A deep eutectic-based, self-emulsifying subcutaneous depot system for apomorphine therapy in Parkinson's disease.

Apomorphine, a dopamine agonist, is a highly effective therapeutic to prevent intermittent off episodes in advanced Parkinson's disease. However, its short systemic half-life necessitates three injections per day. Such a frequent dosing regimen imposes a significant compliance challenge, especially given the nature of the disease. Here, we report a deep eutectic-based formulation that slows the release of apomorphine after subcutaneous injection and extends its pharmacokinetics to convert the current three-injections-a-day therapy into an every-other-day therapy. The formulation comprises a homogeneous mixture of a deep eutectic solvent choline-geranate, a cosolvent n-methyl-pyrrolidone, a stabilizer polyethylene glycol, and water, which spontaneously emulsifies into a microemulsion upon injection in the subcutaneous space, thereby entrapping apomorphine and significantly slowing its release. Ex vivo studies with gels and rat skin demonstrate this self-emulsification process as the mechanism of action for sustained release. In vivo pharmacokinetics studies in rats and pigs further confirmed the extended release and improvement over the clinical comparator Apokyn. In vivo pharmacokinetics, supported by a pharmacokinetic simulation, demonstrate that the deep eutectic formulation reported here allows the maintenance of the therapeutic drug concentration in plasma in humans with a dosing regimen of approximately three injections per week compared to the current clinical practice of three injections per day.

Selective Near-Infrared Blood Detection Driven by Ionic Liquid-Dye-Albumin Nanointeractions.

Due to its abundance in blood, a great deal of research has been undertaken to develop efficient biosensors for serum albumin and provide insight into the interactions that take place between these biosensing molecules and the protein. Near-infrared (NIR, >700 nm) organic dyes have been shown to be effective biosensors of serum albumin, but their effectiveness is diminished in whole blood. Herein, it is shown that an NIR sulfonate indolizine-donor-based squaraine dye, SO3SQ, can be strengthened as a biosensor of albumin through the addition of biocompatible ionic liquids (ILs). Specifically, the IL choline glycolate (1:1), at a concentration of 160 mM, results in the enhanced fluorescence emission ("switch-on") of the dye in the presence of blood. The origin of the fluorescence enhancement was investigated via methods, including DLS, ITC, and molecular dynamics. Further, fluorescence measurements were conducted to see the impact the dye-IL system had on the fluorescence of the tryptophan residue of human serum albumin (HSA), as well as to determine its apparent association constants in relation to albumin. Circular dichroism (CD) spectroscopy was used to provide evidence that the dye-IL system does not alter the secondary structures of albumin or DNA. Our results suggest that the enhanced fluorescence of the dye in the presence of IL and blood is due to diversification of binding sites in albumin, controlled by the interaction of the IL-dye-albumin complex.

Oral ionic liquid for the treatment of diet-induced obesity.

More than 70% of American adults are overweight or obese, a precondition leading to chronic diseases, including diabetes and hypertension. Among other factors, diets with high fat and carbohydrate content have been implicated in obesity. In this study, we hypothesize that the choline and geranate (CAGE) ionic liquid can reduce body weight by decreasing fat absorption through the intestine. In vitro studies performed using docosahexaenoic acid (DHA), a model fat molecule, show that CAGE forms particles 2 to 4 µm in diameter in the presence of fat molecules. Ex vivo permeation studies in rat intestine showed that formation of such large particles reduces intestinal fat absorption. In vivo, CAGE reduces DHA absorption by 60% to 70% compared with controls. DHA administered with CAGE was retained in the intestine even after 6 h. Rats fed with a high-fat diet (HFD) and 10 µL of daily oral CAGE exhibited 12% less body weight gain compared with rats fed with an HFD without CAGE for 30 d. Rats that were given CAGE also ate less food than the control groups. Serum biochemistry and histology results indicated that CAGE was well tolerated by the rats. Collectively, our data support the hypothesis that CAGE interacts with fat molecules to prevent their absorption through intestinal tissue and potentially providing a feeling of satiety. We conclude that CAGE offers an effective means to control body weight and a promising tool to tackle the obesity epidemic.

Quantifying the Polymeric Capping of Nanoparticles with X-Ray Photoelectron Spectroscopy.

X-ray photoelectron spectroscopy was used to characterise silver nanoparticles capped with poly(ethylene) glycol (PEG) in a room-temperature ionic liquid (RTIL), 1-butyl-3-methylimidazolium tetrafluoroborate ([Bmim][BF4 ]). The amounts of oxygen and silver present in nanoparticles capped with different molecular weight thiolated PEG chains were monitored, and the number of thiolated PEG chains per nanoparticle was calculated, an in situ characterisation not previously possible.

Electrochemical Hg2+ detection at tannic acid-gold nanoparticle modified electrodes by square wave voltammetry.

