Assessment of interactions of efavirenz solid drug nanoparticles with human immunological and haematological systems.

Background: Recent work has developed solid drug nanoparticles (SDNs) of efavirenz that have been demonstrated, preclinically, improved oral bioavailability and the potential to enable up to a 50% dose reduction, and is currently being studied in a healthy volunteer clinical trial. Other SDN formulations are being studied for parenteral administration, either as intramuscular long-acting formulations, or for direct administration intravenously. The interaction of nanoparticles with the immunological and haematological systems can be a major barrier to successful translation but has been understudied for SDN formulations.

Lack of interaction of lopinavir solid drug nanoparticles with cells of the immune system.

Aim: We previously demonstrated that solid drug nanoparticles (SDNs) lopinavir (LPV) dispersed into aqueous media display favorable pharmacokinetics.

Methods: The impact of LPV SDNs on the function and phenotype of primary human T cells and macrophages (primary sites of HIV replication) was investigated.

Results: LPV significantly increased IL-1β (ninefold higher than untreated cells; p = 0.

Dual-stimuli responsive injectable microgel/solid drug nanoparticle nanocomposites for release of poorly soluble drugs.

An in situ forming implant (ISFI) for drug delivery combines the potential to improve therapeutic adherence for patients with simple administration by injection. Herein, we describe the preparation of an injectable nanocomposite ISFI composed of thermoresponsive poly(N-isopropylacrylamide) based microgels and solid drug nanoparticles. Monodisperse poly(N-isopropylacrylamide) or poly(N-isopropylacrylamide-co-allylamine) microgels were prepared by precipitation polymerisation with mean diameters of approximately 550 nm at 25 °C.

Towards a rational design of solid drug nanoparticles with optimised pharmacological properties.

Solid drug nanoparticles (SDNs) are a nanotechnology with favourable characteristics to enhance drug delivery and improve the treatment of several diseases, showing benefit for improved oral bioavailability and injectable long-acting medicines. The physicochemical properties and composition of nanoformulations can influence the absorption, distribution, and elimination of nanoparticles; consequently, the development of nanoparticles for drug delivery should consider the potential role of nanoparticle characteristics in the definition of pharmacokinetics. The aim of this study was to investigate the pharmacological behaviour of efavirenz SDNs and the identification of optimal nanoparticle properties and composition.

Accelerated oral nanomedicine discovery from miniaturized screening to clinical production exemplified by paediatric HIV nanotherapies.

Considerable scope exists to vary the physical and chemical properties of nanoparticles, with subsequent impact on biological interactions; however, no accelerated process to access large nanoparticle material space is currently available, hampering the development of new nanomedicines. In particular, no clinically available nanotherapies exist for HIV populations and conventional paediatric HIV medicines are poorly available; one current paediatric formulation utilizes high ethanol concentrations to solubilize lopinavir, a poorly soluble antiretroviral. Here we apply accelerated nanomedicine discovery to generate a potential aqueous paediatric HIV nanotherapy, with clinical translation and regulatory approval for human evaluation.

Stable, polymer-directed and SPION-nucleated magnetic amphiphilic block copolymer nanoprecipitates with readily reversible assembly in magnetic fields.

The formation of inorganic-organic magnetic nanocomposites using reactive chemistry often leads to a loss of super-paramagnetisim when conducted in the presence of iron oxide nanoparticles. We present here a low energy and chemically-mild process of co-nanoprecipitation using SPIONs and homopolymers or amphiphilic block copolymers, of varying architecture and hydrophilic/hydrophobic balance, which efficiently generates near monodisperse SPION-containing polymer nanoparticles with complete retention of magnetism, and highly reversible aggregation and redispersion behaviour. When linear and branched block copolymers with inherent water-solubility are used, a SPION-directed nanoprecipitation mechanism appears to dominate the nanoparticle formation presenting new opportunities for tailoring and scaling highly functional systems for a range of applications.

Augmented Inhibition of CYP3A4 in Human Primary Hepatocytes by Ritonavir Solid Drug Nanoparticles.

Ritonavir is a protease inhibitor utilized primarily as a pharmaco-enhancer with concomitantly administered antiviral drugs including other protease inhibitors. However, poor tolerance, serious side effects, and toxicities associated with drug-drug interactions are common during exposure to ritonavir. The aim of this work was to investigate the impact of nanoformulation on ritonavir pharmacological properties.

