Robert K. Prud’homme

Formation of Stable Nanocarriers by in Situ Ion Pairing during Block-Copolymer-Directed Rapid Precipitation

We present an in situ hydrophobic salt forming technique for the encapsulation of weakly hydrophobic, ionizable active pharmaceutical ingredients (API) into stable nanocarriers (NCs) formed via a rapid precipitation process. Traditionally, NC formation via rapid precipitation has been difficult with APIs in this class because their intermediate solubility makes achieving high supersaturation difficult during the precipitation process and the intermediate solubility causes rapid Ostwald ripening or recrystallization after precipitation. By forming a hydrophobic salt in situ, the API solubility and crystallinity can be tuned to allow for NC formation. Unlike covalent API modification, the hydrophobic salt formation modifies properties via ionic interactions, thus circumventing the need for full FDA reapproval. This technique greatly expands the types of APIs that can be successfully encapsulated in NC form. Three model APIs were investigated and successfully incorporated into NCs by forming salts with hydrophobic counterions: cinnarizine, an antihistamine, clozapine, an antipsychotic, and α-lipoic acid, a common food supplement. We focus on cinnarizine to develop the rules for the in situ nanoprecipitation of salt NCs. These rules include the pK(a)s and solubilities of the API and counterion, the effect of the salt former-to-API ratio on particle stability and encapsulation efficiency, and the control of NC size. Finally, we present results on the release rates of these ion pair APIs from the NCs.

Protected Peptide Nanoparticles: Experiments and Brownian Dynamics Simulations of the Energetics of Assembly

Soluble peptides, susceptible to degradation and clearance in therapeutic applications, have been formulated into protected nanoparticles for the first time through the process of kinetically controlled, block copolymer directed rapid precipitation using Flash NanoPrecipitation. Complementary Brownian dynamics simulations qualitatively model the nanoparticle formation process. The simulations corroborate the hypothesis that the size of nanoparticles decreases with increasing supersaturation. Additionally, the influence of the polymer-peptide interaction energy on the efficiency of nanoparticle protection by polymer surface coverage is elucidated in both experiments and simulations.

Enhanced dissolution of inhalable cyclosporine nano-matrix particles with mannitol as matrix former.

This study aims to improve the dissolution of inhalable cyclosporine A nanoparticles by formulating the drug with mannitol as a hydrophilic nano-matrix former. The effect of mannitol content on the aerosol performance of the nano-matrix particles was also examined. Cyclosporine A nanosuspensions were produced by anti-solvent precipitation using a multi-inlet vortex mixer. Various amounts of mannitol were dissolved into the suspensions before spray drying to obtain micron-sized aggregates (nano-matrix powders). Dissolution properties of the powders in an aqueous medium, with the drug content, aggregate size distribution, surface roughness, physicochemical properties and aerosol performance were determined. The powders contained amorphous cyclosporine A and α-crystalline mannitol, with drug content being very close to the theoretical doses. Inclusion of mannitol enhanced the dissolution rate of the drug, without significantly affecting the aggregate size distribution, surface roughness and aerosol performance. This formulation approach may be applicable to improving the dissolution rate and bioavailability of hydrophobic drugs.

Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo

Significance Lipid-rich plaques in major blood vessels recruit macrophages that further exacerbate the lipid burden and risk of heart attacks or stroke. A local approach to prevent plaque growth has yet to be successfully deployed. In this study, we examine how synthetic ligands counteract macrophage atherogenesis and de-escalate plaque burden. Using a library of sugar-based amphiphilic core-shell layered nanoparticles, we demonstrate the design principles necessary to prevent oxidized lipid uptake and suppress scavenger receptor expression in macrophages, switching them to an “atheroprotective” phenotype. When administered in vivo, nanoparticles were retained at atherosclerotic lesions, where they mitigated cholesterol clefts, inflammation, and artery occlusion. Thus, synthetic nanomedicines could be used to potentially treat acute coronary syndrome, a major unmet need in cardiovascular diseases. Atherosclerosis, the build-up of occlusive, lipid-rich plaques in arterial walls, is a focal trigger of chronic coronary, intracranial, and peripheral arterial diseases, which together account for the leading causes of death worldwide. Although the directed treatment of atherosclerotic plaques remains elusive, macrophages are a natural target for new interventions because they are recruited to lipid-rich lesions, actively internalize modified lipids, and convert to foam cells with diseased phenotypes. In this work, we present a nanomedicine platform to counteract plaque development based on two building blocks: first, at the single macrophage level, sugar-based amphiphilic macromolecules (AMs) were designed to competitively block oxidized lipid uptake via scavenger receptors on macrophages; second, for sustained lesion-level intervention, AMs were fabricated into serum-stable core/shell nanoparticles (NPs) to rapidly associate with plaques and inhibit disease progression in vivo. An AM library was designed and fabricated into NP compositions that showed high binding and down-regulation of both MSR1 and CD36 scavenger receptors, yielding minimal accumulation of oxidized lipids. When intravenously administered to a mouse model of cardiovascular disease, these AM NPs showed a pronounced increase in lesion association compared with the control nanoparticles, causing a significant reduction in neointimal hyperplasia, lipid burden, cholesterol clefts, and overall plaque occlusion. Thus, synthetic macromolecules configured as NPs are not only effectively mobilized to lipid-rich lesions but can also be deployed to counteract atheroinflammatory vascular diseases, highlighting the promise of nanomedicines for hyperlipidemic and metabolic syndromes.

