Real-Time In Vivo Detection of Cellular Senescence through the Controlled Release of the NIR Fluorescent Dye Nile Blue

In vivo detection of cellular senescence is accomplished by using mesoporous silica nanoparticles loaded with the NIR-FDA approved Nile blue (NB) dye and capped with a galactohexasaccharide ( S3 ). NB emission at 672 nm is highly quenched inside S3 , yet a remarkable emission enhancement is observed upon cap hydrolysis in the presence of β-galactosidase and dye release. The efficacy of the probe to detect cellular senescence is tested in vitro in melanoma SK-Mel-103 and breast cancer 4T1 cells and in vivo in palbociclib-treated BALB/cByJ mice bearing breast cancer tumor.     

An Activatable Polymeric Reporter for Near‐Infrared Fluorescent and Photoacoustic Imaging of Invasive Cancer

Discriminative detection of invasive and noninvasive breast cancers is crucial for their effective treatment and prognosis. However, activatable probes able to do so in vivo are rare. Herein, we report an activatable polymeric reporter (P‐Dex) that specifically turns on near‐infrared (NIR) fluorescent and photoacoustic (PA) signals in response to the urokinase‐type plasminogen activator (uPA) overexpressed in invasive breast cancer. P‐Dex has a renal‐clearable dextran backbone that is linked with a NIR dye caged with an uPA‐cleavable peptide substrate. Such a molecular design allows P‐Dex to passively target tumors, activate NIR fluorescence and PA signals to effectively distinguish invasive MDA‐MB‐231 breast cancer from noninvasive MCF‐7 breast cancer, and ultimately undergo renal clearance to minimize the toxicity potential. Thus, this polymeric reporter holds great promise for the early detection of malignant breast cancer.     

Photo‐ and pH‐Tunable Multicolor Fluorescent Nanoparticle‐Based Spiropyran‐ and BODIPY‐Conjugated Polymer with Graphene Oxide

We report a stimuli‐responsive fluorescent nanomaterial, based on graphene oxide coupled with a polymer conjugated with photochromic spiropyran (SP) dye and hydrophobic boron dipyrromethane (BODIPY) dye, for application in triggered target multicolor bioimaging. Graphene oxide (GO) was reduced by catechol‐conjugated polymers under mildly alkaline conditions, which enabled to formation of functionalized multicolor graphene nanoparticles that can be induced by irradiation with UV light and by changing the pH from acidic to neutral. Investigation of these nanoparticles by using AFM, fluorescence emission, and in vitro cell and in vivo imaging revealed that they show different tunable colors in bioimaging applications and, more specifically, in cancer‐cell detection. The stability, biocompatibility, and quenching efficacy of this nanocomposite open a different perspective for cell imaging in different independent colors, sequentially and simultaneously.     

Design and Synthesis of ZnII‐Coordination Polymers Anchored with NSAIDs: Metallovesicle Formation and Multi‐drug Delivery

A series of coordination polymers synthesized from a bis‐pyridyl linker, namely 4,4′‐azopyridine ( L ), selected non‐steroidal‐anti‐inflammatory drugs (NSAIDs), namely diclofenac ( Dic ), ibuprofen ( Ibu ), flurbiprofen ( Flu ), mefenamic acid ( Mefe ), and naproxen ( Nap ), and Zn(NO₃)₂ were characterized by single crystal X‐ray diffraction. One of the coordination polymers, namely CP3 derived from Flu , was able to form metallovesicles in DMSO, DMSO/H₂O and DMSO/DMEM (biological media) as revealed by TEM, AFM and DLS. Metallovesicle formation by CP3 was further supported by loading a fluorescent dye, namely calcein, as well as an anti‐cancer drug, doxorubicin hydrochloride ( DOX ), as revealed by UV‐vis and emission spectra, and fluorescence microscopy. DOX ‐loaded metallovesicles of CP3 ( DOX@CP3‐vesicle ) could be delivered in vitro to a highly aggressive human breast cancer cell line, namely MDA‐MB‐231, as revealed by MTT and cell migration assays, and also cell imaging performed under laser scanning confocal microscope (LSCM). Thus, a proof of concept for developing a multi‐drug delivery system derived from a metallovesicle for delivering an anti‐cancer drug to cancer cells is demonstrated for the first time.     