Flow cytometric analysis of the physical and protein-binding characteristics of solid drug nanoparticle suspensions.

Aim: Oral and intramuscular sustained-release antiretroviral solid drug nanoparticles (SDNs) are in development but there is limited understanding of whether nanoparticles or dissolved drug predominate systemically.

Materials & Methods: A flow cytometric method was developed to analyze SDNs in biological fluids such as plasma, including the putative formation of a protein corona.

Results: SDNs were found to be stable in plasma and could be observed using the techniques developed here.

pH-responsive lanthanide complexes based on reversible ligation of a diphenylphosphinamide.

Ln-dpp-DO3A-based complexes [dpp is a pendant diphenylphosphinamide moiety and DO3A is 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane] exhibit pH-responsive reversible ligation of the phosphinamide for both the gadolinium(III) and europium(III) analogues. pKa values were 8.1 (±0.

High-throughput nanoprecipitation of the organic antimicrobial triclosan and enhancement of activity against Escherichia coli.

Enhancing the activity of existing antimicrobial agents may help to address the emergence of resistant bacteria. Nanoparticles of antimicrobial agents have previously been shown to provide potential activity enhancements and here we report a high-throughput nanoprecipitation approach to identify viable nanosuspensions of the antimicrobial compound triclosan. Through careful choice of the components of the nanoprecipitation, amorphous nanosuspensions were created, freeze-dried and redispersed in water with z-average diameters varying from 170-290 nm.

Antiretroviral solid drug nanoparticles with enhanced oral bioavailability: production, characterization, and in vitro-in vivo correlation.

Nanomedicine strategies have produced many commercial products. However, no orally dosed HIV nanomedicines are available clinically to patients. Although nanosuspensions of drug particles have demonstrated many benefits, experimentally achieving >25 wt% of drug relative to stabilizers is highly challenging.

Mediation of in vitro cytochrome p450 activity by common pharmaceutical excipients.

Polymers and surfactants are commonly used as excipients in oral formulations and are generally considered to be inert. However, relatively few studies have assessed their interaction with enzymes involved in the absorption, distribution, metabolism, and elimination of drugs. We have investigated the impact of twenty-three commonly used excipients (ten polymers and thirteen surfactants) on seven cytochrome P450 (CYP450) isoforms using baculosome-derived CYP450 enzymes across a range of concentrations.

Nanomedicines for HIV therapy.

Heterogeneity in response to HIV treatments has been attributed to several causes including variability in pharmacokinetic exposure. Nanomedicine applications have a variety of advantages compared with traditional formulations, such as the potential to increase bioavailability and specifically target the site of action. Our group is focusing on the development of nanoformulations using a closed-loop design process in which nanoparticle optimization (disposition, activity and safety) is a continuous process based on experimental pharmacological data from in vitro and in vivo models.

Cell-permeable Ln(III) chelate-functionalized InP quantum dots as multimodal imaging agents.

Quantum dots (QDs) are ideal scaffolds for the development of multimodal imaging agents, but their application in clinical diagnostics is limited by the toxicity of classical CdSe QDs. A new bimodal MRI/optical nanosized contrast agent with high gadolinium payload has been prepared through direct covalent attachment of up to 80 Gd(III) chelates on fluorescent nontoxic InP/ZnS QDs. It shows a high relaxivity of 900 mM(-1) s(-1) (13 mM(-1 )s(-1) per Gd ion) at 35 MHz (0.

Luminescence study of Eu(III) analogues of esterase-activated magnetic resonance contrast agents.

A model for an accumulation and enzyme-activation strategy of a magnetic resonance contrast agent was investigated via the luminescence of Eu(III) analogues. Neutral q = 2 Eu(III) ethyl and acetoxymethyl ester LnaDO3A-based complexes showed increased emission intensity in the presence of serum concentrations of carbonate because of inner-sphere water molecule displacement by the anion. The affinity for carbonate is suppressed by the introduction of negative charge to the complex following enzymatic hydrolysis of the ester groups, resulting in quenching of Eu(III) luminescence and changes in spectral form.

An esterase-activated magnetic resonance contrast agent.

A Gd(III) complex bearing pendant acetoxymethyl esters is activated on exposure to porcine liver esterase; the 84% increase in relaxivity is a result of suppression of HCO(3)(-)/CO(3)(2-) binding by the resulting negative charge.