experiment and its HOMO and LUMO energy level were calculated.

1,2-Bis[5-(4-cyano-phen-yl)-2-methyl-3-thien-yl]-3,3,4,4,5,5-hexa-fluoro-cyclo-pent-1-ene: a photochromic diaryl-ethene compound.

The mol-ecules of the title compound, C(29)H(16)F(6)N(2)S(2), a photochromic dithienylethene with 4-cyano-phenyl substituents, adopt an anti-parallel arrangement that is reponsible for photoactivity. The mol-ecule lies on a twofold rotation axis. The dihedral angle between the nearly planar cyclo-pentenyl and heteroaryl rings is 142.5 (3)°, and that between the heteroaryl and benzene rings is 22.4 (3)°. The distance between the heteroaryl rings of adjacent mol-ecules is 3.601 (2) Å, indicating a π-π interaction.

An incremental clustering method based on the boundary profile.

Many important applications continuously generate data, such as financial transaction administration, satellite monitoring, network flow monitoring, and web information processing. The data mining results are always evolving with the newly generated data. Obviously, for the clustering task, it is better to incrementally update the new clustering results based on the old data rather than to recluster all of the data from scratch. The incremental clustering approach is an essential way to solve the problem of clustering with growing Big Data. This paper proposes a boundary-profile-based incremental clustering (BPIC) method to find arbitrarily shaped clusters with dynamically growing datasets. This method represents the existing clustering results with a collection of boundary profiles and discards the inner points of clusters rather than keep all data. It greatly saves both time and space storage costs. To identify the boundary profile, this paper presents a boundary-vector-based boundary point detection (BV-BPD) algorithm that summarizes the structure of the existing clusters. The BPIC method processes each new point in an online fashion and updates the clustering results in a batch mode. When a new point arrives, the BPIC method either immediately labels it or temporarily puts it into a bucket according to the relationship between the new data and the boundary profiles. A bucket is employed to distinguish the noise from the potential seeds of new clusters and alleviate the effects of data order. When the bucket is full, the BPIC method will cluster the data within it and update the clustering results. Thus, the BPIC method is insensitive to noise and the order of new data, which is critical for the robustness of the incremental clustering process. In the experiments, the performance of the boundary point detection algorithm BV-BPD is compared with the state-of-the-art method. The results show that the BV-BPD is better than the state-of-the-art method. Additionally, the performance of BPIC and other two incremental clustering methods are investigated in terms of clustering quality, time and space efficiency. The experimental results indicate that the BPIC method is able to get a qualified clustering result on a large dataset with higher time and space efficiency.

Highly Photostable Near-IR-Excitation Upconversion Nanocapsules Based on Triplet-Triplet Annihilation for in Vivo Bioimaging Application.

Triplet-triplet-annihilation-based upconversion (TTA-UC) imaging boasts a low-excitation irradiance and an uncanny lack of autofluorescence interference. Because of these promising features, this approach has been the subject of intensifying investigation. Despite the ideal features, the classical approach of TTA-UC imaging suffers from some crucial drawbacks. A major deficiency of the system lies within its poor photostability, especially for a near-IR-excitation system. Here we report a reduction strategy to improve the TTA-UC photostability. The poor photostability of TTA-UC can be attributed to singlet oxygen generation by the sensitizer under irradiation. We control the singlet oxygen by including a reductive solvent, which consumes the singlet oxygen, thereby improving the TTA-UC photostability. We also prepared TTA-UC nanocapsules with reductive solvent soybean oil inside. In comparison to nonreductive solvents such as toluene, our system shows a significant enhancement to the TTA-UC photostability. The prepared TTA-UC nanocapsules were then used for whole-animal deep imaging with a high signal-to-noise ratio.

In Situ Growth of CuS/SiO2-Based Multifunctional Nanotherapeutic Agents for Combined Photodynamic/Photothermal Cancer Therapy.

A scalable and low-cost strategy is developed to fabricate a novel CuS/SiO2-based nanotherapeutic agent for dual-model imaging-guided photothermal/photodynamic combined therapy. In this design, mesoporous silica nanoparticles (MSNs) with CuS bundled in the channel are obtained in aqueous solution via in situ growth route for the first time. Furthermore, to achieve a more efficient therapy, photosensitizer (complex Ir-2) and bovine serum albumin are sequentially assembled via layer-by-layer method. The as-prepared complex Ir-2 presents a remarkably high 1O2 generation (ΦΔ = 1.3) under light illumination to offer effective photodynamic cell killing, and MSN/CuS exhibits high photothermal conversion efficiency (η = 31.7%) under illumination by 808 nm light to offer hyperthermia tumor ablation. In vitro and in vivo analyses show that the as-obtained nanotherapeutic agents exhibit excellent performance in tumor therapy even under irradiation with low power because of the high yield of 1O2 combined with the high photothermal conversion efficiency. Additionally, the nanotherapeutic agents are readily visualized in vivo via near-infrared fluorescence and thermal imaging. More importantly, based on the strategy of in situ growth and layer-by-layer assembly developed in this study, the development of other "all-in-one" multifunctional theranostic platform with high efficiency can be predictable.