Flavylium Polymethine Fluorophores for Near‐ and Shortwave Infrared Imaging

Bright fluorophores in the near‐infrared and shortwave infrared (SWIR) regions of the electromagnetic spectrum are essential for optical imaging in vivo. In this work, we utilized a 7‐dimethylamino flavylium heterocycle to construct a panel of novel red‐shifted polymethine dyes, with emission wavelengths from 680 to 1045 nm. Photophysical characterization revealed that the 1‐ and 3‐methine dyes display enhanced photostability and the 5‐ and 7‐methine dyes exhibit exceptional brightness for their respective spectral regions. A micelle formulation of the 7‐methine facilitated SWIR imaging in mice. This report presents the first polymethine dye designed and synthesized for SWIR in vivo imaging.     

Toward the Design of a Catalytic Metallodrug: Selective Cleavage of G‐Quadruplex Telomeric DNA by an Anticancer Copper–Acridine–ATCUN Complex

Telomeric DNA represents a novel target for the development of anticancer drugs. By application of a catalytic metallodrug strategy, a copper–acridine–ATCUN complex (CuGGHK‐Acr) has been designed that targets G‐quadruplex telomeric DNA. Both fluorescence solution assays and gel sequencing demonstrate the CuGGHK‐Acr catalyst to selectively bind and cleave the G‐quadruplex telomere sequence. The cleavage pathway has been mapped by matrix assisted laser desorption ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS) experiments. CuGGHK‐Acr promotes significant inhibition of cancer cell proliferation and shortening of telomere length. Both senescence and apoptosis are induced in the breast cancer cell line MCF7.     

Nanoaggregate Probe for Breast Cancer Metastasis through Multispectral Optoacoustic Tomography and Aggregation‐Induced NIR‐I/II Fluorescence Imaging

An activatable nanoprobe for imaging breast cancer metastases through near infrared‐I (NIR‐I)/NIR‐II fluorescence imaging and multispectral optoacoustic tomography (MSOT) imaging was designed. With a dihydroxanthene moiety serving as the electron donor, quinolinium as the electron acceptor and nitrobenzyloxydiphenylamino as the recognition element, the probe can specifically respond to nitroreductase and transform into an activated D‐π‐A structure with a NIR emission band extending beyond 900 nm. The activated nanoprobe exhibits NIR emission enhanced by aggregation‐induced emission (AIE) and produces strong optoacoustic signal. The nanoprobe was used to detect and image metastases from the orthotopic breast tumors to lymph nodes and then to lung in two breast cancer mouse models. Moreover, the nanoprobe can monitor the treatment efficacy during chemotherapeutic course through fluorescence and MSOT imaging.     

Synthesis,characterization and in vitro antimicrobial and anti‐breast cancer activity studies of metal complexes of novel pentadentate azo dye ligand

A new azo dye with N3O2 donor set of atoms has been synthesized via coupling reaction of 2,6‐diaminopyridine with p‐methoxybenzaldehyde. The molecular and electronic structure of the azo dye ligand (L) was optimized theoretically and the quantum chemical parameters were calculated. Molecular docking was used to predict the binding between L and the receptors of breast cancer mutant 3hb5‐oxidoreductase, crystal structure of Escherichia coli (3 T88) and crystal structure of Staphylococcus aureus (3q8u). The newly synthesized L was used for complex formation with Cr(III), Mn(II), Fe(III), Co.(II), Ni(II), Cu(II), Zn(II) and Cd(II) ions. The nature of bonding and the stoichiometry of L and its mononuclear complexes were deduced from elemental analyses, spectroscopic, magnetic susceptibility, molar conductance, electron spin resonance and conductivity measurements, thermogravimetric analyses and powder X‐ray diffraction. Elemental analysis data show that the complexes have composition of ML type with an octahedral geometry for all the complexes. The activation thermodynamic parameters were calculated. The prepared azo dye and its metal complexes were tested against various Gram‐positive and Gram‐negative bacteria and a fungus. Most complexes exhibit antibacterial and antifungal activities against these organisms. Anticancer evaluation studies against standard breast cancer cell line were performed using various concentrations. The activity index was calculated. Copyright © 2016 John Wiley & Sons, Ltd.     

Ethoxy‐substituted Oligo‐phenylenevinylene‐Bridged Organic Dyes for Efficient Dye‐Sensitized Solar Cells

Organic dyes with ethoxy‐substituted oligo‐phenylenevinylene as chromophores were synthesized for dye‐sensitized solar cells (DSSCs), and the detailed relationships between the dye structures, photophysical properties, electrochemical properties, and performances of DSSCs were described. The dye S3O showed broad IPCE spectra in the spectral range of 350–750 nm, and the dye S1P showed solar energy‐to‐electricity conversion efficiency (() of up to 4.23% under AM 1.5 irradiation (100 mW/cm²) in comparison with the reference Ru‐complex (N719 dye) with an η value of 5.90% under similar experimental conditions.     

