BODIPY-Based Mitochondrial Targeted NIR-Responsive CO-Releasing Platform for the On-Demand Release of CO to Treat Cancer.

It is an established fact that cancer is one of the most serious public health issues after coronary artery disease. Thus, exploring more effective and efficient therapeutic protocols over the traditional chemotherapeutic strategy is imperative to improving cancer survivorship and patient quality of life. In this respect, recent reports on molecularly engineered meso-substituted BODIPY have shown remarkable effects as a photoresponsive CO-releasing platform for the on-demand release of CO to treat cancer. Herein, we designed and synthesized two meso-substituted BODIPY photoresponsive CO-releasing molecules (photoCORMs). These BODIPY derivatives were tethered to a phenoxymethylpyridine moiety and oligoethylene glycol to maintain a hydrophilic-hydrophobic balance and improved cell permeability. The cell imaging experiments demonstrated that oligoethylene glycol containing photoCORM-1 efficiently internalized and preferentially localized at the mitochondria. To understand the mechanistic aspect of preferential localization into the mitochondria, live cell imaging was also carried out. Photorelease of CO was directly monitored by the inline IR spectroscopic technique. Finally, in vitro cytotoxicity and apoptosis assays on MDA-MB-231 cell lines clearly showed that photoCORM-1 induced apoptosis-mediated cell killing on account of photoreleased CO, which otherwise showed insignificant toxicity even at a very high concentration of ∼50 µM.

Spatiotemporal photo-release of hydrogen sulphide from ß-carboline-derived nanoparticles for therapeutic applications.

Hydrogen sulfide (H2S) is an important gasotransmitter that plays a significant role in the regulation of various physiological activities. The therapeutic effect of H2S is highly concentration-dependent and has recently been recognized for wound healing applications. Until now, the reported H2S delivery systems for wound healing applications have been focused on polymer-coated cargo systems for the encapsulation of H2S donors that are based just on endogenous stimuli-responsive systems such as pH or glutathione. These delivery systems lack spatio-temporal control and can cause premature H2S release depending on the wound microenvironment. In this regard, polymer-coated light-activated gasotransmitter donors provide a promising and efficient means of delivering high spatial and temporal control along with localized delivery. Hence, for the first time, we developed a ß-carboline photocage-based H2S donor (BCS) and formulated it into two photo-controlled H2S delivery systems: (i) Pluronic-coated nanoparticles loaded with BCS (Plu@BCS nano); and (ii) a hydrogel platform impregnated with BCS (Plu@BCS hydrogel). We investigated the mechanism of photo-release and the photo-regulated H2S release profile from the BCS photocage. We found that the Plu@BCS nano and Plu@BCS hydrogel systems were stable and did not release H2S without light treatment. Interestingly, external light manipulation, such as changing the irradiation wavelength, time, and location, regulate the release of H2S precisely. Biological studies (in vitro) suggest that the Pluronic coating on the BCS photocage makes the donor highly biocompatible and desirable for biological applications.

NIR-Responsive Lysosomotropic Phototrigger: An "AIE + ESIPT" Active Naphthalene-Based Single-Component Photoresponsive Nanocarrier with Two-Photon Uncaging and Real-Time Monitoring Ability.

In recent times, organelle-targeted drug delivery systems have gained tremendous attention due to the site-specific delivery of active drug molecules, resulting in enhanced bioefficacy. In this context, a phototriggered drug delivery system (DDS) for releasing an active molecule is superior, as it provides spatial and temporal control over the release. So far, a near-infrared (NIR) light-responsive organelle-targeted DDS has not yet been developed. Hence, we introduced a two-photon NIR light-responsive lysosome-targeted "AIE + ESIPT" active single-component DDS based on the naphthalene chromophore. The two-photon absorption cross section of our DDS is 142 GM at 850 nm. The DDS was converted into pure organic nanoparticles for biological applications. Our nano-DDS is capable of selective targeting, AIE luminogenic imaging, and drug release within the lysosome. In vitro studies using cancerous cell lines showed that our single-component photoresponsive nanocarrier exhibited enhanced cytotoxicity and real-time monitoring ability of drug release.

