p-Phosphonic acid calix[8]arene mediated synthesis of ultra-large, ultra-thin, single-crystal gold nanoplatelets.

Single-crystal Au nanoplatelets, as large as 28 µm in cross section and as thin as 6 nm, are generated by bubbling hydrogen gas into an aqueous solution of HAuCl4 in the presence of p-phosphonic acid calix[8]arene, which acts as both a catalyst and stabiliser. The use of the ultrathin Au nanoplatelets in oxygen gas sensing has also been established.

Multifunctional nanoparticles for co-delivery of paclitaxel and carboplatin against ovarian cancer by inactivating the JMJD3-HER2 axis.

Ovarian cancer (OC) is the most lethal gynecologic cancer. Survival statistics have show no significant developments over the last three decades, highlighting the fact that current therapeutic strategies require substantial improvements. In this study, we designed a novel folic acid-PEG-conjugated p-phosphonated calix[4]arene nanoparticle (Fp-PCN) for the simultaneous delivery of paclitaxel (PAC) and carboplatin (CAR) at an optimal ratio (5 : 1, mol : mol) to utilize their potential synergistic effect against OC cells. The Fp-PCNs loaded with PAC and CAR (Fp-PCNPAC+CAR) resulted in a remarkable efficacy in the suppression of OC, both in vitro and in vivo. Compared to free drugs, Fp-PCNPAC+CAR showed stronger apoptosis induction as well as invasion and self-renewal capacity suppression in SKOV-3 cells. The molecular mechanism to address the synergism is that Fp-PCNPAC+CAR downregulated JMJD3 expression to modulate the H3K27me3 epigenetic mark of the promoters of HER2 and MYCN. Furthermore, the expressions of JMJD3 and HER2 were significantly associated with poor outcomes for ovarian patients. Our study demonstrates that co-delivery of PAC and CAR can be achieved with the Fp-PCNs, and reveals a previously unrecognized and unexpected role of the JMJD3-HER2 signaling axis in PAC and CAR treatment of OC.

p-Phosphonated Calix[n]arene Stabilizes Superparamagnetic Nanoparticles for Nitrate and Phosphate Uptake.

Highly faceted superparamagnetic magnetite nanoparticles roughly 11 nm in diameter are readily accessible in the presence of p-phosphonated calix[n]arenes of different ring sizes (n=4, 5 and 6), through the use of a simple co-precipitation technique. In contrast, the larger calix[8]arene affords spherical particles of comparable size. The maximum magnetization is 70-60 emu g-1 , which decreases with increasing size of the calixarene macrocycle, and the evidence indicates that the calixarenes bind to the surface of the nanoparticles via the phosphonate head groups rather than the phenolic oxygen centers. The stabilized nanoparticles show dual functionality: they remove up to 62 % of nitrate nitrogen and 48 % of phosphate from an aqueous effluent after 24 hours at concentrations of only 1 g L-1 of calixarene-coated nanoparticles.

Paclitaxel-loaded phosphonated calixarene nanovesicles as a modular drug delivery platform.

A modular p-phosphonated calix[4]arene vesicle (PCV) loaded with paclitaxel (PTX) and conjugated with folic acid as a cancer targeting ligand has been prepared using a thin film-sonication method. It has a pH-responsive capacity to trigger the release of the encapsulated PTX payload under mildly acidic conditions. PTX-loaded PCV conjugated with alkyne-modified PEG-folic acid ligands prepared via click ligation (fP-PCVPTX) has enhanced potency against folate receptor (FR)-positive SKOV-3 ovarian tumour cells over FR-negative A549 lung tumour cells. Moreover, fP-PCVPTX is also four times more potent than the non-targeting PCVPTX platform towards SKOV-3 cells. Overall, as a delivery platform the PCVs have the potential to enhance efficacy of anticancer drugs by targeting a chemotherapeutic payload specifically to tumours and triggering the release of the encapsulated drug in the vicinity of cancer cells.

