Diblock Copolymer Targeted Lipid Nanoparticles: Next-Generation Nucleic Acid Delivery System Produced by Confined Impinging Jet Mixers.

Despite the recent advances and clinical demonstration of lipid nanoparticles (LNPs) for therapeutic and prophylactic applications, the extrahepatic delivery of nucleic acids remains a significant challenge in the field. This limitation arises from the rapid desorption of lipid-PEG in the bloodstream and clearance to the liver, which hinders extrahepatic delivery. In response, we explore the substitution of lipid-PEG with biodegradable block copolymers (BCPs), specifically poly(ε-caprolactone)--poly(ethylene glycol) (PCL--PEG).

Co-encapsulation of organic polymers and inorganic superparamagnetic iron oxide colloidal crystals requires matched diffusion time scales.

Nanoparticles (NPs) that contain both organic molecules and inorganic metal or metal oxide colloids in the same NP core are "composite nanoparticles" which are of interest in many applications, particularly in biomedicine as "theranostics" for the combined delivery of colloidal diagnostic imaging agents with therapeutic drugs. The rapid precipitation technique Flash NanoPrecipitation (FNP) enables continuous and scalable production of composite nanoparticles with hydrodynamic diameters between 40-200 nanometers (nm) that contain hydrophobic superparamagnetic iron oxide primary colloids. Composite NPs co-encapsulate these primary colloids (diameters of 6 nm, 15 nm, or 29 nm), a fluorescent dye (600 Daltons), and poly(styrene) homopolymer (1800, 50 000, or 200 000 Daltons) with NPs stabilized by a poly(styrene)--poly(ethylene glycol) (1600 Da--5000 Da) block copolymer.

Intestinal distribution of anionic, cationic, and neutral polymer-stabilized nanocarriers measured with a lanthanide (europium) tracer assay.

Nanocarriers, more commonly called nanoparticles (NPs), have found increasing use as delivery vehicles which increase the oral bioavailability of poorly water-soluble and peptide therapeutics. Therapeutic bioavailability is commonly assessed by measuring plasma concentrations that reflect the absorption kinetics. This bioavailability is a convolution of the gastrointestinal distribution of the NP vehicle, the release rate of the encapsulated therapeutic cargo, and the absorption-metabolism-distribution kinetics of the released therapeutic.

A Strategic Blend of Stabilizing Polymers to Control Particle Surface Charge for Enhanced Mucus Transport and Cell Binding.

Mucus layers, viscoelastic gels abundant in anionic mucin glycoproteins, obstruct therapeutic delivery across all mucosal surfaces. We found that strongly positively charged nanoparticles (NPs) rapidly adsorb a mucin protein corona in mucus, impeding cell binding and uptake. To overcome this, we developed mucus-evading, cell-adhesive (MECS) NPs with variable surface charge using Flash NanoPrecipitation, by blending a neutral poly(ethylene glycol) (PEG) corona for mucus transport with a small amount, 5 wt%, of polycationic dimethylaminoethyl methacrylate (PDMAEMA) for increased cell targeting.

Synthesizing Lipid Nanoparticles by Turbulent Flow in Confined Impinging Jet Mixers.

Lipid nanoparticles (LNPs) have demonstrated their enormous potential as therapeutic delivery vehicles, as evidenced by the approval and global usage of two COVID-19 messenger RNA (mRNA) vaccines. On a small scale, LNPs are often made using microfluidics; however, the limitations of these devices preclude their use on a large scale. The COVID-19 vaccines are manufactured in large quantities using confined impinging jet (CIJ) turbulent mixers.

Pharmacokinetic control of orally dosed cyclosporine A with mucosal drug delivery system.

This study aimed to control the oral absorption of cyclosporine A (CsA) with the use of a mucosal drug delivery system (mDDS). Mucopenetrating nanocarriers (MP/NCs) and mucoadhesive nanocarriers (MA/NCs) were prepared by flash nanoprecipitation employing polystyrene-block-poly(ethylene glycol) and polystyrene-block-poly(N,N-dimethyl aminoethyl methacrylate), respectively. Their particle distribution in the rat gastrointestinal tract were visualized by fluorescent imaging.

