Search

Recently, nanovaccine-based immunotherapy has been robustly investigated due to its potential in governing the immune response and generating long-term protective immunity. However, the presentation of a tumor peptide-major histocompatibility complex to T lymphocytes is still a challenge that needs to be addressed for eliciting potent antitumor immunity. Type 1 conventional dendritic cell (cDC1) subset is of particular interest due to its pivotal contribution in the cross-presentation of exogenous antigens to CD8+T cells. Here, the DC-derived nanovaccine (denoted as Si9GM) selectively targets cDC1s with marginal loss of premature antigen release for effective stimulator of interferon genes (STING)-mediated antigen cross-presentation. Bone marrow dendritic cell (BMDC)-derived membranes, conjugated to cDC1-specific antibody (αCLEC9A) and binding to tumor peptide (OVA257-264), are coated onto dendrimer-like polyethylenimine (PEI)-grafted silica nanoparticles. Distinct molecular weight-cargos (αCLEC9A-OVA257-264conjugates and 2′3′-cGAMP STING agonists) are loaded in hierarchical center-radial pores that enables lysosome escape for potent antigen-cross presentation and activates interferon type I, respectively. Impressively, Si9GM vaccination leads to the upregulation of cytotoxic T cells, a reduction in tumor regulatory T cells (Tregs), M1/M2 macrophage polarization, and immune response that synergizes with αPD-1 immune checkpoint blockade. This nanovaccine fulfills a dual role for both direct T cell activation as an artificial antigen-presenting cell and DC subset maturation, indicating its utility in clinical therapy and precision medicine.

To comprehensively describe the operation of photo-induced force microscopy (PiFM), we have developed a model based on coupled harmonic oscillators. This model features two point masses connected by massless elastic wires, offering greater intuitiveness compared to existing PiFM models. It simplifies these models into a unified theoretical framework. By solving the equations of motion using adjusted oscillator parameters, we have successfully replicated all dynamic features from previous theories. These features include resonance frequencies and shapes of eigenmodes, as well as the responses to various external forces in the two PiFM modes: direct coupling and sideband coupling. Furthermore, by integrating our model with a recently developed photo-induced thermal expansion force model, which covers both tip-enhanced and global expansions, we have managed to uncover the underlying physical mechanism responsible for the unique signal behaviors observed in sideband coupling mode, where the signal plot, as a function of sample thickness, unexpectedly exhibits a peak followed by a valley, rather than a proportionally increasing signal. Our study has the potential to enhance the comprehension of various other physical phenomena associated with PiFM in the future.

Purpose: This study aimed to fabricate tumor-originated extracellular vesicles (EVs) targeting tumors for use in combination with immunotherapy and chemotherapy. Methods: The antitumor immune EVs (iEVs) consisted of EVs anchored to hyaluronic acid conjugated with 3-(diethylamino)propylamine (HDEA, as a pH-sensitive segment), monophosphoryl lipid A [MPLA, as a Toll-like receptor 4 (TLR4) targeted moiety], and mucin 1 antigen (MUC1, as a tumor-associated antigen) using the sonication method to carry tumor-associated antigens, and were referred to as (HDEA/MPLA/MUC1)@EVs. The chemotherapeutic EVs (cEVs) consisted of EVs anchored to HDEA (as a pH-sensitive segment) and (KLAKLAK)2peptide (KLAK, as an antitumor model peptide drug) to carry a tumor-killing peptide, and were referred to as (HDEA/KLAK)@EVs. The blended EVs (bEVs) were prepared by physically mixing iEVs and cEVs for combined antitumor immunotherapy and chemotherapy. Results: The bEVs were efficiently internalized by the dendritic cells (DCs) viaMPLA-TLR4 receptor mediated endocytosis and by the MDA-MB-231 tumor cells viaHA-CD44 receptor mediated endocytosis. In particular, the internalized EVs were physically destabilized owing to the protonation of DEAP (pKb~6.8) in the endosomal compartments, thereby accelerating the release of MUC1 antigen (promoting the antitumor immune response) and KLAK peptide (promoting the tumor-killing activity), and resulting in improved antitumor activity compared with that achieved by single EV administration Conclusion: We demonstrated the antitumor effect of the bEVs in vitro/in vivo tumor model studies. These results indicate that the bEVs can provide a synergistic effect compared to single EV administration.