Dual-Emissive Phosphorescent Polymer Probe for Accurate Temperature Sensing in Living Cells and Zebrafish Using Ratiometric and Phosphorescence Lifetime Imaging Microscopy.

Temperature plays an important part in many biochemical processes. Accurate diagnosis and proper treatment usually depend on precise measurement of temperature. In this work, a dual-emissive phosphorescent polymer temperature probe, composed of iridium(III) complexes as temperature sensitive unit with phosphorescence lifetime of ∼500 ns and europium(III) complexes as reference unit with lifetime of ∼400 µs, has been rationally designed and synthesized. Upon the increase of the temperature, the luminescence intensity from the iridium(III) complexes is enhanced, while that from the europium(III) complexes remains unchanged, which makes it possible for the ratiometric detection of temperature. Furthermore, the polymer also displays a significant change in emission lifetime accompanied by the temperature variation. By utilizing the laser scanning confocal microscope and time-resolved luminescence imaging systems, ratiometric and time-resolved luminescence imaging in Hela cells and zebrafish have been carried out. Notably, the intensity ratio and long-lifetime-based imaging can offer higher sensitivity, decrease the detection limit, and minimize the background interference from biosamples.

Highly Stable and Multifunctional Aza-BODIPY-Based Phototherapeutic Agent for Anticancer Treatment.

Phototherapy, as an important class of noninvasive tumor treatment methods, has attracted extensive research interest. Although a large amount of the near-infrared (NIR) phototherapeutic agents have been reported, the low efficiency, complicated structures, tedious synthetic procedures, and poor photostability limit their practical applications. To solve these problems, herein, a donor-acceptor-donor (D-A-D) type organic phototherapeutic agent (B-3) based on NIR aza-boron-dipyrromethene (aza-BODIPY) dye has been constructed, which shows the enhanced photothermal conversion efficiency and high singlet oxygen generation ability by simultaneously utilizing intramolecular photoinduced electron transfer (IPET) mechanism and heavy atom effects. After facile encapsulation of B-3 by amphiphilic DSPE-mPEG5000 and F108, the formed nanoparticles (B-3 NPs) exhibit the excellent photothermal stabilities and reactive oxygen and nitrogen species (RONS) resistance compared with indocyanine green (ICG) proved for theranostic application. Noteworthily, the B-3 NPs can remain outstanding photothermal conversion efficiency (η = 43.0%) as well as continuous singlet oxygen generation ability upon irradiation under a single-wavelength light. Importantly, B-3 NPs can effectively eliminate the tumors with no recurrence via synergistic photothermal/photodynamic therapy under mild condition. The exploration elaborates the photothermal conversion mechanism of small organic compounds and provides a guidance to develop excellent multifunctional NIR phototherapeutic agents for the promising clinical applications.

Single upconversion nanoparticle imaging at sub-10 W cm-2 irradiance.

Lanthanide-doped upconversion nanoparticles (UCNPs) are promising single-molecule probes given their non-blinking, photobleach-resistant luminescence upon infrared excitation. However, the weak luminescence of sub-50 nm UCNPs limits their single-particle detection to above 10 kWcm-2 that is impractical for live cell imaging. Here, we systematically characterize single-particle luminescence for UCNPs with various formulations over a 106 variation in incident power, down to 8 Wcm-2. A core-shell-shell (CSS) structure (NaYF4@NaYb1-xF4:Erx@NaYF4) is shown to be significantly brighter than the commonly used NaY0.78F4:Yb0.2Er0.02. At 8 Wcm-2, the 8% Er3+ CSS particles exhibit a 150-fold enhancement given their high sensitizer Yb3+ content and the presence of an inert shell to prevent energy migration to defects. Moreover, we reveal power-dependent luminescence enhancement from the inert shell, which explains the discrepancy in enhancement factors reported by ensemble and previous single-particle measurements. These brighter probes open the possibility of cellular and single-molecule tracking at low irradiance.

Utilizing Intramolecular Photoinduced Electron Transfer to Enhance Photothermal Tumor Treatment of Aza-BODIPY-Based Near-Infrared Nanoparticles.

Photothermal therapy (PTT) as a kind of noninvasive tumor treatment has attracted increasing research interest. However, the efficiency of existing PTT agents in the near-infrared (NIR) region is the major problem that has hindered further development of PTT. Herein, we present an effective strategy to construct the efficient photothermal agent by utilizing an intramolecular photoinduced electron transfer (PeT) mechanism, which is able to dramatically improve photothermal conversion efficiency in the NIR region. Specifically, an NIR dye (A1) constructed with dimethylamine moiety as the electron donor and the aza-BODIPY core as the electron acceptor is designed and synthesized, which can be used as a class of imaging-guided PTT agents via intramolecular PeT. After encapsulation with biodegradable polymer DSPE-mPEG5000, nanophotothermal agents with a small size exhibit excellent water solubility, photostability, and long-time retention in tumor. Importantly, such nanoparticles exhibit excellent photothermal conversion efficiency of ∼35.0%, and the PTT effect in vivo still remains very well even with a low dosage of 0.05 mg kg-1 upon 808 nm NIR laser irradiation (0.5 W cm-2). Therefore, this reasonable design via intramolecular PeT offers guidance to construct excellent photothermal agents and subsequently may provide a novel opportunity for future clinical cancer treatment.