We report the electrochemical sensing of Hg2+ based on tannic acid capped gold nanoparticle (AuNP@TA) complexes. At optimal conditions using square wave voltammetry, the presented analytical method exhibits a "measurable lower limit" of 100.0 fM. This limit is considerably below the permissible level of 30.0 nM for inorganic mercury in drinking water, specified by the World Health Organization (WHO). The effect of potentially interfering ions, such as Zn2+ and Al3+, was studied and results indicate an excellent selectivity for Hg2+. The transfer of the proposed strategy onto AuNP@TA modified screen-printed electrodes demonstrates its applicability to routine monitoring of Hg2+ in tap water.

The mechanism of electrochemical reduction of hydrogen peroxide on silver nanoparticles.

The reduction of hydrogen peroxide on a silver nanoparticle modified boron doped diamond electrode in a neutral solution is shown to proceed through a CE mechanism. Hydrogen peroxide undergoes a disproportionation reaction to form oxygen (and water) on the silver surface, creating a diffusion layer of oxygen, which, at a sufficiently biased electrode, is then reduced to hydrogen peroxide. Voltammetry and a full mechanistic simulation are undertaken to confirm the mechanism, showing at short times a dependence of the reductive signal on waiting time prior to voltammetric analysis reflecting the extent of the disproportionation step which occurs prior to voltammetric analysis.

Understanding gold nanoparticle dissolution in cyanide-containing solution via impact-chemistry.

The electrochemical dissolution of citrate-capped gold nanoparticles (AuNPs) was studied in cyanide (CN-) containing solutions. It was found that the gold nanoparticles exhibited different dissolution behaviours as ensembles compared to the single particles. At the single particle level, a nearly complete oxidation of 60 nm AuNPs was achieved at concentrations greater than or equal to 35.0 mM CN- and at a potential of 1.0 V. Mechanistic insights and rate data are reported.

Electrochemical Detection of Ultratrace (Picomolar) Levels of Hg2+ Using a Silver Nanoparticle-Modified Glassy Carbon Electrode.

Ultratrace levels of Hg2+ have been quantified by undertaking linear sweep voltammetry with a silver nanoparticle-modified glassy carbon electrode (AgNP-GCE) in aqueous solutions containing Hg2+. This is achieved by monitoring the change in the silver stripping peak with Hg2+ concentration resulting from the galvanic displacement of silver by mercury: Ag(np) + 1/2Hg2+(aq) → Ag+(aq) + 1/2Hg(l). This facile and reproducible detection method exhibits an excellent linear dynamic range of 100.0 pM to 10.0 nM Hg2+ concentration with R2 = 0.982. The limit of detection (LoD) based on 3σ is 28 pM Hg2+, while the lowest detectable level for quantification purposes is 100.0 pM. This method is appropriate for routine environmental monitoring and drinking water quality assessment since the guideline value set by the US Environmental Protection Agency (EPA) for inorganic mercury in drinking water is 0.002 mg L-1 (10 nM).

Adsorption on graphene: flat to edge to end transitions of phenyl hydroquinone.

The adsorption of phenyl hydroquinone (PHQ) on graphene surfaces at the liquid-solid interface is investigated revealing a flat orientation and two different vertically adsorbed states of PHQ on graphene nanoplatelets (GNPs), namely edgewise or endwise adsorption. The transition between these states is driven by increasing concentrations of PHQ in solution leading to increased absolute coverages on the graphene surface. At low adsorbate concentrations (≤21 mM), the adsorption process is also shown to be Langmuirian with an adsorption constant of (9.5 ± 0.2) mM-1. Independent measurements are conducted using a single particle electrochemical technique to confirm the surface coverage of PHQ on GNPs at low concentrations, showing excellent agreement with the UV-Vis studies.

Electroanalytical study of dopamine oxidation on carbon electrodes: from the macro- to the micro-scale.

The oxidation of dopamine in strongly acidic (pH = 0) solution is investigated using microdisc, microcylinder and macro-electrodes together with a range of voltage scan rates. Kinetic and mechanistic analysis over the full range of mass transport conditions show a behaviour consistent with an ECE process with a fast chemical step and in which the second electron transfer is thermodynamically more favourable than the first step. Accordingly the reaction effectively behaves as an EE process.

DNA capping agent control of electron transfer from silver nanoparticles.

Silver nanoparticles capped with either DNA or citrate are investigated electrochemically using stripping voltammetry and nano-impacts. Whilst the citrate capped particles are readily oxidised to silver cations at 0.7 V, the DNA capped particles undergo electron transfer from the silver core to the electrode in two distinct potential ranges -0.8 to 1.1 V and 1.125 to 1.2 V, and only undergo complete oxidation at the higher potential range. These potentials reflect the oxidation of guanine and adenine respectively, with a potential sufficient to oxidise both base pairs being necessary to observe full silver oxidation. The DNA thus serves as a tunnelling barrier to electrically insulate the particle, and allows for selective oxidation to occur by controlling the potential applied.