Inspired by erythrocytes that contain oxygen-carrying hemoglobin (Hb) and that exhibit photo-driven activity, we introduce homogenous-sized erythrocyte-like Hb microgel (μGel) systems (5–6 μm) that can (i) emit heat, (ii) supply oxygen, and (iii) generate reactive oxygen species (ROS; 1O2) in response to near-infrared (NIR) laser irradiation. Hb μGels consist of Hb, bovine serum albumin (BSA), chlorin e6 (Ce6) and erbium@lutetium upconverting nanoparticles (UCNPs; ∼35 nm) that effectively convert 808 nm NIR light to 660 nm visible light. These Hb μGels are capable of releasing oxygen to help generate sufficient reactive oxygen species (1O2) from UCNPs/Ce6 under severely hypoxic condition upon NIR stimulation for efficient photodynamic activity. Moreover, the Hb μGels emit heat and increase surface temperature due to NIR light absorption by heme (iron protoporphyrin IX) and display photothermal activity. By changing the Hb/UCNP/Ce6 ratio and controlling the amount of NIR laser irradiation, it is possible to formulate bespoke Hb μGels with either photothermal or photodynamic activity or both in the context of combined therapeutic effect. These Hb μGels effectively suppress highly hypoxic 4T1 cell spheroid growth and xenograft mice tumors in vivo.

As an emerging anticancer strategy, ferroptosis has recently been developed in combination with current therapeutic modalities to overcome the existing limitations of conventional therapies. Herein, an ultraviolet (UV) upconversion luminescence-fueled nanoreactor is explored to combine ferroptosis and apoptosis through the UV-catalyzed Fenton reaction of an iron supplement (ferric ammonium citrate) loaded in a mesoporous silica layer in addition to the support of a chemotherapeutic agent (cisplatin) attached on the functionalized silica surface for the treatment of triple negative breast cancer (TNBC). The nanoplatform can circumvent the low penetration depth typical of UV light by upconverting near-infrared irradiation and emitting UV photons that convert Fe3+to Fe2+to boost the generation of hydroxyl radicals (·OH), causing devastating lipid peroxidation. Apart from DNA damage-induced apoptosis, cisplatin can also catalyze Fenton-based therapy by its abundant production of hydrogen peroxide (H2O2). As a bioinspired lipid membrane, the folate receptor-targeted liposome as the coating layer offers high biocompatibility and colloidal stability for the upconversion nanoparticles, in addition to prevention of the premature release of encapsulated hydrophilic compounds, before driving the nanoformulation to the target tumor site. As a result, superior antitumor efficacy has been observed in a 4T1 tumor-bearing mouse model with negligible side effects, suggesting that such a nanoformulation could play a pivotal role in effective apoptosis-strengthened ferroptosis TNBC therapy.

Purpose: This study was aimed to develop a tumor-originated extracellular vesicle (EV)-based vaccine mixture with a pH-responsive ability to treat various tumors. Methods: The EVs vaccine mixture consisted of different EVs (MEVs extracted from MDA-MB-231 tumor cells and HEVs extracted from HepG2 tumor cells) encoded with a pH-responsive moiety (HDEA), Toll-like receptor 4 ligand (TLR4), and tumor-targeting vaccine antigen (MUC1 antigen for targeting MDA-MB-231 cells and WT1 antigen for targeting HepG2 cells) using the sonication. The physicochemical properties and in vitro/in vivo antitumor efficacy of the developed EVs mixture were characterized. Results: The EVs vaccine mixtures were efficiently internalized to dendritic cells (DCs) via hyaluronic acid (HA)-mediated CD44 receptor binding and TLR4-mediated signaling on the DCs surface. In particular, the internalized EVs vaccine mixture released MUC1 and WT1 antigens by HDEA-mediated vesicle destabilization at acidic endosomal pH, resulting in increasing the antitumor effect on both MDA-MB-231 and HepG2 tumor cells. Conclusion: We demonstrated the antitumor activity of EVs vaccine mixture in in vitro/in vivo tumor model studies. These results indicate that EVs vaccine mixture can provide an effective immunotherapy strategy for heterogeneous tumors.

In this study, functional twin liposomes (TLs) were designed by linking avidin-anchored single liposomes and biotin-anchored single liposomes via avidin-biotin interactions. Here, we first punched a hole on the liposome surface using the liposome magnetoporation method to prepare functional single liposomes, which were used for safely encapsulating quercetin (QER, as a model prodrug) or laccase (LAC, as a bioactive enzyme) inside the liposomes without the use of organic solvents; the pores were then plugged by pH-sensitive glycol chitosan grafted with 3-diethylaminopropylamine (GDEAP) and avidin (or biotin). As a result, single liposomes with QER and biotin–GDEAP were efficiently coupled with other liposomes with LAC and avidin–GDEAP. We demonstrated that the TLs could accelerate QER and LAC release at acidic pH (6.8), improving the LAC-mediated oxidization of QER and significantly elevating tumor cell death, suggesting that this strategy can be used as an efficient method for the programmed action of prodrugs.