Shear induced carboplatin binding within the cavity of a phospholipid mimic for increased anticancer efficacy.

Vesicles 107 ± 19 nm in diameter, based on the self-assembly of tetra-para-phosphonomethyl calix[4]- arene bearing n-hexyl moieties attached to the phenolic oxygen centres, are effective in binding carboplatin within the cavity of the macrocycle under shear induced within a dynamic thin film in a continuous flow vortex fluidic device. Post shearing the vesicles maintain similar diameters and retain carboplatin within the cavity of the calixarene in a hierarchical structure, with their size and morphology investigated using DLS, TEM, SEM and AFM. Location of the carboplatin was confirmed using NMR, FTIR, ESI-MS and EFTEM, with molecular modelling favouring the polar groups of carboplatin hydrogen bonded to phosphonic acid moieties and the four member cyclobutane ring directed into the cavity of the calixarene. The loading efficiency and release profile of carboplatin was investigated using LC-TOF/MS, with the high loading of the drug achieved under shear and preferential released at pH 5.5, offering scope for anti-cancer drug delivery. The hierarchical structured vesicles increase the efficacy of carboplatin by 4.5 fold on ovarian cancer cells, lowered the IC50 concentration by 10 fold, and markedly increased the percent of cells in the S-phase (DNA replication) of the cell cycle.

Decoloration rates of a photomerocyanine dye as a visual probe into hydrogen bonding interactions.

We have developed a visual marker for the investigation of hydrogen bonding (HB) effects. The decoloration rate of a photochromic dye that incorporates a latent intra-molecular HB feature can be linked to the HB character of the media. Kinetic and thermodynamic parameters of this simple decoloration approach for HB sensing are investigated both experimentally and by high level theoretical studies. This principle has been applied for the detection of changes in the HB character of stationary and fluidic systems. A major finding is the observation of a shear-related perturbation of the balance between intra- and inter-molecular HB within a dynamic thin film.

p-Phosphonic acid calix[8]arene assisted dispersion and stabilisation of pea-pod C60@multi-walled carbon nanotubes in water.

A facile approach has been developed for non-covalently stabilising pristine C60 and multi-walled carbon nanotubes (MWCNTs) in water in the presence of p-phosphonic acid calix[8]arene, along with the formation of a 'pea-pod' encapsulation of the fullerene inside the MWCNTs. Aqueous dispersions of the different carbon nano-materials are readily decorated with palladium nanoparticles.

Template-free assembly of three-dimensional networks of graphene hollow spheres at the water/toluene interface.

HYPOTHESIS: The Pickering emulsion system, generated by amphiphilic graphene oxide (GO) sheets trapped between water/toluene liquid interfaces, can be directly used for template-free formation of three-dimensional (3D) structure of GO hollow spheres. EXPERIMENTS: The method involves the formation of highly stable micron-sized Pickering emulsions via mild sonication of GO aqueous solution and toluene in the presence of polyvinyl alcohol (PVA), followed by direct freeze-drying of the mixture for preserving the unique 3D hollow spherical structures. FINDINGS: The 3D structure of interconnected GO hollow spheres, with a diameter in the range ∼2 to 10 µm, has been prepared. Transmission and scanning electron microscopy analyses confirmed the formation of the 3D structure directly from the Pickering emulsion system. The presence of PVA is critical in supporting the GO hollow spherical structures. Raman analysis confirmed the structural integrity of the GO in the 3D products.

Development and validation of a LC/TOF MS method for the determination of carboplatin and paclitaxel in nanovesicles.

