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Hybrid nanostructures are promising for ultrasound-triggered drug delivery and treatment, called sonotheranostics. Structures based on plasmonic nanoparticles for photothermal-induced microbubble inflation for ultrasound imaging exist. However, they have limited therapeutic applications because of short microbubble lifetimes and limited contrast. Photochemistry-based sonotheranostics is an attractive alternative, but building near-infrared (NIR)-responsive echogenic nanostructures for deep tissue applications is challenging because photolysis requires high-energy (UV-visible) photons. Here, we report a photochemistry-based echogenic nanoparticle for in situ NIR-controlled ultrasound imaging and ultrasound-mediated drug delivery. Our nanoparticle has an upconversion nanoparticle core and an organic shell carrying gas generator molecules and drugs. The core converts low-energy NIR photons into ultraviolet emission for photolysis of the gas generator. Carbon dioxide gases generated in the tumor-penetrated nanoparticle inflate into microbubbles for sonotheranostics. Using different NIR laser power allows dual-modal upconversion luminescence planar imaging and cross-sectional ultrasonography. Low-frequency (10 MHz) ultrasound stimulated microbubble collapse, releasing drugs deep inside the tumor through cavitation-induced transport. We believe that the photoechogenic inflatable hierarchical nanostructure approach introduced here can have broad applications for image-guided multimodal theranostics.

Since oxidative stress has been recognized as a major factor contributing to the progression of several neurodegenerative disorders, reactive oxygen species (ROS) including superoxide have received great attention as a representative molecular marker for the diagnosis of Alzheimer's disease (AD). Here, superoxide-sensitive fluorogenic molecular probes, benzenesulfonylated resorufin derivatives (BSRs), were newly devised for optical bioimaging of oxidative events in neurodegenerative processes. BSRs, fluorescence-quenched benzenesulfonylated derivatives of resorufin, were designed to recover their fluorescence upon exposure to superoxide through a selective nucleophilic uncaging reaction of the benzenesulfonyl cage. Among BSRs, BSR6 presented the best sensitivity and selectivity to superoxide likely due to the optimal reactivity matching between the nucleophilicity of superoxide and its electrophilicity ascribed to the highly electron-withdrawing pentafluoro-substitution on the benzenesulfonyl cage. Fluorescence imaging of inflammatory cells and animal models presented the potential of BSR6 for optical sensing of superoxide in vitro and in vivo. Furthermore, microglial cell (Bv2) imaging with BSR6 enabled the optical monitoring of intracellular oxidative events upon treatment with an oxidative stimulus (amyloid beta, Aβ) or the byproduct of oxidative stress (4-hydroxynonenal, HNE).

Self-assembly of peptides containing both l- and d-isomers often results in nanostructures with enhanced properties compared to their enantiomeric analogues, such as faster kinetics of formation, higher mechanical strength, and enzymatic stability. However, occurrence and consequences of the heterochiral assembly in the cellular microenvironment are unknown. In this study, we monitored heterochiral assembly of amphiphilic peptides inside the cell, specifically mitochondria of cancer cells, resulting in nanostructures with refined morphological and biological properties owing to the superior interaction between the backbones of opposite chirality. We have designed a mitochondria penetrating tripeptide containing a diphenyl alanine building unit, named as Mito-FF due to their mitochondria targeting ability. The short peptide amphiphile, Mito-FF co-assembled with its mirror pair, Mito-ff, induced superfibrils of around 100 nm in diameter and 0.5-1 μm in length, while enantiomers formed only narrow fibers of 10 nm in diameter. The co-administration of Mito-FF and Mito-ff in the cell induced drastic mitochondrial disruption both