Triple-negative breast cancer (TNBC) is characterized by rapid tumor growth and resistance to cancer therapy, and has a poor prognosis. Accumulating data have revealed that cancer metabolism relies on both the Warburg effect and oxidative phosphorylation (OXPHOS), which are strongly related to the high proliferation and chemoresistance of cancer cells. Phototherapy is considered as a non-invasive method to precisely control drug activity with reduced side effects. Herein, our group introduced an Abraxane-like nanoplatform, named LCIR NPs, which significantly eradicates cancer cells viasynergism between metabolic reprogramming and phototherapy effects. Endowed with mitochondria-targeting residues, the nanoparticles efficiently inhibited mitochondrial complexes I and IV as well as hexokinase II, leading to the depletion of intracellular ATP. Consequently, the photodynamic and photothermal effect triggered by NIR irradiation was enhanced due to the alleviation of hypoxia and the thermoresistance mechanism that rely on mitochondrial metabolism. In vivoexperiments showed that the tumor size of mice that received the combination treatment was only 50.7 mm3, which was 21 times smaller than that of the untreated group and was much lower than those of other single treatments after 21 days. Additionally, almost no systemic undesired toxicity was detected during the observation period. We believe that the concept of LCIR as presented here offers a potential platform to overcome the resistance to conventional therapies by the incorporation with the energy metabolism inhibition approach.

Charge doping to Mott insulators is critical to realize high-temperature superconductivity, quantum spin liquid state, and Majorana fermion, which would contribute to quantum computation. Mott insulators also have a great potential for optoelectronic applications; however, they showed insufficient photoresponse in previous reports. To enhance the photoresponse of Mott insulators, charge doping is a promising strategy since it leads to effective modification of electronic structure near the Fermi level. Intercalation, which is the ion insertion into the van der Waals gap of layered materials, is an effective charge-doping method without defect generation. Herein, we showed significant enhancement of optoelectronic properties of a layered Mott insulator, α-RuCl3, through electron doping by organic cation intercalation. The electron-doping results in substantial electronic structure change, leading to the bandgap shrinkage from 1.2 eV to 0.7 eV. Due to localized excessive electrons in RuCl3, distinct density of states is generated in the valence band, leading to the optical absorption change rather than metallic transition even in substantial doping concentration. The stable near-infrared photodetector using electronic modulated RuCl3showed 50 times higher photoresponsivity and 3 times faster response time compared to those of pristine RuCl3, which contributes to overcoming the disadvantage of a Mott insulator as a promising optoelectronic device and expanding the material libraries.

The photoinduced dipole force (PiDF) is an attractive force arising from the Coulombic interaction between the light-induced dipoles on the illuminated tip and the sample. It shows extreme sample-tip distance and refractive index dependence, which is promising for nanoscale infrared (IR) imaging of ultrathin samples. However, the existence of PiDF in the mid-IR region has not been experimentally demonstrated due to the coexistence of photoinduced thermal force (PiTF), typically one to two orders of magnitude higher than PiDF. In this study, we demonstrate that, with the assistance of surface phonon polaritons, the PiDF of c-quartz can be enhanced to surpass its PiTF, enabling a clear observation of PiDF spectra reflecting the properties of the real part of permittivity. Leveraging the detection of the PiDF of phonon polaritonic substrate, we propose a strategy to enhance the sensitivity and contrast of photoinduced force responses in transmission images, facilitating the precise differentiation of the heterogeneous distribution of ultrathin samples.Infrared photo-induced dipole force enhanced by substrate surface phonon polariton has been used for high-contrast imaging of ultrathin samples.

In this study, the strategy of transient generation of holes in the liposome surface has been shown to enable safe encapsulation of a high-molecular weight antibody (rituximab, Mw∼140 kDa) within liposomes. These transient holes generated using our magnetoporation method allowed rituximab to safely enter the liposomes, and then the holes were plugged using hyaluronic acid grafted with 3-diethylaminopropylamine (DEAP). In the tumor microenvironment, the resulting liposomal rituximab was destabilized because of the ionization of the DEAP moiety at the acidic pH 6.5, resulting in extensive release of rituximab. Consequently, the rituximab released from the liposomes accumulated at high levels in tumors and bound to the CD20 receptors overexpressed on Burkitt lymphomaRamos cells. This event led to significant enhancement in tumor cell ablation through rituximab-mediated complement-dependent cytotoxicity and Bcl-2 signaling inhibition-induced cell apoptosis.

In this study, we developed an extremely small-sized water-soluble hyaluronate dot (dHA) conjugated with cyclic RGD (cRGD) and cleavable doxorubicin (DOX, as a model antitumor drug), named cRGD@dHA-c-DOX. This dot with HA moieties (as specific ligands to tumor CD44 receptors) and cRGD moieties (as specific ligands to tumor integrin αvβ3) was designed to enable multivalent tumor targeting. In particular, the imine bonds, linking the DOX and dHA, can exhibit cleavage performance at endosomal pH, resulting in pH-triggered DOX release from cRGD@dHA-c-DOX. We demonstrated that cRGD@dHA-c-DOX resulted in highly improved cellular uptake and cell death in MDA-MB-231 tumor cells (CD44+, integrin αvβ3+) compared to those in Huh7 tumor cells (CD44–, integrin αvβ3−). In vivo studies using MDA-MB-231 tumor-bearing mice revealed that cRGD@dHA-c-DOX enhanced the tumor inhibition efficacy. These results suggest that cRGD@dHA-c-DOX can be utilized as a promising multivalent tumor-targeting drug carrier for highly efficient tumor treatment.