Stabilized Astaxanthin Nanoparticles Developed Using Flash Nanoprecipitation to Improve Oral Bioavailability and Hepatoprotective Effects.

In this study, we developed stabilized astaxanthin (AX) nanoparticles (sNP/AX) to improve the physicochemical properties, oral bioavailability, and hepatoprotection of AX. A flash nanoprecipitation technique was used with a multi-inlet vortex mixer to prepare the sNP/AX. Vitamins E (VE) and C (VC) were used as co-stabilizers with poloxamer 407 as a stabilizer to inhibit the oxidative degradation of AX during sNP/AX formation and storage.

Formulation and Scale-up of Delamanid Nanoparticles via Emulsification for Oral Tuberculosis Treatment.

Delamanid (DLM) is a hydrophobic small molecule therapeutic used to treat drug-resistant tuberculosis (DR-TB). Due to its hydrophobicity and resulting poor aqueous solubility, formulation strategies such as amorphous solid dispersions (ASDs) have been investigated to enhance its aqueous dissolution kinetics and thereby improve oral bioavailability. However, ASD formulations are susceptible to temperature- and humidity-induced phase separation and recrystallization under harsh storage conditions typically encountered in areas with high tuberculosis incidence.

Sequential Flash NanoPrecipitation for the scalable formulation of stable core-shell nanoparticles with core loadings up to 90.

Flash NanoPrecipitation (FNP) is a scalable, single-step process that uses rapid mixing to prepare nanoparticles with a hydrophobic core and amphiphilic stabilizing shell. Because the two steps of particle self-assembly - (1) core nucleation and growth and (2) adsorption of a stabilizing polymer onto the growing core surface - occur simultaneously during FNP, nanoparticles formulated at core loadings above approximately 70% typically exhibit poor stability or do not form at all. Additionally, a fundamental limit on the concentration of total solids that can be introduced into the FNP process has been reported previously.

Formulation and Scale-Up of Fast-Dissolving Lumefantrine Nanoparticles for Oral Malaria Therapy.

Lumefantrine (LMN) is one of the first-line drugs in the treatment of malaria due to its long circulation half-life, which results in enhanced effectiveness against drug-resistant strains of malaria. However, LMN's therapeutic efficacy is diminished due to its low bioavailability when dosed as a crystalline solid. The goal of this work was to produce low-cost, highly bioavailable, stable LMN powders for oral delivery that would be suitable for global health applications.

Effects of the polymer glass transition on the stability of nanoparticle dispersions.

In addition to the repulsive and attractive interaction forces described by Derjaguin-Landau-Verwey-Overbeek (DLVO) theory, many charged colloid systems are stabilized by non-DLVO contributions stemming from specific material attributes. Here, we investigate non-DLVO contributions to the stability of polymer colloids stemming from the intra-particle glass transition temperature (). Flash nanoprecipitation is used to fabricate nanoparticles (NPs) from a library of polymers and dispersion stability is studied in the presence of both hydrophilic and hydrophobic salts.

Formulation of pH-Responsive Methacrylate-Based Polyelectrolyte-Stabilized Nanoparticles for Applications in Drug Delivery.

pH-responsive polyelectrolytes, including methacrylate-based anionic copolymers (MACs), are widely used as enteric coatings and matrices in oral drug delivery. Despite their widespread use in these macroscopic applications, the molecular understanding of their use as stabilizers for nanoparticles (NPs) is lacking. Here, we investigate how MACs can be used to create NPs for therapeutic drug delivery and the role of MAC molecular properties on the assembly of NPs via flash nanoprecipitation.

Rapid Precipitation of Ionomers for Stabilization of Polymeric Colloids.