Dual-emissive systems showing color-specific photoswitching are promising in bioimaging and super-resolution microscopy. However, their switching efficiency has been limited because a delicate manipulation of all the energy transfer crosstalks in the systems is unfeasible. Here, we report a perfect color-specific photoswitching, which is rationally designed by combining the complete off-to-on fluorescence switching capability of a fluorescent photochromic diarylethene and the frustrated energy transfer to the other fluorescent dye based on the excited-state intramolecular proton transfer (ESIPT) process. Upon alternation of UV and visible light irradiations, the system achieves 100% switching on/off of blue emission from the diarylethene while orange emission from the ESIPT dye is unchanged in the polymer film. By fabricating this system into biocompatible polymer nanoparticles, we demonstrate microscopic imaging of RAW264.7 macrophage cells with reversible blue-color specific fluorescence switching that enables super-resolution imaging with a resolution of 70 nm., Photoswitchable nanoparticles can be used for selective imaging in biological systems but usually have only one color. Here the authors develop a two-color fluorescent emissive system that allows full on-off switching of one component color of the system while the other color is unaffected, which has implications for super-resolution imaging.

Microbubbles are clinically used as an imaging agent for contrast-enhanced ultrasound image. Beyond the preformed microbubbles, nanoscale gas-generating chemical systems that are capable of stimulu...

Targeted delivery of therapeutic agents is of particular interest in the field of cancer treatment. However, there is an urgent need for developing clinically promising targeting approaches that can be readily administered in a green manner. Methods: Five phthalocyanine derivatives bearing different anionic and cationic groups were designed and synthesized. Then, their binding affinity with albumin were studied using gel assays, optical spectra and computational simulation. Finally, in vitro and in vivo fluorescence imaging and photodynamic therapy (PDT) evaluations were carried out. Results: The two positively charged compounds could selectively bind to albumin dimer over albumin monomer, while the three negatively charged phthalocyanines could bind to both albumin monomer and dimer. Following systemic administration, the phthalocyanines show improved tumor accumulation via transport by natural albumin. PDT evaluations indicate that one of the positively charged compounds, ZnPcN4, shows outstanding phototherapeutic efficacy against tumors in preclinical models. Conclusion: Our findings demonstrate that the use of water-soluble phthalocyanines as photosensitizers and in vivo albumin as a natural carrier may provide a green and efficient approach for tumor-targeted imaging and therapy.

Current theranostic approaches in cancer therapy demand delivery systems that can carry multiple drugs or imaging agents in a single nanoplatform with uniform biodistribution and improved target specificity. In this study, we have developed amphiphilized poly(ethyleneimine) nanoparticles (aPEI NPs) as a versatile multi-cargo delivery platform. The aPEI NPs were engineered to have the loading capacity for both hydrophobic molecules and negatively charged hydrophilic colloidal cargos through amphiphilic modification, i.e., octadecylation and subsequent PEGylation of poly(ethyleneimine). In the aqueous phase, the resulting aPEIs underwent amphiphilic self-assembly into spherical nanoparticles whose structure is constituted of the hydrophobic core with the positively charged surface and the hydrophilic neutral corona. The high degree of PEGylation resulted in the tiny colloidal size (

Two new cyanine-based fluorescent probes 1 and 2 have been developed. Probe 1 bears two cyanine units in a single molecule, and probe 2 contains a bis(trifluoromethyl)benzenethiol moiety. Both are non-fluorescent. The addition of intracellular glutathione (GSH) significantly enhanced the NIR fluorescence of the two probes. Both probes were used to image varying amounts of GSH in living cells. In tumor bearing mice, the in vivo fluorescence intensity of both probes was higher in tumors, where GSH is overexpressed, than in normal tissues. These results suggest that these new fluorogenic probes have potential for GSH-targeting diagnostic imaging.

This study discusses diverse patterns of piracy across time and regions. By comparing various features of piracy, this study highlights recurrent characteristics behind the scenes of piracy inciden...

Nanocarriers (NCs) are a group of nano-sized vehicles devised to deliver drugs to targeted malignant tissues or organs that provide remarkably improved targeting efficiency and therapeutic efficacy for cancer therapy. A variety of NCs have been developed to accommodate appropriate loading and release of drugs with a wide spectrum of chemical and physical characteristics. In addition, physicochemical modifications to the surface or interior of NCs allow for modulation of pharmacokinetic features reflecting clinical demands. However, cancer-related mortality is still high and drug-mediated cancer treatment remains a challenging research field despite the remarkable advances in targeting efficiency and therapeutic efficacy resulting from NCs. In this review, we focus on typical approaches and recent trends in NC-mediated drug delivery systems and their potential for targeted cancer therapy.