AbstractThis study was conducted to establish reasonable forest management plan by developing site index curves about Pinus densiflorastands that is major species growing in Jeolla-do in Republic of Korea. A total of 613 Pinus densifloraplots and 20m × 20m sampling plot was installed for each stand. The altitude height, slope, orientation bearing, soil type, the height and diameter at breast height (1.2 m from the ground) of a dominant tree, and the age of trees were measured. After developing site index curves using Chapman-Richards, Schumacher and Gompertz models, top three geographical factors were added to asymptote and shape parameters. In results, Gompertz model for Pinus densiflorastands was chosen for best model of height and site index model. Also, soil type, parent rock and topography were added into Gompertz model for Pinus densiflorastand as the independent variables, using the random forest analysis method. As result of adding geographical factors to asymptote and shape of Gompertz model for Pinus densiflorastand, the precision of the model has increased with decreasing MSE. As hybrid site index model including geographical factors indicated influence growth of Pinus densiflora, reasonable forest management plan is determined.

We investigate the tip-enhanced thermal expansion force for nanoscale chemical imaging and spectroscopy in the tip–sample junction. It is found, both theoretically and experimentally, that the tip-enhanced absorption of the near-field at the tip followed by sample expansion shows characteristic behaviors with respect to the sample thickness and the incident laser pulse width. The van der Waals interaction plays a major role in exerting a force on the tip from the thermally expanded sample. The force behavior of the photoinduced force microscope (PiFM) is compared with that of the existing photothermal-induced resonance technique (PTIR) to unravel the ambiguous thermal expansion force mechanism. The present study opens up new opportunities for enhancing the performance of optical nanoscopy and spectroscopy such as chemical imaging of nanobiomaterials and the local field mapping of photonic devices, including surface polaritons on van der Waals materials with the assistance of the thermal expansion of a functionalized tip.

We provide immense insulin absorption from the gastrointestinal tract, combining apical sodium-dependent bile acid transporter-mediated intestinal uptake and the lymphatic transport pathway. This strategy has proven to employ chondroitin sulfate-g-taurocholic acid coated, insulin-loaded partially uncapped liposome (IPUL-CST) for type 1 diabetes mellitus (T1DM) treatment. The loading efficiency of insulin in IPUL-CST increased significantly from 33% to 75% via the partially uncapped liposome preparation method. Moreover, the IPUL-CST revealed an improved insulin protection efficacy in GIT simulated pH and digestive enzyme conditions. The high dose of IPUL-CST in the small intestine was detected 4 h post-oral administration using ex vivooptical imaging and fluorescence intensity. The IPUL-CST exhibited significantly enhanced intestinal absorption (oral bioavailability, 34%; Tmax, 9 h) and reduced blood glucose levels for 16 h in T1DM. The results demonstrated that the new investigated IPUL-CST is a promising carrier for oral insulin delivery.

We report functional gold nanoparticles (AuNPs) with a pH-sensitive γ-cyclodextrin (CD) cap. These particles include two chargeable CD molecules on their surface. CD with dopamine and amine (NH2) groups (hereafter termed as dCD-NH2) was anchored to the gold surface and then electrostatically complexed with the CD with 2,3-dimethylmaleic acid (DMA) and chlorin e6 (Ce6) (hereafter termed as cCD-DMA), producing an ionic complex consisting of dCD-NH2and cCD-DMA. Under the acidic environment (pH 6.8) existing in most solid tumors, the ionic complex was destabilized because of the decoupling of DMA, resulting in the release of cCD (without DMA) from the AuNPs, resulting in extensive tumoral uptake of AuNPs with dCD-NH2(because of their electrostatic attraction to tumor cells). This event resulted in a significant increase in the efficiency of cellular AuNP uptake and light-driven (AuNP-mediated photothermal and Ce6-mediated photodynamic) ablation of acidic solid tumors, suggesting marked potential for tumor therapy.