(Benzyl isocyanide)gold(I) pyrimidine‐2‐thiolate complex: Synthesis and biological activity

The reaction of [(Me₂S)AuCl] with an equimolar amount of benzyl isocyanide (PhCH₂NC) ligand led to the formation of complex [(PhCH₂NC)AuCl] ( 1 ). The solid‐state structure of 1 was determined using the X‐ray diffraction method. Through a salt metathesis reaction, the chloride ligand in 1 was replaced by pyrimidine‐2‐thiolate (SpyN^?) to afford the complex [(PhCH₂NC)Au(η¹‐S‐Spy)] ( 2 ), which was characterized spectroscopically. The cytotoxic activities of 1 and 2 were evaluated against three human cancer cell lines: ovarian carcinoma (SKOV3), lung carcinoma (A549) and breast carcinoma (MCF‐7). Complex 2 showed higher cytotoxicity than cisplatin against SKOV3 and MCF‐7 cancer cell lines. It showed a strong anti‐proliferative activity with IC₅₀ of 7.80, 6.26 and 6.14 μM, compared with that measured for cisplatin which was 7.62, 12.36 and 11.47 μM, against A549, SKOV3 and MCF‐7 cell lines, respectively. The induction of cellular apoptosis by 2 was also studied on MCF‐7 cell line. Our results indicated that 2 could induce apoptosis in cancerous cells in a dose‐dependent manner.     

Photoluminescence of bridged polysilsesquioxanes containing urea groups: Doping with Safranine‐O to generate red‐light emission

Bridged polysilsesquioxanes containing urea groups (ureasils) exhibit a broad photoluminescent emission in the visible spectrum. For a particular bridged polysilsesquioxane synthesized by the hydrolytic condensation of a precursor prepared by reaction of 4,4′‐[1,3 phenylenebis‐(1‐methylethylidene)]bis(aniline) (BSA) with 3‐(isocyanatepropyl)triethoxysilane (IPTES), we show that the broad photoluminescent band could be transformed into a relatively narrow emission band located in the red region of the spectra, by doping with Safranine‐O. The spectral overlap between the host emission and the dye absorption generated an efficient energy transfer process (antenna effect). Absorption, emission, and triplet–triplet absorption spectra revealed an efficient dispersion of the dye in the ureasil as well as the presence of strong host‐guest specific interactions. © 2007 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 46: 289–296, 2008     

Tumor‐Microenvironment‐Induced Degradation of Ultrathin Gadolinium Oxide Nanoscrolls for Magnetic‐Resonance‐Imaging‐Monitored,Activatable Cancer Chemotherapy

The development of biodegradable inorganic nanoparticles with a tumor microenvironment‐activated therapeutic mode of action is urgently needed for precision cancer medicine. Herein, the synthesis of ultrathin lanthanide nanoscrolls (Gd₂O₃ NSs) is reported, which biodegrade upon encountering the tumor microenvironment. The Gd₂O₃ NSs showed highly controlled magnetic properties, which enabled their high‐resolution magnetic resonance imaging (MRI). Importantly, Gd₂O₃ NSs degrade in a pH‐responsive manner and selectively penetrate tumor tissue, enabling the targeted release of anti‐cancer drugs. Gd₂O₃ NSs can be efficiently loaded with an anti‐cancer drug (DOX, 80 %) and significantly inhibit tumor growth with negligible cellular and tissue toxicity both in vitro and in vivo. This study may provide a novel strategy to design tumor microenvironment‐responsive inorganic nanomaterials for biocompatible bioimaging and biodegradation‐enhanced cancer therapy.     

Inhibition of HER2‐Positive Breast Cancer Growth by Blocking the HER2 Signaling Pathway with HER2‐Glycan‐Imprinted Nanoparticles

Blocking the HER2 signaling pathway has been an effective strategy in the treatment of HER2‐positive breast cancer. It mainly relies on the use of monoclonal antibodies and tyrosine‐kinase inhibitors. Herein, we present a new strategy, the nano molecularly imprinted polymer (nanoMIP). The nanoMIPs, imprinted using HER2 N‐glycans, could bind almost all HER2 glycans and suppress the dimerization of HER2 with other HER family members, blocking the downstream signaling pathways, thereby inhibiting HER2+ breast cancer growth. In vitro experiments demonstrated that the nanoMIPs specifically targeted HER2+ cells and inhibited cell proliferation by 30 %. In vivo experiments indicated that the mean tumor volume of the nanoMIP‐treated group was only about half of that of the non‐treated groups. This study provides not only a new possibility to treat of HER2+ breast cancer but also new evidence to boost further development of nanoMIPs for cancer therapy.     