Fluorogenic nanoprobes capable of providing microenvironmental information have extensively been developed to improve the diagnostic accuracy for early or metastatic cancer detection. In cancer-associated microenvironment, matrix metalloproteinase-2,9 (MMP-2,9) has drawn attention as a representative enzymatic marker for diagnosis, prognosis, and prediction of various cancers, which is overexpressed in the primary site as well as metastatic regions. Here, we devised dual-emissive fluorogenic nanoprobe (DFNP) emitting both MMP-2,9-sensitive and insensitive fluorescence signals, for accurate monitoring of the MMP-2,9 activity in metastatic regions. DFNP was nanoscopically constructed by amphiphilic self-assembly between a constantly fluorescent polymer surfactant labeled with Cy7 (F127-Cy7) and an initially nonfluorescent hydrophobic peptide (Cy5.5-MMP-Q) that is fluorogenic in response to MMP-2,9. Ratiometric readout (Cy5.5/Cy7) by dual-channel imaging could normalize the enzyme-responsive sensing signal relative to the constantly emissive internal reference that reflects the probe amount, allowing for semi-quantitative analysis on the MMP-2,9-related tissue microenvironment. In addition to the dual-channel emission, the nanoconstructed colloidal structure of DFNP enabled efficient accumulation to lymph node in vivo. Because of these two colloidal characteristics, when injected intradermally to a mouse model of lymph node metastasis, DFNP could produce reliable ratiometric signals to provide information on the MMP-2,9 activity in the lymph nodes depending on metastatic progression, which corresponded well to the temporal histologic analysis. Furthermore, ratiometric lymph node imaging with DFNP after photodynamic therapy allowed for monitoring a therapeutic response to the given cancer treatment, demonstrating diagnostic and prognostic potential of the nanoconstructed colloidal sensor of tumor microenvironment in cancer treatment.

Proton transfer polymerization between thiol and epoxide groups is shown to be an adaptable and utilitarian method for the synthesis of hydrogels. For instance, the polymerization catalyst can be organic or inorganic, and the polymerization medium can be pure water, buffer solutions, or organic solvents. The gelation mechanism can be triggered at ambient conditions, at a physiological temperature of 37 °C, or through using light as an external stimulus. The ambient and photochemical methods both allow for nanoimprint lithography to produce freestanding patterned thick films. The required thiol- and epoxide-carrying precursors can be chosen from a long list of commercially available small molecular as well as polymeric materials. The water uptake, mechanical, and biodegradation properties of the gels can, therefore, be tuned through the choice of appropriate gelation precursors and polymerization conditions. Finally, the thio-ether groups of the cross-linked networks can be functionalized through a postgelation modification reaction to access sulfonium-based cationic structures. Such structural changes endow antibacterial properties to the networks. In their pristine form, however, the gels are biocompatible and nonadhesive, allowing cancer cells to grow in a cluster formation.

Traumatic brain injury (TBI) is an intracranial injury which can induce immediate neuroinflammation and long-term neurological deficits. Methylene blue (MB) as a nootropic has a great potential to treat neurodegeneration after TBI because of its anti-inflmmatory and neuroprotective functions. However, its limited accumulation to the brain across the blood-brain barrier (BBB) remains a major hurdle to be overcome. In this paper, we present a polymer surfactant-encapsulated nanocomplex of MB as a delivery system with high BBB permeability for efficacious treatment of TBI-induced neurodegeneration. MB was formulated via electrostatically/hydrophobically directed assembly with fatty acid and Pluronic surfactant (F-127 or F-68) to construct nanocomplexes of two different colloidal sizes (

Theranostic photonic nanoparticles (TPNs) that cross the blood–brain barrier (BBB) and efficiently deliver a therapeutic agent to treat brain diseases, simultaneously providing optical tracking of drug delivery and release, are introduced. These TPNs are constructed by physical encapsulation of visible and/or near-infrared photonic molecules, in an ultrasmall micellar structure (

Nanoscopic dense integration between solid-state emission and photochromism provides nanoprobes capable of photoswitching of bright NIR fluorescence with high on/off contrast, bistability and improved signal identification, being suitable for imaging applications in autofluorescence-rich in vivo environments.