Sorafenib, marketed under the brand name Nexavar®, is a multiple tyrosine kinase inhibitor drug that has been actively used in the clinical setting for the treatment of several cancers. However, the low solubility and bioavailability of sorafenib constitute a significant barrier to achieving a good therapeutic outcome. We developed a sorafenib-loaded self-nanoemulsifying drug delivery system (SNEDDS) formulation composed of capmul MCM, tween 80, and tetraglycol, and demonstrated that the SNEDDS formulation could improve drug solubility with excellent self-emulsification ability. Moreover, the sorafenib-loaded SNEDDS exhibited anticancer activity against Hep3B and KB cells, which are the most commonly used hepatocellular carcinoma and oral cancer cell lines, respectively. Subsequently, to improve the storage stability and to increase the possibility of commercialization, a solid SNEDDS for sorafenib was further developed through the spray drying method using Aerosil® 200 and PVP K 30. X-ray diffraction and differential scanning calorimeter data showed that the crystallinity of the drug was markedly reduced, and the dissolution rate of the drug was further improved in formulation in simulated gastric and intestinal fluid conditions. In vivostudy, the bioavailability of the orally administered formulation increases dramatically compared to the free drug. Our results highlight the use of the solid-SNEDDS formulation to enhance sorafenib's bioavailability and outlines potential translational directions for oral drug development.

Nanoemulsions (NE) are advantageous nanosized delivery agents for ophthalmic medications because of their ability to penetrate into the ocular structure, as well as their sustained effects. We prepared a NE system composed of isopropyl myristate, triacetin, Tween 80, and ethyl alcohol to increase the solubility and permeability of lutein, an effective medication in macular degeneration. The pseudo-ternary phase diagram was constructed to identify the self-emulsifying region. Eight formulations were selected to characterize each formulation. We examined physical characteristics including particle size, drug solubility, formulation stability, and turbidity. We selected the optimized formulations NE 5 (NE-5) and NE-8, both of which are transparent. The particle size of NE was ca.10–12 nm with a narrow size distribution. Neither separation nor change in the particle size was observed for 7 days. The lutein loading NEs demonstrated a significant increase in lutein release and sustained release. In contrast, lutein prepared with oil and starch had limited drug release profiles under 5%. The prepared lutein NE formulation is a potential alternative for lutein delivery systems.

Ultrathin black phosphorus (BP) is one of the promising two-dimensional (2D) materials for future optoelectronic devices. Its chemical instability in ambient conditions and lack of a bottom-up approach for its synthesis necessitate efficient etching methods that generate BP films of designed thickness with stable and high-quality surfaces. Herein, reporting a photochemical etching method, we demonstrate a controlled layer-by-layer thinning of thick BP films down to a few layers or a single layer and confirm their Raman and photoluminescence characteristics. Ozone molecules generated by O2photolysis oxidize BP, forming P2O5-like oxides. When the resulting phosphorus oxides are removed by water, the surface of BP with preset thickness is highly flat and self-protective by surface oxygen functional groups. This method provides a fabrication strategy of BP and possibly other 2D semiconductors with band gaps tuned by their thickness.

A new method is presented for visualizing the electric field distributions associated with propagating surface-plasmon-polariton (SPP) modes directly in the near-field. The method is based on detecting the photo-induced gradient force exerted by the evanescent field onto a sharp and polarizable tip. Using a photo-induced force microscope (PiFM), images of propagating SPPs are obtained on flat gold surfaces.

In this study we demonstrate ultrahigh-resolution spectral domain optical coherence tomography (UHR SD-OCT) with a linear-wavenumber (k) spectrometer, to accelerate signal processing and to display two-dimensional (2-D) images in real time. First, we performed a numerical simulation to find the optimal parameters for the linear-k spectrometer to achieve ultrahigh axial resolution, such as the number of grooves in a grating, the material for a dispersive prism, and the rotational angle between the grating and the dispersive prism. We found that a grating with 1200 grooves and an F2 equilateral prism at a rotational angle of $26.07^{\circ}$, in combination with a lens of focal length 85.1 mm, are suitable for UHR SD-OCT with the imaging depth range (limited by spectrometer resolution) set at 2.0 mm. As guided by the simulation results, we constructed the linear-k spectrometer needed to implement a UHR SD-OCT. The actual imaging depth range was measured to be approximately 2.1 mm, and axial resolution of $3.8{\mu}m$ in air was achieved, corresponding to $2.8{\mu}m$ in tissue (n = 1.35). The sensitivity was -91 dB with -10 dB roll-off at 1.5 mm depth. We demonstrated a 128.2 fps acquisition rate for OCT images with 800 lines/frame, by taking advantage of NVIDIA's compute unified device architecture (CUDA) technology, which allowed for real-time signal processing compatible with the speed of the spectrometer's data acquisition.

We report functional gold nanoparticles (AuNP) with antibody-like ligands. These particles consist of Y-shaped ligands and AuNP. Transferrin (Tf) and Tat peptide were linked to each head of a Y-shaped poly(ethylene glycol) (PEG)-containing dopamine at one tail site. Also, Y-shaped ligands (with Tf and Tat peptide) were anchored to the surface of the AuNP as the result of noncovalent conjugation of dopamine and the AuNP. Interestingly, the partial shielding of Tat peptides by large Tf molecules rather improved Tf-mediated endocytosis of the AuNP, while minimizing the natural nonspecific cell interaction of Tat peptides. This system resulted in highly improved in vitro/in vivotumor-selective uptake over AuNP bearing a single ligand (Tf or Tat peptides). Furthermore, this system resulted in significant enhancement of in vivophotothermal tumor cell ablation under light-irradiation conditions for AuNP. We believe that this design is a promising method to easily modify conventional antibodies or ligands to improve their disease-recognition ability.