One- and Two-Photon Uncaging of Carbon Monoxide (CO) with Real-Time Monitoring: On-Demand Carbazole-Based Dual CO-Releasing Platform to Test over Single and Combinatorial Approaches for the Efficient Regression of Orthotopic Murine Melanoma In Vivo.

Herein, we report three new metal-free, photochemically active single, dual, and combinatorial CORMs (photoCORMs) based on a carbazole-fused 1,3-dioxol-2-one moiety which released one equivalent of CO, two equivalent of CO, and a combination of one equivalent of each CO and anticancer drug upon one- and two-photon excitation, respectively. The photoCORMs exhibited good cellular uptake and real-time monitoring ability of CO uncaging by a color change approach in cancerous B16F10 cells. Interestingly, the cytotoxicity assay on B16F10 cells indicated that the dual photoCORM has increased anticancer activity over the single and combinatorial photoCORMs upon irradiation. Our results also showed that CO could accelerate the effectiveness of the well-known anticancer drug (chlorambucil). Finally, the in vivo evaluation of the dual photoCORM on an established murine melanoma tumor (C57BL/6J mouse model) manifested a significant regression of tumor volume and led to significant improvement (>50%) in the overall survivability.

Mitochondria-localized in situ generation of rhodamine photocage with fluorescence turn-on enabling cancer cell-specific drug delivery triggered by green light.

In this work, we have developed a rhodamine dye based water-soluble, mitochondria-indicating photocage, which gets activated in the mitochondria producing a fluorescent signal and on-demand releases the caged anticancer drug, chlorambucil, in the cancer cells selectively upon irradiation of green light.

An improved tumor-specific therapeutic strategy by the spatio-temporally controlled in situ formation of a Cu(ii) complex, leading to prompt cell apoptosis via photoactivation of a prodrug.

The anti-tumor activity of Cu complexes is well established in cancer research. We developed a biotin-tagged Cu-chelating prodrug that is activated by one-photon and two-photon irradiation for the target-specific and spatio-temporally controlled in situ generation of a Cu complex. In this way, we transform copper from a "cancer-promoting" agent to an anticancer agent.

A lysosome-specific near-infrared fluorescent probe for in vitro cancer cell detection and non-invasive in vivo imaging.

Near-infrared (NIR) fluorescent probes have been developed as potential bio-materials having profound applications in diagnosis and clinical practice. Herein, we wish to disclose a highly photostable ultra-bright NIR probe for the specific detection of lysosomes in numerous cell lines. Furthermore, the applicability of the developed NIR probe was evaluated for in vivo imaging.

'AIE + ESIPT' assisted photorelease: fluorescent organic nanoparticles for dual anticancer drug delivery with real-time monitoring ability.

'Aggregation Induced Emission + Excited State Intramolecular Proton Transfer (AIE + ESIPT)'-assisted photorelease of an anticancer drug by a p-hydroxyphenacyl (pHP) phototrigger with real-time monitoring has been demonstrated.

ESIPT-induced fluorescent o-hydroxycinnamate: a self-monitoring phototrigger for prompt image-guided uncaging of alcohols.

o-Hydroxycinnamate derivatives are well-known phototriggers for fast and direct release of alcohols and amines without proceeding through the cleavage of carbonate or carbamate linkages. Despite these unique features, o-hydroxycinnamates lack extensive applications in biological systems mainly because of their non-fluorescent nature. To overcome this limitation, we have attached a 2-(2'-hydroxyphenyl) benzothiazole (HBT) moiety, capable of rapid excited-state intramolecular proton transfer (ESIPT) to the o-hydroxycinnamate group. The ESIPT effect induced two major advantages to the o-hydroxycinnamate group: (i) large Stokes' shifted fluorescence (orange colour) properties and (ii) distinct fluorescence colour change upon photorelease. In vitro studies exhibited an image guided, photoregulated release of bioactive molecules by the o-hydroxycinnamate-benzothiazole-methyl salicylate conjugate and real-time monitoring of the release action.