Carboplatin and paclitaxel co-loaded nanovesicles (CPT-PTX-CLV), a novel intravenous formulation void of cremophor EL, may have significant advantages over conventional carboplatin and paclitaxel formulations with respect to tumor targeting, sustained drug release, reduced toxicity, and synergistic efficacy profiles. The aim of this study was to develop and validate a rapid, specific, sensitive, and reliable liquid chromatography-time of flight-mass spectrometry (LC/TOF MS)-based bioanalytical method for the simultaneous quantification of CPT and PTX in a fetal bovine serum (FBS) vehicle containing the dispersed nanovesicles. The analytes were extracted from FBS by simple protein precipitation, with subsequent separation of CPT and PTX on a Waters HPLC SunFire C18 column at a flow rate of 0.25 ml/min using gradient elution mode. The total analytical time was only 12 min. Detection and quantitation was performed by electrospray ionization (ESI) in the positive ionization mode with selective ion monitoring (SIM) at m/z 310.0152 for CPT and 876.3224 for PTX. The calibration curves were linear over the concentration range of 10-4,000 ng/ml for CPT and 5-2,000 ng/ml for PTX (r (2) > 0.99), with the respective lower limit of quantification (LLOQ) at 10 and 5 ng/ml. The intra- and inter-day precision and accuracy of analysis of the quality control samples at low, medium, and high concentration levels were ≤13.6 % relative standard deviation (RSD) and ≤14.6 % relative errors (RE). The rapid, sensitive, and reproducible LC/TOF MS method may be used to support preclinical and clinical pharmacological studies of the CPT-PTX-CLV administered by injection in animal and human cancer models.

Antioxidant phospholipid calix[4]arene mimics as micellular delivery systems.

Amphiphilic calix[4]arenes were designed as phospholipid mimics by incorporating PO3H2 or NMe3(+) head groups. Using PC12 cells and three stressors (H2O2, menadione and glutamate), we established safe calix[4]arene levels that are able not only to deliver antioxidant payloads of curcumin, but intriguingly also have inherent antioxidant properties. The calix[4]arenes appear to be potent synthetic antioxidants that could be used as nano-carriers for drug delivery.

Nitrate uptake by p-phosphonic acid calix[8]arene stabilized graphene.

In situ sonic probe exfoliated graphene sheets in the presence of various concentrations of p-phosphonic acid calix[8]arene are effective in removing nitrate from aquatic effluents, with the efficiency increasing for higher ratios of calixarene to graphite. Mild sonication of the nitrate-adsorbed material releases some nitrate ions back to the effluent.

Shear flow assisted decoration of carbon nano-onions with platinum nanoparticles.

Aqueous based controlled decoration of platinum nanoparticles on plasma treated carbon nano-onions (CNOs) occurs within the shear flow generated by a vortex fluidic device (VFD), using ascorbic acid as the reducing agent, with the electrocatalytic potential of the resulting Pt-NPs@CNOs nano-composites demonstrated.

p-Phosphonic acid calix[8]arene assisted exfoliation and stabilization of 2D materials in water.

Exfoliated 2D materials including graphene, BN, MoS(2) and WS(2) are accessible in water over a wide range of pH for a synergistic process involving sonication in the presence of p-phosphonic acid calix[8]arene.

Probing the effect of the solution environment around redox-active moieties using rigid anthraquinone terminated molecular rulers.

Herein, we report the influence of the position and the solution environment around surface-bound redox-active moieties on their redox reaction. The study was made possible by using rigid norbornylogous bridges, which possess anthraquinone (AQ) moieties. An L-shaped norbornylogous bridge (L-NB) and straight-shaped norbornylogous bridge (S-NB) were used to situate AQ moieties at well-defined position and environments above a mixed alkanethiol self-assembled monolayer (SAM) on Au (111) surfaces. Sum frequency generation (SFG) vibrational spectroscopy was employed to evaluate the interaction between the S-NB and L-NB with diluent molecules in the mixed SAMs. The SFG measurements demonstrated that hydrogen-bonding interactions were formed between AQ moieties of L-NB and diluent molecules terminated by hydroxyl group within a suitable separation. The SFG observations provided information about the relative position of the AQ moieties in each SAM, which significantly affects the thermodynamics and the kinetics of the electron transfer on the electrode/solution interface. The rate constant (k(et)) of the electron transfer between the AQ moiety and the gold surface and the apparent formal potential (E(0')) were studied using cyclic voltammetry (CV), alternating current voltammetry (ACV), and electrochemical impedance spectroscopy (EIS). It was found that the k(et) increases and E(0') shifts to more anodic values as the distance between the AQ moiety and the surface of the diluent was increased, for both methyl and hydroxyl terminated diluent. These results are discussed in relation to H-bonding interactions with water surrounding the AQ moieties.