In this study, we demonstrated multimodal nonlinear optical (NLO) microscopy integrated simultaneously with two-photon excitation fluorescence (TPEF), second-harmonic generation (SHG), and coherent anti-Stokes Raman scattering (CARS) in order to obtain targeted cellular and label-free images in an immunofluorescence assay of the atherosclerotic aorta from apolipoprotein E-deficient mice. The multimodal NLO microscope used two laser systems: picosecond (ps) and femtosecond (fs) pulsed lasers. A pair of ps-pulsed lights served for CARS (817 nm and 1064 nm) and SHG (817 nm) images; light from the fs-pulsed laser with the center wavelength of 720 nm was incident into the sample to obtain autofluorescence and targeted molecular TPEF images for high efficiency of fluorescence intensity without cross-talk. For multicolor-targeted TPEF imaging, we stained smooth-muscle cells and macrophages with fluorescent dyes (Alexa Fluor 350 and Alexa Fluor 594) for an immunofluorescence assay. Each depth-sectioned image consisted of $512{\times}512$ pixels with a field of view of $250{\times}250{\mu}m^2$, a lateral resolution of $0.4{\mu}m$, and an axial resolution of $1.3{\mu}m$. We obtained composite multicolor images with conventional label-free NLO images and targeted TPEF images in atherosclerotic-plaque samples. Multicolor 3-D imaging of atherosclerotic-plaque structural and functional composition will be helpful for understanding the pathogenesis of cardiovascular disease.

We use a hemispheric sapphire lens in combination with an off-axis parabolic mirror to demonstrate high-resolution vibrationally resonant sum-frequency generation (VR-SFG) microscopy in the mid-infrared range. With the sapphire lens as an immersed solid medium, the numerical aperture (NA) of the parabolic mirror objective is enhanced by a factor of 1.72, from 0.42 to 0.72, close to the theoretical value of 1.76 ( = n_sapphire). The measured lateral resolution is as high as 0.64 μm. We show the practical utility of the sapphire immersion lens by imaging collagen-rich tissues with and without the solid immersion lens.

We present a method to improve the isotropy of spatial resolution in a structured illumination microscopy (SIM) implemented for imaging non-fluorescent samples. To alleviate the problem of anisotropic resolution involved with the previous scheme of coherent SIM that employs the two orthogonal standing-wave illumination, referred to as the orthogonal SIM, we introduce a hexagonal-lattice illumination that incorporates three standing-wave fields simultaneously superimposed at the orientations equally divided in the lateral plane. A theoretical formulation is worked out rigorously for the coherent image formation with such a simultaneous multiple-beam illumination and an explicit Fourier-domain framework is derived for reconstructing an image with enhanced resolution. Using a computer-synthesized resolution target as a 2D coherent sample, we perform numerical simulations to examine the imaging characteristics of our three-angle SIM compared with the orthogonal SIM. The investigation on the 2D resolving power with the various test patterns of different periods and orientations reveal that the orientation-dependent undulation of lateral resolution can be reduced from 27% to 8% by using the three-angle SIM while the best resolution (0.54 times the resolution limit of conventional coherent imaging) in the directions of structured illumination is slightly deteriorated by 4.6% from that of the orthogonal SIM.

Lymph node involvement in cervical cancer is an indication of poor prognosis and the risk tends to increase according to the level of lymph node involvement. However, the specific prognostic significance of retrocrural lymph node involvement has not been well characterized because of its small size and deep location. The aim of this study was to assess its prognostic value.

A diffraction grating is a highly symmetric optical element with a physical structure that is invariant under translational spatial movements. The translational symmetry is reflected in the fields that are diffracted from the grating. Here, we introduce a plane-parallel mirror pair onto the grating, which translates the fields through double reflections, and we describe a method of exploiting the symmetry to enhance the spectral resolution of a diffraction grating beyond the limit that is set by the number of grooves. The mirror pair creates another virtual grating beside the original one, effectively doubling the number of grooves. Addition of more mirror pairs can further increase the effective number of grooves despite the increased complexity and difficulty of experimental implementation. We experimentally demonstrate the spectral linewidth reduction by a factor of four in a neon fluorescence spectrum. Even though the geometrical restriction on the mirror deployment limits our method to a certain range of the whole spectrum, as a practical application example, a bulky spectrometer that is nearly empty inside can be made compact without sacrificing the resolution.