Understanding nanoparticle porosity via nanoimpacts and XPS: electro-oxidation of platinum nanoparticle aggregates.

The porosity of platinum nanoparticle aggregates (PtNPs) is investigated electrochemically via particle-electrode impacts and by XPS. The mean charge per oxidative transient is measured from nanoimpacts; XPS shows the formation of PtO and PtO2 in relative amounts defined by the electrode potential and an average oxidation state is deduced as a function of potential. The number of platinum atoms oxidised per PtNP is calculated and compared with two models: solid and porous spheres, within which there are two cases: full and surface oxidation. This allows insight into extent to which the internal surface of the aggregate is 'seen' by the solution and is electrochemically active.

Fluorescence Electrochemical Microscopy: Capping Agent Effects with Ethidium Bromide/DNA Capped Silver Nanoparticles.

Fluorescence microscopy and electrochemistry were employed to examine capping agent dynamics in silver nanoparticles capped with DNA intercalated with ethidium bromide, a fluorescent molecule. The capped NPs were studied first electrochemically, demonstrating that the intercalation of the capping agent promotes oxidation of the silver core, occurring at 0.50 V (vs. Ag, compared with 1.15 V for Ag NPs capped in DNA alone). Second, fluorescence electrochemical microscopy revealed that the electron transfer from the nanoparticles is gated by the capping agent, allowing dynamic insights unobservable using electrochemistry alone.

Nanoparticle Capping Agent Controlled Electron-Transfer Dynamics in Ionic Liquids.

Herein, we report a change in the mechanism of the oxidation of silver nanoparticles (Ag NPs) with the molecular weight of a poly(ethylene) glycol (PEG) capping agent. Characterisation of the modified nanoparticles is undertaken using dynamic light scattering and UV/Vis spectroscopy. Electrochemical analyses reveal that the oxidation of 6000 molecular weight (MW) PEG is consistent with a polymer-gated mechanism, whilst for 2000 MW PEG the polymer does not hinder the oxidation. The 10,000 MW PEG Ag NPs are rendered almost electrochemically inactive. This study demonstrates the ability to alter and better understand the electron-transfer mechanism in a room temperature ionic liquid (RTIL) by systematically altering the capping agent.

Exploring nanoparticle porosity using nano-impacts: platinum nanoparticle aggregates.

The porosity of platinum nanoparticles (PtNPs) is explored for the first time using tag-redox coulometry (TRC). This is achieved by monitoring the reduction of the 4-nitrobenzenethiol (NTP)-tagged PtNPs on carbon electrodes via both immobilisation and nanoimpacts. The average charge per impact is measured and attributed to the reduction of NTP adsorbed on individual PtNPs. The number of NTP molecules and thus the "active surface area" of the PtNPs is calculated and compared with two models: fully solid and porous nanoparticles, and the extent of the particle porosity is revealed. This allows a fuller understanding of the (electro-)catalytic behaviour of nanoparticles by providing insight into their porosity and "true/active surface areas".

Ionic liquid-coated lipid nanoparticles increase siRNA uptake into CNS targets.

Lipidoid nanoparticles (LNPs) have transformed the field of drug delivery and are clinically used for the delivery of nucleic acids to liver and muscle targets. Post-intravenous administration, LNPs are naturally directed to the liver due to the adsorption of plasma proteins like apolipoprotein E. In the present work, we have re-engineered LNPs with ionic liquids (ILs) to reduce plasma protein adsorption and potentially increase the accumulation of LNPs in hard-to-deliver central nervous system (CNS) targets such as brain endothelial cells (BECs) and neurons. We have developed two approaches to re-engineer LNPs using a choline trans-2-hexenoate IL: first, we have optimized an IL-coating process using the standard LNP formulation and in the second approach, we have incorporated ILs into the LNPs by replacing the PEG-lipid component in the standard formulation using ILs. IL-coated as well as IL-incorporated LNPs were colloidally stable with morphologies similar to the standard LNPs. IL-coated LNPs showed superior uptake into mouse BECs and neurons and demonstrated reduced mouse plasma protein adsorption compared to the standard LNPs. Overall, our results (1) demonstrate the feasibility of re-engineering the clinically approved LNP platform with highly tunable biomaterials like ILs for the delivery of therapeutics to CNS targets like BECs and neurons and (2) suggest that the surface properties of LNPs play a critical role in altering their affinity to and uptake into hard-to-deliver cell types.

Imidazolium-based zwitterionic liquid-modified PEG-PLGA nanoparticles as a potential intravenous drug delivery carrier.