Redox-responsive xanthene-coumarin-chlorambucil-based FRET-guided theranostics for "activatable" combination therapy with real-time monitoring.

A FRET donor-acceptor xanthene-coumarin conjugate has been designed for redox-regulated synergic treatment of photodynamic therapy and chemotherapy with real-time monitoring. The "locked" FRET pair was selectively "unlocked" by biological reducing thiols via rupture of a sacrificial disulfide linker. A distinct change in fluorescence color and selective cancer cell toxicity were observed in vitro.

Intramolecular macrolactonization, photophysical and biological studies of new class of polycyclic pyrrole derivatives.

Herein, we report an efficient synthesis of N-substituted pyrrole derivatives and their application to construct macrocyclic oxazocinone via a two-component coupling reaction followed by base mediated intramolecular cyclization. This methodology provides an easy two-step approach to constitute a library of fused pyrrolo-oxazocinone derivatives in good yields under mild reaction conditions. The present methodology offers an easy access to the synthesis of a library of fluorescent pyrole derivatives. Among them, tert-butyl 2-(2-(3-hydroxypropyl)-7-methoxy-4,5-dihydro-2H-benzo[e]isoindol-1-yl)acetate has been employed in bio-analytical imaging which shows efficient cellular internalization along with no obvious cellular toxicity.

Coumarin polycaprolactone polymeric nanoparticles: light and tumor microenvironment activated cocktail drug delivery.

Highly sensitive hypoxia (H2O2)-activated photoresponsive polymeric nanoparticles for cocktail delivery of anticancer drugs doxorubicin (Dox) and chlorambucil (Cbl) were developed. The photoresponsive polymer conjugate was constructed by ring-opening polymerization (ROP) of caprolactone (as the tail) with 7-hydroxycoumarin chlorambucil (as the head). During nanoprecipitation, the polycaprolactone chain wrapped around the hydrophobic core (coumarin chlorambucil) to form a "shell". Interestingly, the polycaprolactone-tagged coumarin-chlorambucil (PCL-CC) NPs provided sufficient space for co-encapsulation of another hydrophobic anticancer drug Dox with a loading efficiency of 13 wt%. The controlled release of Dox and Cbl from Dox-PCL-CC NPs was investigated under three different conditions: (i) in the presence of H2O2 (tumor microenvironment), (ii) photoirradiation using UV light of ≥365 nm for 60 min, and (iii) photoirradiation using UV light of ≥365 nm for 15 min in the presence of H2O2. Results showed that photoirradiation in the presence of H2O2 results in generation of reactive oxygen species (HOO-, OH-), which assist hydrolysis of the ester group in the polymeric backbone of Dox-PCL-CC NPs and UV irradiation leads to cleavage of the coumarin-chlorambucil ester linkage, leading to burst release of Dox and Cbl. The drug release profile from the NPs under three different conditions was monitored by different instrumental techniques, e.g. emission spectroscopy, MALDI-Tof mass spectrometry, DLS and HPLC analysis. In vitro biological studies revealed that the present system can efficiently deliver the cocktail anticancer drugs with full control over release into the tumor cells by means of H2O2 and light activation.

Photocaging of Single and Dual (Similar or Different) Carboxylic and Amino Acids by Acetyl Carbazole and its Application as Dual Drug Delivery in Cancer Therapy.

A new fluorescent photoremovable protecting group (FPRPG) based on acetylcarbazole framework has been explored for the first time release of single and dual (similar or different) substrates from single chromophore. Mechanistic studies of the photorelease process revealed that photorelease of two (similar or different) substrates from acetyl carbazole proceeds via a stepwise pathway. Further, we constructed photoresponsive dual drug delivery system (DDS) to release two different anticancer drugs (caffeic acid and chlorambucil, 1 equiv each). In vitro study reveals that our DDS exhibit excellent properties like biocompatibility, cellular uptake, and photoregulated dual drug release.