Tumor‐Microenvironment‐Induced Degradation of Ultrathin Gadolinium Oxide Nanoscrolls for Magnetic‐Resonance‐Imaging‐Monitored,Activatable Cancer Chemotherapy

The development of biodegradable inorganic nanoparticles with a tumor microenvironment‐activated therapeutic mode of action is urgently needed for precision cancer medicine. Herein, the synthesis of ultrathin lanthanide nanoscrolls (Gd₂O₃ NSs) is reported, which biodegrade upon encountering the tumor microenvironment. The Gd₂O₃ NSs showed highly controlled magnetic properties, which enabled their high‐resolution magnetic resonance imaging (MRI). Importantly, Gd₂O₃ NSs degrade in a pH‐responsive manner and selectively penetrate tumor tissue, enabling the targeted release of anti‐cancer drugs. Gd₂O₃ NSs can be efficiently loaded with an anti‐cancer drug (DOX, 80 %) and significantly inhibit tumor growth with negligible cellular and tissue toxicity both in vitro and in vivo. This study may provide a novel strategy to design tumor microenvironment‐responsive inorganic nanomaterials for biocompatible bioimaging and biodegradation‐enhanced cancer therapy.     

Assessment of Luminescent Downshifting Layers for the Improvement of Light‐Harvesting Efficiency in Dye‐Sensitized Solar Cells

Luminescence downshifting (LDS) of light can be a practical photon management technique to compensate the narrow absorption band of high‐extinction‐coefficient dyes in dye‐sensitized solar cells (DSSCs). Herein, an optical analysis on the loss mechanisms in a reflective LDS (R‐LDS)/DSSC configuration is reported. For squaraine dye (550–700 nm absorption band) and CaAlSiN₃:Eu²⁺ LDS material (550–700 nm emission band), the major loss channels are found to be non‐unity luminescence quantum efficiency (QE) and electrolyte absorption. By using an ideal LDS layer (QE=100 %), a less absorbing electrolyte (Co‐based), and antireflection coatings, approximately 20 % better light harvesting is obtained. If the absorption/emission band of dye/LDS is shifted to 800 nm, a maximal short‐circuit current density (J_sc) of 22.1 mA cm^?2 can be achieved. By putting the LDS layer in front of the DSSC (transmissive mode), more significant loss channels are observed, and hence a lower overall efficiency than the R‐LDS configuration.     

Molecular Scaffolds as Double‐Targeting Agents For the Diagnosis and Treatment of Neuroblastoma

The selective delivery of therapeutic and imaging agents to tumoral cells has been postulated as one of the most important challenges in the nanomedicine field. Meta‐iodobenzilguanidine (MIBG) is widely used for the diagnosis of neuroblastoma (NB) due to its strong affinity for the norepinephrine transporter (NET), usually overexpressed on the membrane of malignant cells. Herein, a family of novel Y‐shaped scaffolds has been synthesized, which have structural analogues of MIBG covalently attached at each end of the Y‐structure. The cellular uptake capacity of these double‐targeting ligands has been evaluated in vitro and in vivo, yielding one specific Y‐shaped structure that is able to be engulfed by the malignant cells, and accumulates in the tumoral tissue, at significantly higher levels than the structure containing only one single targeting agent. This Y‐shaped ligand can provide a powerful tool for the current treatment and diagnosis of this disease.     

First Highly Efficient and Photostable E and C Derivatives of 4,4‐Difluoro‐4‐bora‐3a,4a‐diaza‐s‐indacene (BODIPY) as Dye Lasers in the Liquid Phase,Thin Films,and Solid‐State Rods

A new library of E‐ and C‐4,4‐difluoro‐4‐bora‐3a,4a‐diaza‐s‐indacene (BODIPY) derivatives has been synthesized through a straightforward protocol from commercially available BODIPY complexes, and a systematic study of the photophysical properties and laser behavior related to the electronic properties of the B‐substituent group (alkynyl, cyano, vinyl, aryl, and alkyl) has been carried out. The replacement of fluorine atoms by electron‐withdrawing groups enhances the fluorescence response of the dye, whereas electron‐donor groups diminish the fluorescence efficiency. As a consequence, these compounds exhibit enhanced laser action with respect to their parent dyes, both in liquid solution and in the solid phase, with lasing efficiencies under transversal pumping up to 73 % in liquid solution and 53 % in a solid matrix. The new dyes also showed enhanced photostability. In a solid matrix, the derivative of commercial dye PM597 that incorporated cyano groups at the boron center exhibited a very high lasing stability, with the laser emission remaining at the initial level after 100 000 pump pulses in the same position of the sample at a 10 Hz repetition rate. Distributed feedback laser emission was demonstrated with organic films that incorporated parent dye PM597 and its cyano derivative. The films were deposited onto quartz substrates engraved with appropriate periodical structures. The C derivative exhibited a laser threshold lower than that of the parent dye as well as lasing intensities up to three orders of magnitude higher.     