Zwitterionic-based systems offer promise as next-generation drug delivery biomaterials capable of enhancing nanoparticle (NP) stimuli-responsiveness, biorecognition, and biocompatibility. Further, imidazole-functionalized amphiphilic zwitterions are able to readily bind to various biological macromolecules, enabling antifouling properties for enhanced drug delivery efficacy and bio-targeting. Herein, we describe structurally tuned zwitterionic imidazole-based ionic liquid (ZIL)-coated PEG-PLGA nanoparticles made with sonicated nanoprecipitation. Upon ZIL surface modification, the hydrodynamic radius increased by nearly 20 nm, and the surface charge significantly shifted closer to neutral. 1H NMR spectra suggests that the amount of ZIL on the nanoparticle surface is controlled by the structure of the ZIL and that the assembly occurs as a result of non-covalent interactions of ZIL-coated nanoparticle with the polymer surface. These nanoparticle-zwitterionic liquid (ZIL) constructs demonstrate selective affinity towards red blood cells in whole mouse blood and show relatively low human hemolysis at ∼5%. Additionally, we observe higher nanoparticle accumulation of ZIL-NPs compared with unmodified NP controls in human triple-negative breast cancer cells (MDA-MB-231). Furthermore, although the ZIL shows similar protein adsorption by SDS-PAGE, LC-MS/MS protein analysis data demonstrate a difference in the relative abundance and depletion of proteins in mouse and human serum. Hence, we show that ZIL-coated nanoparticles provide a new potential platform to enhance RBC-based drug delivery systems for cancer treatments.

Cytotoxicity and cell membrane interactions of choline-based ionic liquids: Comparing amino acids, acetate, and geranate anions.

Ionic liquids (ILs) have found diverse applications in research and industry. Biocompatible ILs, a subset considered less toxic than traditional ILs, have expanded their applications into biomedical fields. However, there is limited understanding of the toxicity profiles, safe concentrations, and underlying factors driving their toxicity. In this study, we investigated the cytotoxicity of 13 choline-based ILs using four different cell lines: Human dermal fibroblasts (HDF), epidermoid carcinoma cells (A431), cervical cancer cells (HeLa), and gastric cancer cells (AGS). Additionally, we explored the haemolytic activity of these ILs. Our findings showed that the cytotoxic and haemolytic activities of ILs can be attributed to the hydrophobicity of the anions and the pH of the IL solutions. Furthermore, utilising quartz crystal microbalance with dissipation (QCM-D), we delved into the interaction of selected ILs, including choline acetate [Cho][Ac] and choline geranate [Cho][Ge], with model cell membranes composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). The QCM-D data showed that ILs with higher toxicities exhibited more pronounced interactions with membranes. Increased variations in frequency and dissipation reflected substantial changes in membrane fluidity and mass following the addition of the more toxic ILs. Furthermore, total internal reflection fluorescence microscopy study revealed that [Cho][Ac] could cause lipid rearrangements and pore formation in the membrane, while [Cho][Ge] disrupted the bilayer packing. This study advances our understanding of the cellular toxicities associated with choline-based ILs and provides valuable insights into their mechanisms of action concerning IL-membrane interactions. These findings have significant implications for the safe and informed utilisation of biocompatible ILs in the realm of drug delivery and biotechnology.

Ionic Liquid Coating-Driven Nanoparticle Delivery to the Brain: Applications for NeuroHIV.

Delivering cargo to the central nervous system (CNS) remains a pharmacological challenge. For infectious diseases such as HIV, the CNS acts as a latent reservoir that is inadequately managed by systemic antiretrovirals (ARTs). ARTs thus cannot eradicate HIV, and given CNS infection, patients experience neurological deficits collectively referred to as "neuroHIV". Herein, the development of bioinspired ionic liquid-coated nanoparticles (IL-NPs) for in situ hitchhiking on red blood cells (RBCs) is reported, which enables 48% brain delivery of intracarotid arterial- infused cargo. Moreover, IL choline trans-2-hexenoate (CA2HA 1:2) demonstrates preferential accumulation in parenchymal microglia over endothelial cells post-delivery. This study further demonstrates successful loading of abacavir (ABC), an ART that is challenging to encapsulate, into IL-NPs, and verifies retention of antiviral efficacy in vitro. IL-NPs are not cytotoxic to primary human peripheral blood mononuclear cells (PBMCs) and the CA2HA 1:2 coating itself confers notable anti-viremic capacity. In addition, in vitro cell culture assays show markedly increased uptake of IL-NPs into neural cells compared to bare PLGA nanoparticles. This work debuts bioinspired ionic liquids as promising nanoparticle coatings to assist CNS biodistribution and has the potential to revolutionize the delivery of cargos (i.e., drugs, viral vectors) through compartmental barriers such as the blood-brain-barrier (BBB).