Surface-bound molecular rulers for probing the electrical double layer.

Herein, we report the first experimental investigation on the effect of varying the position of redox-active moieties, within the electrical double layer, on the apparent formal potential and on the electron transfer rate constant. This was achieved using a rigid class of molecules, norbornylogous bridges, to place redox species (ferrocene) at a fixed position above the surface of the electrode. Cyclic voltammetry and alternating current voltammetry were used to calculate the apparent formal potential and the electron transfer rate constant for the electron transfer between the ferrocene and the gold electrode. We use the effect of electric field on the apparent formal potential measurement of the surface-bound redox species to calculate the potential drop from the initiation of the electrical double layer to different distances above it. It was found that self-assembled monolayers formed from ω-hydroxyalkanethiol have a potential profile very similar to that described by classical theories for bare metal electrodes. A steep drop in potential in the Stern layer was observed followed by a smaller potential drop in the Gouy-Chapman layer. The electron transfer rate constant was found to decrease as the distance between the ferrocene moiety and the initiation of the double layer is increased. Thus, the electron transfer rate constant appears to be dependent on ion concentration.

Electroactive self-assembled monolayers of unique geometric structures by using rigid norbornylogous bridges.

Herein, we describe the synthesis of straight (S) and L-shaped (L) norbornylogous bridges (NBs) with an anthraquinone moiety at the distal end as the redox-active head group and two thiol feet at the proximal end, by which the molecules assemble on gold surfaces. The NB molecules were shown to form self-assembled monolayers (SAMs) with a well-behaved surface redox process. The SAMs were characterized by using in situ IR spectroscopy, cyclic voltammetry, scanning tunnelling microscopy and electrochemical impedance spectroscopy. The surface selection rules associated with the IR band intensities allowed the estimation of the position of the anthraquinone moiety with respect to the surface and the tilt of the bridge with respect to the surface normal, both in pure and diluted monolayers. It is shown that the S- and L-NBs hold the plane of the anthraquinone moiety close to the surface normal or the surface tangent, respectively. Neither NB molecule changes its orientation if spaced by diluents on the surface. The difference in the structure of the S- and L-NB SAMs provides a suitable framework for the investigation of factors that govern electron transfer of anthraquinone moieties across self-assembled monolayers with limited structural ambiguity, as compared with the commonly used structurally flexible alkanethiol monolayers.

Self-assembled monolayers formed using zero net curvature norbornylogous bridges: the influence of potential on molecular orientation.

A new class of electroactive norbornylogous bridges, with no net curvature, that form self-assembled monolayers on gold electrodes were studied by electrochemistry and in situ infrared spectroscopy. The influence of the electrode potential on the structure and conformation of the self-assembled monolayers (SAMs) was investigated. This was performed using two different lengths of rigid norbornylogous bridges with terminal ferrocene moieties and ω-hydroxyalkanethiols. It was found that single component monolayers of the rigid norbornylogous bridges changed their tilt angle with their transition from the ferrocene to ferricinium. However, when the norbornylogous SAMs were diluted with ω-hydroxyalkanethiols the tilt angle remained unchanged upon oxidation of ferrocene to ferricinium. It was also observed that the tilt angle of the diluent, ω-hydroxyalkanethiols changed at potentials exceeding 500 mV.