Current approaches in use of water-insoluble photosensitizers for photodynamic therapy (PDT) of cancer often demand a nano-delivery system. Here, we report a photosensitizer-loaded biocompatible nano-delivery formulation (PPaN-20) whose size was engineered to ca. 20 nm to offer improved cell/tissue penetration and efficient generation of cytotoxic singlet oxygen. PPaN-20 was fabricated through the physical assembly of all biocompatible constituents: pyropheophorbide-a (PPa, water-insoluble photosensitizer), polycaprolactone (PCL, hydrophobic/biodegradable polymer), and Pluronic F-68 (clinically approved polymeric surfactant). Repeated microemulsification/evaporation method resulted in a fine colloidal dispersion of PPaN-20 in water, where the particulate PCL matrix containing well-dispersed PPa molecules inside was stabilized by the Pluronic corona. Compared to a control sample of large-sized nanoparticles (PPaN-200) prepared by a conventional solvent displacement method, PPaN-20 revealed optimal singlet oxygen generation and efficient cellular uptake by virtue of the suitably engineered size and constitution, leading to high in vitro phototoxicity against cancer cells. Upon administration to tumor-bearing mice by peritumoral route, PPaN-20 showed efficient tumor accumulation by the enhanced cell/tissue penetration evidenced by in vivo near-infrared fluorescence imaging. The in vivo PDT treatment with peritumorally administrated PPaN-20 showed significantly enhanced suppression of tumor growth compared to the control group, demonstrating great potential as a biocompatible photosensitizing agent for locoregional PDT treatment of cancer.

This study describes a novel and one-step procedure for the PEGylation of conjugated linoleic acid (CLA) in the melting state without solvents or catalysts for oxidative stabilization of CLA. The double bonds of CLA in PEGylated CLA (PCLA) were clearly detected by 1H NMR (nuclear magnetic resonance) spectroscopy, indicating the successful PEGylation of CLA without oxidation during PEGylation, even at high temperatures. The level of headspace oxygen depletion by PCLA was lower than CLA, indicating that the oxidation of CLA was protected by PEGylation. This easy and simple one-pot PEGylation of CLA is an effective way of preparing fatty acids with increased stability to oxidation, which would be quite useful for nutritional and pharmaceutical studies.

Semiconducting organic materials based on π-conjugated molecules or polymers have recently received considerable attention for their use as imaging and therapeutic agents for biomedical applications. Because π-conjugated materials exhibit desirable characteristics such as high brightness, photostability, emission tunability, and low toxicity, they are an attractive alternative to conventional fluorophores. In this review, the recent development of π-conjugated molecular nanoparticles for in vitro and in vivo biomedical applications is discussed.

Ar cluster was generated by an adiabatic expansion using a converging–diverging Laval nozzle at the pressure 5–7 bar and at room temperature. The size distribution of the cluster was estimated by a time-of-flight (TOF) spectroscopy and the mean size of the cluster at 5 bar was about 500 molecules. Ar cluster was ionized by electron impact and then irradiated on Si(100) and GaAs(100) semiconductor crystal surfaces at the very low fluence to investigate the interaction of cluster with the solid surface. From the isolated cluster impact at the acceleration 15–25 keV, nanoprotrusion with a few tens and hundreds of nanometer diameter and a few nanometer height was observed. This formation of out-grown nano-structure instead of inward crater is predicted due to the increase of the local pressure up to 10–100 GPa and local heating 104–105 K in ps by an impingement of cluster ion beam and re-bounce of liquid medium from the solid and subsequently quenching effect. In addition, the change of Si (100) surface roughness was investigated with the variations of Ar cluster ion dose, and from which phenomenological ESE model of cluster ion impact with solid surface, i.e., surface embossment(E), surface sputtering/smoothing(S), and surface etching(E), is proposed to happen in sequence.