Constant size, variable density aerosol particles by ultrasonic spray freeze drying

This work provides a new understanding of critical process parameters involved in the production of inhalation aerosol particles by ultrasonic spray freeze drying to enable precise control over particle size and aerodynamic properties. A series of highly porous mannitol, lysozyme, and bovine serum albumin (BSA) particles were produced, varying only the solute concentration in the liquid feed, c(s), from 1 to 5 wt%. The particle sizes of mannitol, BSA, and lysozyme powders were independent of solute concentration, and depend only on the drop size produced by atomization. Both mannitol and lysozyme formulations showed a linear relationship between the computed Fine Particle Fraction (FPF) and the square root of c(s), which is proportional to the particle density, ρ, given a constant particle size d(g). The FPF decreased with increasing c(s) from 57.0% to 16.6% for mannitol and 44.5% to 17.2% for lysozyme. Due to cohesion, the BSA powder FPF measured by cascade impaction was less than 10% and independent of c(s). Ultrasonic spray freeze drying enables separate control over particle size, d(g), and aerodynamic size, d(a) which has allowed us to make the first experimental demonstration of the widely accepted rule d(a)=d(g)(ρ/ρ(o))(1/2) with particles of constant d(g), but variable density, ρ (ρ(o) is unit density).

Polymer Directed Self-Assembly of pH-Responsive Antioxidant Nanoparticles

We have developed pH-responsive, multifunctional nanoparticles based on encapsulation of an antioxidant, tannic acid (TA), using flash nanoprecipitation, a polymer directed self-assembly method. Formation of insoluble coordination complexes of tannic acid and iron during mixing drives nanoparticle assembly. Tuning the core material to polymer ratio, the size of the nanoparticles can be readily tuned between 50 and 265 nm. The resulting nanoparticle is pH-responsive, i.e., stable at pH 7.4 and soluble under acidic conditions due to the nature of the coordination complex. Further, the coordination complex can be coprecipitated with other hydrophobic materials such as therapeutics or imaging agents. For example, coprecipitation with a hydrophobic fluorescent dye creates fluorescent nanoparticles. In vitro, the nanoparticles have low cytotoxicity and show antioxidant activity. Therefore, these particles may facilitate intracellular delivery of antioxidants.

Flow improvement of waxy oils mediated by self-aggregating partially crystallizable diblock copolymers

Precipitation and gelation of long chain paraffins from oil presents a challenge to the recovery and processing of waxy crude oils and fuel stocks. Diblock polymers consisting of a crystallizable polyethylene (PE) block and an amorphous poly(ethylenepropylene) (PEP) block self-assemble in oil to form expansive plate-like aggregates, consisting of a PE core within a PEP brush layer. In the presence of crystallizable paraffins the crystalline PE core can promote nucleation of solubilized long chain paraffins or may cocrystallize with the paraffin phase with the soluble PEP brush providing steric stabilization of the wax crystals. We examine the effect of PE-b-PEP additives of varying PEP brush length (5 and 11 K) on the yield stresses of straight chain paraffin gels (ranging in length from 24 to 36 carbons) in decane. PE-b-PEP addition at levels as low as 500 ppm produce reductions of wax gel yield stresses by factors of 3000. At higher PE-b-PEP addition levels gels can be formed with higher yield values than solutions without polymer. The location of the minimum in the yield stress with respect to polymer addition depends on the molecular weight of the paraffin and the PEP brush length. Microscopic crystal dimensions and mobility correlate with the observed rheological results. Potential underlying mechanisms for the observed efficiencies are discussed.

Optical transmission in highly concentrated dispersions

The intensity temporal profiles of diffusive light propagation in highly concentrated (up to volume fraction ϕ∼0.55) dispersions measured by 100-fs laser pulses showed an increase in transport scattering mean free path above a critical concentration. This observation confirms the previous theoretical predictions of enhanced transmission at high particle concentrations due to correlated scattering. The correlation effects are accounted for by incorporating a hard sphere Percus–Yevick static structure factor into the prediction of transport mean free path.

Novel methods of targeted drug delivery: the potential of multifunctional nanoparticles

Nanomaterials have been demonstrated as useful tools for molecular imaging, molecular diagnosis and targeted therapy in biomedical research. The main advantages of such nanomaterials are improved circulation times, precise targeting, enhancement of dissolution rates and enhanced contrast. A challenge and opportunity for nanotechnological strategies is that multiple functionalities, such as therapeutics, targeting, imaging and stimuli responsiveness can be achieved within one nanoparticle. Multifunctional nanoparticles are now actively under investigation and are imminent as the next generation of nanoparticles for providing custom and tailored treatment. This review considers contemporary approaches and possible future directions in the emerging area of multifunctional nanoparticles with a special focus on targeted drug delivery.

Detection of water-ice transition using a lead zirconate titanate/brass transducer

We have examined experimentally and theoretically the resonance frequency of a lead zirconate titanate (PZT)/brass unimorph disk transducer with a water (ice) layer on the brass surface. We showed that the flexural resonance frequency decreased with the presence of a water layer and the decrease in resonance frequency increased with an increasing water amount. Upon lowering the temperature, the freezing transition of the deposited water layer was detected when the resonance frequency of the transducer increased abruptly at the freezing temperature. In contrast to water, an ice layer increased the resonance frequency and the increase in the resonance frequency increased with the ice layer thickness. Theoretically, an analytic expression for the flexural resonance frequency of a unimorph transducer in the presence of an ice (water) layer on the brass surface was obtained in terms of the Young’s moduli, densities, and thickness of the PZT, brass, and ice (water) layers. The theoretical predictions were shown...