Epitaxial Seeded Growth of Rare‐Earth Nanocrystals with Efficient 800 nm Near‐Infrared to 1525 nm Short‐Wavelength Infrared Downconversion Photoluminescence for In Vivo Bioimaging

Novel β‐NaGdF₄/Na(Gd,Yb)F₄:Er/NaYF₄:Yb/NaNdF₄:Yb core/shell 1/shell 2/shell 3 (C/S1/S2/S3) multi‐shell nanocrystals (NCs) have been synthesized and used as probes for in vivo imaging. They can be excited by near‐infrared (800 nm) radiation and emit short‐wavelength infrared (SWIR, 1525 nm) radiation. Excitation at 800 nm falls into the “biological transparency window”, which features low absorption by water and low heat generation and is considered to be the ideal excitation wavelength with the least impact on biological tissues. After coating with phospholipids, the water‐soluble NCs showed good biocompatibility and low toxicity. With efficient SWIR emission at 1525 nm, the probe is detectable in tissues at depths of up to 18 mm with a low detection threshold concentration (5 nM for the stomach of nude mice and 100 nM for the stomach of SD rats). These results highlight the potential of the probe for the in vivo monitoring of areas that are otherwise difficult to analyze.     

Targeted Imaging and Proteomic Analysis of Tumor‐Associated Glycans in Living Animals

Although it has been well known that dynamic changes in glycosylation are associated with tumor progression, it remains challenging to selectively visualize the cancer glycome in vivo. Herein, a strategy for the targeted imaging of tumor‐associated glycans by using ligand‐targeted liposomes encapsulating azidosugars is described. The intravenously injected liposomal nanoparticles selectively bound to the cancer‐cell‐specific receptors and installed azides into the melanoma glycans in a xenograft mouse model in a tissue‐specific manner. Subsequently, a copper‐free click reaction was performed in vivo to chemoselectively conjugate the azides with a near‐infrared fluorescent dye. The glycosylation dynamics during tumor growth were monitored by in vivo fluorescence imaging. Furthermore, the newly synthesized sialylated glycoproteins were enriched during tumor growth and identified by glycoproteomics. Compared with the labeling methods using free azidosugars, this method offers improved labeling efficiency and high specificity and should facilitate the elucidation of the functional role of glycans in cancer biology.     

Enzyme‐Responsive Intracellular‐Controlled Release Using Silica Mesoporous Nanoparticles Capped with ε‐Poly‐L‐lysine

The synthesis and characterization of two new capped silica mesoporous nanoparticles for controlled delivery purposes are described. Capped hybrid systems consist of MCM‐41 nanoparticles functionalized on the outer surface with polymer ε‐poly‐L ‐lysine by two different anchoring strategies. In both cases, nanoparticles were loaded with model dye molecule [Ru(bipy)₃]²⁺. An anchoring strategy involved the random formation of urea bonds by the treatment of propyl isocyanate‐functionalized MCM‐41 nanoparticles with the lysine amino groups located on the ε‐poly‐L ‐lysine backbone (solid Ru‐rLys‐S1 ). The second strategy involved a specific attachment through the carboxyl terminus of the polypeptide with azidopropyl‐functionalized MCM‐41 nanoparticles (solid Ru‐tLys‐S1 ). Once synthesized, both nanoparticles showed a nearly zero cargo release in water due to the coverage of the nanoparticle surface by polymer ε‐poly‐L ‐lysine. In contrast, a remarkable payload delivery was observed in the presence of proteases due to the hydrolysis of the polymer’s amide bonds. Once chemically characterized, studies of the viability and the lysosomal enzyme‐controlled release of the dye in intracellular media were carried out. Finally, the possibility of using these materials as drug‐delivery systems was tested by preparing the corresponding ε‐poly‐L ‐lysine capped mesoporous silica nanoparticles loaded with cytotoxic drug camptothecin (CPT), CPT‐rLys‐S1 and CPT‐tLys‐S1 . Cellular uptake and cell‐death induction were studied. The efficiency of both nanoparticles as new potential platforms for cancer treatment was demonstrated.