Trojanisches Pferd: Ein neu entwickeltes Polysaccharid‐Wirkstoff‐Konjugat (siehe Bild) reagiert auf Änderungen des pH‐Werts und kann in HeLa‐Mäusetumoren eindringen, wie durch Fluoreszenzbildgebung gezeigt wurde. Das Konjugat hat Anwendungspotenzial in der photodynamischen Therapie: Es greift gezielt den Tumor an, ohne das umgebende Gewebe zu schädigen.

Sharper image: A newly developed polysaccharide/drug conjugate (see picture) responds to changes in pH value and was shown to penetrate HeLa tumors in mice as determined by fluorescence imaging. It has the potential to be used in photodynamic therapy, thereby targeting the tumor while having no detrimental effects on the surrounding tissue.

We studied the nonlinear signal generated in the fiber at an anti-Stokes wavelength during the delivery of the picosecond (ps) pump and Stokes beams in coherent anti-Stokes Raman scattering (CARS) microscopy. A small non-phase-matched four-wave mixing (FWM) signal was prevalently observed in the fiber at the power level where other nonlinear processes, including self-phase modulation and cross-phase modulation, were well suppressed. We analyzed the features of the FWM signal generation by varying the location of temporal overlap between two input pulses in the fiber to compare this to the CARS signal generated in the sample. Numerical modeling based on the nonlinear Schrödinger equation was also conducted and clearly explains the results in the experiment. In addition, we experimentally verified the interferometric feature of this FWM signal with the CARS signal by employing a phase-shifting unit, which potentially suggests the use of the FWM signal as a local oscillator for the interferometric CARS system.

The second generation of pH-sensitive micelles composed of poly(l-histidine-co-l-phenlyalanine(16 mol %))(MW:5K)-b-PEG(MW:2K) and poly(l-lactic acid)(MW:3K)-b-PEG(MW:2K)-folate (80/20 wt/wt %) was previously optimized by physicochemical and in vitro tests for both folate receptor and early endosomal pH targeting (pH ∼6.0). In this study, the therapeutic efficacy of the doxorubicin (DOX)-loaded micelles (DOX loading content: 20 wt %) was evaluated using in vivo tests. Multidrug-resistant (MDR) ovarian tumor-xenografted mouse models were employed. The skin-fold dorsal window chamber model was applied for visualization of extravasation and drug retention for the initial one hour after iv injection. Noninvasive imaging followed, providing evidence of drug accumulation in the tumor after the first hour. The biodistribution study further supported the long circulation of the drug carrier, tumor-selective accumulation and intracellular drug delivery. Comprehensive tumor growth inhibition experiments examined the collective efficacy of the pH-sensitive micelles. The micelle formulation effectively suppressed the growth of existing MDR tumors in mice for at least 50 days by three iv injections at a 3-day interval at a dose of 10 mg of DOX/kg. The body weight of the animals treated with the test micelle formulation gradually increased over the experimental time period, rather than decreasing. The micelle formulation was superior to its first generation, which targeted pH 6.8 and folate receptor.

A lack of processability is one of the major problems associated with practical applications of conductive and electroactive polypyrrole. Polypyrrole nanoparticles that were sterically stabilized in a solution and supported by an amphiphilic elastomer of poly(ethylene glycol) (M_n 2000 g mol⁻¹)/poly(tetramethylene ether glycol) (M_n 2000 g mol⁻¹) multiblock copolymer, were investigated in terms of conductivity, processability and mechanical properties. The hydrogel, amphiphilic elastomer was soluble in various organic solvents such as methanol, acetone and ethanol, but only swellable in water. The synthetic conditions of polypyrrole nanoparticles in the presence of the multiblock copolymer were optimized. The conductivity of polypyrrole film formed from the nanoparticle suspension was measured with the van der Pauw four-probe method and reached as high as 3.0 ± 0.2 S cm⁻¹. The film also showed elastomeric properties, which were influenced by the amount of multiblock copolymer added during nanoparticle synthesis. Copyright © 2004 Society of Chemical Industry

We applied nonlinear interferometry of coherent anti-Stokes Raman spectroscopy (CARS) to measure the nonresonant third-order susceptibilities of various gases. Using argon as an internal calibration standard, we determined the effective nonresonant susceptibilities of acetylene, carbon dioxide, methane, nitrogen, oxygen, propane, carbon monoxide, Freon, and hydrogen from the amplitudes of the interference fringes of the CARS signals generated in the two gas cells. The electronic susceptibility was calculated by subtracting the offresonant term of each molecule from the measured effective nonresonant susceptibility, and the results of this work are compared with the published data. The overall uncertainty is estimated to be less than 5%.

We have controlled the relative phase between two successively generated coherent anti-Stokes Raman-scattering signals with a homemade phase-shifting unit, the thickness of which could be automatically adjusted as the wavelength of Stokes beam scanned in a wide spectral range. With this technique we have recovered the Q-branch spectrum of carbon monoxide distorted by a large nonresonant contribution from propane. Also, we have selectively recorded the spectrum of hydrogen chloride buried in the spectrum of propane.