Three-Arm, Biotin-Tagged Carbazole-Dicyanovinyl-Chlorambucil Conjugate: Simultaneous Tumor Targeting, Sensing, and Photoresponsive Anticancer Drug Delivery.

The design, synthesis, and in vitro biological studies of a biotin-carbazole-dicyanovinyl-chlorambucil conjugate (Bio-CBZ-DCV-CBL; 6) are reported. This conjugate (6) is a multifunctional single-molecule appliance composed of a thiol-sensor DCV functionality, a CBZ-derived phototrigger as well as fluorescent reporter, and CBL as the anticancer drug, and Bio as the cancer-targeting ligand. In conjugate 6, the DCV bond undergoes a thiol-ene click reaction at pH<7 with intracellular thiols, thereby shutting down internal charge transfer between the donor CBZ and acceptor DCV units, resulting in a change of the fluorescence color from green to blue, and thereby, sensing the tumor microenvironment. Subsequent photoirradiation results in release of the anticancer drug CBL in a controlled manner.

Size-Dependent Catalytic Activity of Palladium Nanoparticles Fabricated in Porous Organic Polymers for Alkene Hydrogenation at Room Temperature.

Ultrafine palladium nanoparticles (Pd NPs) with 8 and 3 nm sizes were effectively fabricated in triazine functionalized porous organic polymer (POP) TRIA that was developed by nonaqueous polymerization of 2,4,6-triallyoxy-1,3,5-triazine. The Pd NPs encapsulated POP (Pd-POP) was fully characterized using several techniques. Further studies revealed an excellent capability of Pd-POP for catalytic transfer hydrogenation of alkenes at room temperature with superior catalytic performance and high selectivity of desired products. Highly flammable H2 gas balloon at high pressure and temperature used in conventional hydrogenation reactions was not needed in the present synthetic system. Catalytic activity is strongly dependent on the size of encapsulated Pd NPs in the POP. The Pd-POP catalyst with Pd NPs of 8 nm in diameter exhibited higher catalytic activity for alkene hydrogenation as compared with the Pd-POP catalyst encapsulating 3 nm Pd NPs. Computational studies were undertaken to gain insights into different catalytic activities of these two Pd-POP catalysts. High reusability and stability as well as no Pd leaching of these Pd-POP catalysts make them highly applicable for hydrogenation reactions at room temperature.

Refined Sulfur Nanoparticles Immobilized in Metal-Organic Polyhedron as Stable Cathodes for Li-S Battery.

The lithium-sulfur (Li-S) battery presents a promising rechargeable energy storage technology for the increasing energy demand in a worldwide range. However, current main challenges in Li-S battery are structural degradation and instability of the solid-electrolyte interphase caused by the dissolution of polysulfides during cycling, resulting in the corrosion and loss of active materials. Herein, we developed novel hybrids by employing metal-organic polyhedron (MOP) encapsulated PVP-functionalized sulfur nanoparticles (S@MOP), where the active sulfur component was efficiently encapsulated within the core of MOP and PVP as a surfactant was helpful to stabilize the sulfur nanoparticles and control the size and shape of corresponding hybrids during their syntheses. The amount of sulfur embedded into MOP could be controlled according to requirements. By using the S@MOP hybrids as cathodes, an obvious enhancement in the performance of Li-S battery was achieved, including high specific capacity with good cycling stability. The MOP encapsulation could enhance the utilization efficiency of sulfur. Importantly, the structure of the S@MOP hybrids was very stable, and they could last for almost 1000 cycles as cathodes in Li-S battery. Such high performance has rarely been obtained using metal-organic framework systems. The present approach opens up a promising route for further applications of MOP as host materials in electrochemical and energy storage fields.