Formation of efficient electron transfer pathways by adsorbing gold nanoparticles to self-assembled monolayer modified electrodes.

The influence of the length of a self-assembled monolayer (SAM) linker on the electrochemical performance of electrode-linker-gold nanoparticle molecular constructs is investigated. Electrodes were first modified with amino-1-alkanethiols of four different lengths (C=2, 6, 8, and 11). The SAM showed progressively greater blocking ability to ruthenium hexamine as the length of the alkyl chain increased to the point where no significant Faradaic peak was observed for the amino-1-undecanethiol SAM. Upon the attachment of gold nanoparticles, distinct Faradaic electrochemistry of the ruthenium hexamine was observed for all four length SAMs with the electrochemistry being similar to that observed on a bare electrode. The charge transfer resistance to this Faradaic process was observed to be insensitive to the length of the intervening SAM, indicating it is electron transfer between the redox species and the nanoparticles, rather than tunneling across the SAM, which is the rate-limiting step. Some comments on the mechanism of charge transfer are provided. When forming multilayers of the linker-nanoparticle constructs, fabricated in a stepwise manner, whenever the distal species was the SAM the Faradaic process was blocked and whenever it was the nanoparticle a distinct Faradaic process was observed. With up to five layers of linker-nanoparticles, there was little increase in charge transfer resistance and again the charge transfer resistance was insensitive to the length of the linker.

Structure and properties of redox active self-assembled monolayers formed from norbornylogous bridges.

Three different length rigid norbornylogous bridges with terminal ferrocene moieties were synthesized. Pure self-assembled monolayers (SAMs) of the norbornylogous bridges and SAMs with the bridges diluted using either hydroxyl-terminated or methyl-terminated diluents were formed for each length of norbornylogous bridge. The SAMs were imaged with scanning tunneling micrsocopy (STM) and the electrochemical properties were investigated. It was found that SAMs composed of only norbornylogous bridges were crystalline-like, while in mixed SAMs, where the norbornylogous bridge was diluted, the ferrocene stood above the surface of the diluent because of the rigidity of the norbornylogous bridges and were homogeneously distributed across the surface. Further, the rate of electron transfer of the norbornylogous bridges was observed to be similar to an alkanethiol-derived ferrocene whose construct was designed to be as close as possible to that of the norbornylogous bridge. Finally, the rate of electron transfer for the norbornylogous bridges in a diluted SAM was slower with a hydroxyl-terminated diluent than with a methyl-terminated diluent.

Silicon (100) electrodes resistant to oxidation in aqueous solutions: an unexpected benefit of surface acetylene moieties.

Here we report on the functionalization of alkyne-terminated alkyl monolayers on highly doped Si(100) using "click" reactions to immobilize ferrocene derivatives. The reaction of hydrogen-terminated silicon surfaces with a diyne species was shown to afford very robust functional surfaces where the oxidation of the underlying substrate was negligible. Detailed characterization using X-ray photoelectron spectroscopy, X-ray reflectometry, and cyclic voltammetry demonstrated that the surface acetylenes had reacted in moderate yield to give surfaces exposing ferrocene moieties. Upon extensive exposure of the redox-active architecture to oxidative environments during preparative and characterization steps, no evidence of SiOx contaminants was shown for derivatized SAMs prepared from single-component 1,8-nonadiyne, fully acetylenylated, monolayers. An analysis of the redox behavior of the prepared Si(100) electrodes based on relevant parameters such as peak splitting and position and shape of the reduction/oxidation waves depicted a well-behaved redox architecture whose spectroscopic and electrochemical properties were not significantly altered even after prolonged cycling in aqueous media between -100 and 800 mV versus Ag|AgCl. The reported strategy represents an experimentally simple approach for the preparation of silicon-based electrodes where, in addition to close-to-ideal redox behavior, remarkable electrode stability can be achieved. Both the presence of a distal alkyne moiety and temperatures of formation above 100 degrees C were required to achieve this surface stabilization.