A simple scheme of an optical setup to enhance the spectral resolution of diffraction gratings without increasing the number of grooves is presented. A plane-parallel mirror pair, which consists of a 100% reflectivity mirror and a 50% reflectivity mirror, is placed upon a grating. For certain values of the mirror gap and the angle between the grating and the mirrors, the effective size of the grating doubles, as does the resolution. Using a grating of 830??grooves/mm and a narrow-band diode laser that is tunable around 773 nm, we experimentally demonstrated an enhancement of the resolution by a factor of 2.

In a conventional coherent anti-Stokes Raman scattering (CARS) microscope system, we generate a local oscillator CARS field and a sample CARS field successively along a single-beam path. A large gradient of relative spectral phase between the two fields is naturally induced by highly dispersive microscope elements. The resulting spectral interferogram is a form of fast varying sinusoidal fringes modulated by the amplitude and phase of the sample CARS field. With the help of the Hilbert transform on the heterodyne part of the interferogram, both real and imaginary quadratures of the sample CARS spectrum are extracted with an improved signal-to-noise ratio.

In illuminated tip–sample junctions, the absorption of light by the sample is accompanied by local heating and subsequent thermal expansion of the material. In photoinduced force microscopy (PiFM) experiments, thermal expansion is expected to affect the measured photoinduced force through the thermally modulated van der Waals force. Evidence for such thermal contributions in PiFM measurements has been demonstrated in the mid-infrared range, where the primary excitations are molecular vibrational modes. For PiFM measurements in the vis/NIR, where light-matter energy transfer is mediated through electronic excitations, clear experimental evidence of thermal contributions remains elusive. By developing a frequency domain version of PiFM, we retrieve variations in the photoinduced force on the sub-μs time-scales, allowing a direct registration of the thermal relaxation dynamics of the sample after photoexcitation. Our measurements confirm the presence of the thermal contribution to the PiFM signal in the mid-infrared range and provide strong experimental evidence that thermal components also play a role in the forces measured in PiFM in the vis/NIR range of the spectrum.

Although hydrogels are promising transdermal patches, they face spatiotemporal problems related to controlled drug release. From the “spatio” perspective, hydrogels are not malleable, therefore they do not fully contact curved skin, such as that found on the nose and fingers. From the “temporal” perspective, the internal network of a hydrogel retards cargo release. Herein, a malleable and rapid‐cargo‐releasing poly(vinyl alcohol)‐borax hydrogel that embeds freely mobile poly(hydroxyethyl methacrylate) (PHEMA) micelles is prepared. The in situ polymerization of PHEMA within the matrix produces large compound micelle particles that are not bound by the matrix. The micelles act as expellers by sweeping out cargo upon exposure to wet conditions through a concentration gradient. The hydrogel embedded with the micellar cargo‐expellers delivers a 25‐fold larger 3‐min release quantity of Nile Red (a model cargo) than the control hydrogel. The particles absorb mechanical shocks and the dynamic borate‐diol bonds engender the hydrogel with self‐healing properties, which results in a hydrogel that tightly contacts highly curved skin. Moreover, the hydrogel shows no toxicity in in vivo and skin irritation tests. This malleable hydrogel will inspire novel prompt skin‐patch systems for pharmaceutical and cosmetics purposes. An extremely malleable, stretchable, self‐healable, and biocompatible poly(vinyl alcohol)‐borax hydrogel embedded with free poly(hydroxyethyl methacrylate) micelles is designed for prompt therapeutic transdermal patches, in which the free micelles satisfy the conditions of perfect skin contact and rapid cargo release as a stress absorbent and an expelling “conveyor belt,” respectively.

In article number 2000876, Sung Yeon Hwang, Dongyeop X. Oh, Jeyoung Park, and co‐workers fabricate a malleable and rapid‐cargo‐releasing poly(vinyl alcohol)‐borax hydrogel that embeds freely mobile poly(hydroxyethyl methacrylate) micelles. Upon exposure to wet conditions, the micelle particles escaping from the hydrogel act as a “conveyor belt” to effectively expel the cargo into the external environment.

We demonstrate a new type of four-pass dye laser amplifier that can reduce the possibility of parasitic oscillation between optical components used in the amplifier. Pumping the amplifier with a 5.6-mJ Q-switched doubled Nd:YAG laser output, we obtain high-peak-power pulsed output of an incident cw narrow-bandwidth dye laser beam with a power gain greater than 2 × 10^6. Subsequent amplification of the pulse with a conventional dye amplifier yields 42% energy efficiency. When a temporally stretched pumping pulse is used, the eventual bandwidth of the final output is measured to be 130 MHz.