Remarkable Vapochromic Behavior of Pure Organic Octahedron Embedded in Porous Frameworks.

Vapochromic behavior is employed to selectively monitor the vapor changes in surrounding environment, particularly for toxic gas leaking and floating detection. Thus, sensitive trapping and accurate response to different toxic vapors are critical factors in vapochromic sensing. In this work, a self-assembled hybrid that consists of fluorescent organic octahedron encapsulated by metal-organic polyhedron (MOP) is reported. The fluorescent octahedron is used as a responsive sensor to probe various solvent vapors, while the MOP is employed as a protector to prevent the corrosion of solvents to the organic octahedron. The hybrid exhibits remarkable vapochromic behavior to different solvents, and shows the highest selectivity and sensitivity specifically to acetone. In addition, acetone vapor under different conditions is utilized for further studying the response mechanism of the hybrid. This work presents a promising vapochromic sensor with good stability, selectivity, and sensitivity. The study is expected to open up the applicability of MOP-based hybrids for specific molecular capture, interim storage, controlled release, and advanced sensing.

Perylenetetracarboxylic-metal assemblies and anisotropic charge transport in a Cu(II) assembly.

Structural diversity and uniformity of nanomaterials are usually prerequisites for many practical applications involving the oriented fabrication of various devices with full control over their desired physiochemical properties. Particularly in the optoelectronic field, ordered assembly inside cells is required not only for obtaining attractive configurations but also for playing an important role in the characteristics of photoconduction and conductivity. Here, we present a synergetic self-assembly driven by coordination and intermolecular interactions for the construction of organic-inorganic hybrids with multi-morphologies and tunable physical properties. 3,4,9,10-Perylenetetracarboxylic dianhydride was treated with base to produce various assemblies by coordination with metal ions, showing morphologies of nanowires, nanosheets, nanoribbons and nanorods. The organic π-spacer affords an extension in different directions through the suitable incorporation of metal ions with different coordination modes for the formation of metal-ligand complexes. Interestingly, the obtained nanorods were twisted rods with obvious screw threads on the rod wall, supporting the synergetic self-assembly. Then, anisotropic mobility measurements of the obtained Cu(2+)-ligand assembly were carried out to show the importance of the size- and shape-confined synthesis of the hybrids. By presenting a series of ordered metal-ligand complex superstructures driven by synergetic self-assembly, this work is expected to pave the way for future anisotropic measurements of complex assemblies.

Nanoscale covalent organic frameworks as smart carriers for drug delivery.

Two porous covalent organic frameworks (COFs) with good biocompatibility were employed as drug nanocarriers, where three different drugs were loaded for subsequent drug release in vitro. The present work demonstrates that COFs are applicable in drug delivery for therapeutic applications.

Morphology Tuning of Self-Assembled Perylene Monoimide from Nanoparticles to Colloidosomes with Enhanced Excimeric NIR Emission for Bioimaging.

Organic near-infrared (NIR) fluorescent probes have been recognized as an emerging class of materials exhibiting a great potential in advanced bioanalytical applications. However, synthesizing such organic probes that could simultaneously work in the NIR spectral range and have large Stokes shift, high stability in biological systems, and high photostability have been proven challenging. In this work, aggregation induced excimeric NIR emission in aqueous media was observed from a suitably substituted perylene monoimide (PeIm) dye. Controlled entrapment of the dye into pluronic F127 micellar system to preserve its monomeric green emission in aqueous media was also established. The aggregation process of the PeIm dye to form organic nanoparticles (NPs) was evaluated experimentally by the means of transmission electron microscope imaging as well as theoretically by the molecular dynamics simulation studies. Tuning the morphology along with the formation of colloidosomes by the controlled self-aggregation of PeIm NPs in aqueous suspension was demonstrated successfully. Finally, both excimeric and monomeric emissive PeIm NPs as well as PeIm colloidosomes were employed for the bioimaging in vitro.