Imaging nanoprobes are a group of nano-sized contrast agents devised for providing improved contrast and spatial resolution for bioimaging. Among various imaging nanoprobes, optical nanoprobes capable of monitoring biological events or progresses in the cellular and molecular levels have been developed for early detection, accurate diagnosis, and personalized image-guided treatment of diseases. The optical activities of nanoprobes can be tuned on demand for specific applications by engineering their size, surface nature, morphology, and composition. In addition, by virtue of the nanostructure, nanoprobes have displayed favorable pharmacokinetic features and target specificity reflecting clinical demands. In this review, we focus on typical approaches and recent trends in development of nanoprobe-mediated optical imaging and their potential as a clinical diagnostic modality. (C) 2016 Optical Society of America

Photodynamic therapy (PDT) is a non-invasive treatment modality for selective destruction of cancer and other diseases and involves the colocalization of light, oxygen, and a photosensitizer (PS) to achieve photocytotoxicity. Although this therapeutic method has considerably improved the quality of life and life expectancy of cancer patients, further advances in selectivity and therapeutic efficacy are required to overcome numerous side effects related to classical PDT. The application of nanoscale photosensitizers (NPSs) comprising molecular PSs and nanocarriers with or without other biological/photophysical functions is a promising approach for improving PDT. In this review, we focus on four nanomedical approaches for advanced PDT: (1) nanocarriers for targeted delivery of PS, (2) introduction of active targeting moieties for disease-specific PDT, (3) stimulus-responsive NPSs for selective PDT, and (4) photophysical improvements in NPS for enhanced PDT efficacy. Highlights ► Conservation of normal tissues demands non-invasive therapeutic methods. ► PDT is a light-activated, non-invasive modality for selective destruction of cancers.► Success of PDT requires further advances to overcome the limitations of classical PDT. ►Nanophotosensitizers help improve target selectivity and therapeutic efficacy of PDT.

Organic one dimensional (1-D) structures such as nanowires (NWs) and nanotubes (NTs), including carbon nanotubes (CNTs), have recently undergone extensive investigation for possible applications in biosensing, photothermal and/or radiofrequency ablation therapy of cancer, and bioimaging. As few data exist on this particular topic, the aim of this chapter is to encompass the state of the art of these peculiar materials, by describing the various fabrication technologies for NWs and NTs, which include self-assembly, template synthesis, and modification of CNTs. Also described are some representative recent applications of NWs and NTs in biomedical areas, including biosensors, cancer therapy via photothermal and/or radiofrequency ablation, and optical bioimaging. Future research to solve the currently pending problems, and to broaden the application areas of NWs and NTs, are also discussed. Keywords: organic nanowires; organic nanotubes; carbon nanotubes; biosensing; cancer therapy; bioimaging

Hydrogen bonding is a major intermolecular interaction for self-assembly occurring in nature. Here we report novel polymeric carbohydrates, i.e., poly(oxyethylene galactaramide)s (PEGAs), as biomimetic building blocks to construct hydrogen bond-mediated self-assembled nanoparticles that are useful for biomedical in vivo applications. PEGAs were conceptually designed as a biocompatible hybrid between polysaccharide and poly(ethylene glycol) (PEG) to attain multivalent hydrogen bonding as well as fully hydrophilic, non-ionic and antifouling characteristics. It was revealed that PEGAs are capable of homospecies hydrogen bonding in water and constructing multi-chain assembled nanoparticles whose structural integrity is highly stable with varying concentration, temperature and pH. Using near-infrared fluorescence imaging we demonstrate facile blood circulation and efficient tumor accumulation of the self-assembled PEGA nanoparticles that were intravenously injected into mice. These in vivo behaviors elucidate the combined merits of our design strategy, i.e., biocompatible chemical constitution capable of multivalent hydrogen bonding, antifouling properties, minimal cell interaction and mesoscopic colloidal self-assembly, as well as size-motivated tumor targeting.