Polymeric colloids have shown potential as "building blocks" in applications ranging from formulations of Pickering emulsions and drug delivery systems to advanced materials, including colloidal crystals and composites. However, for applications requiring tunable properties of charged colloids, obstacles in fabrication can arise through limitations in process scalability and chemical versatility. In this work, the capabilities of flash nanoprecipitation (FNP), a scalable nanoparticle (NP) fabrication technology, are expanded to produce charged polystyrene colloids using sulfonated polystyrene ionomers as a new class of NP stabilizers.

Quantifying the benefits of reducing synthetic nitrogen application policy on ecosystem carbon sequestration and biodiversity.

Synthetic Nitrogen (N) usage in agriculture has greatly increased food supply over the past century. However, the intensive use of N fertilizer is nevertheless the source of numerous environmental issues and remains a major challenge for policymakers to understand, measure, and quantify the interactions and trade-offs between ecosystem carbon and terrestrial biodiversity loss. In this study, we investigate the impacts of a public policy scenario that aims to halve N fertilizer application across European Union (EU) agriculture on both carbon (C) sequestration and biodiversity changes.

Chemorepellent-Loaded Nanocarriers Promote Localized Interference of Transport to Inhibit Biofilm Formation.

To mitigate antimicrobial resistance, we developed polymeric nanocarrier delivery of the chemorepellent signaling agent, nickel, to interfere with transport to a surface, an incipient biofilm formation stage. The dynamics of nickel nanocarrier (Ni NC) chemorepellent release and induced chemorepellent response required to effectively modulate bacterial transport for biofilm prevention were characterized in this work. Ni NCs were fabricated with the established Flash NanoPrecipitation method.

Tuning Morphologies and Reactivities of Hybrid Organic-Inorganic Nanoparticles.

Hybrid nanoparticles (hNPs), or nanoparticles composed of both organic and inorganic components, hold promise for diverse energy and environmental applications due to their ability to stabilize reactive nanomaterials against aggregation, enhancing their ability to pervade tortuous spaces and travel long distances to degrade contaminants . Past studies have investigated the use of polymer or surfactant coatings to stabilize nanomaterials against aggregation. However, fabrication of these materials often requires multiple steps and lacks specificity in the control of their morphologies and reactivities.

Sensors in a Flash! Oxygen Nanosensors for Microbial Metabolic Monitoring Synthesized by Flash Nanoprecipitation.

Flash nanoprecipitation (FNP) is an efficient and scalable nanoparticle synthesis method that has not previously been applied to nanosensor fabrication. Current nanosensor fabrication methods have traditionally exhibited poor replicability and consistency resulting in high batch-to-batch variability, highlighting the need for a more tunable and efficient method such as FNP. We used FNP to fabricate nanosensors to sense oxygen based on an oxygen-sensitive dye and a reference dye, as a tool for measuring microbial metabolism.

Rerouting the internal thoracic vessels as recipient vessels in head and neck reconstruction: Comparison of two anatomic approaches.

Introduction: The vessel-depleted neck situation is a challenge for the surgeon in search of suitable recipient vessels for microvascular reconstruction of the head and neck. The internal thoracic vessels (ITVs) have proven useful as "rescue" recipient vessel resource. The objective of this report is to assess the feasibility of using ITVs by rerouting the pedicle for free flap reconstruction of the head and neck by comparing two different approaches.

Hysteresis in the thermally induced phase transition of cellulose ethers.

Functionalized cellulosics have shown promise as naturally derived thermoresponsive gelling agents. However, the dynamics of thermally induced phase transitions of these polymers at the lower critical solution temperature (LCST) are not fully understood. Here, with experiments and theoretical considerations, we address how molecular architecture dictates the mechanisms and dynamics of phase transitions for cellulose ethers.

Development of an Release Assay for Low-Density Cannabidiol Nanoparticles Prepared by Flash NanoPrecipitation.

Nanoparticle encapsulation is an attractive approach to improve the oral bioavailability of hydrophobic therapeutics. The high specific surface area of nanoparticle formulations, combined with the thermodynamically driven increased solubility of an amorphous drug core, promotes rapid drug dissolution. However, the physicochemical properties of the hydrophobic therapeutic can present obstacles to characterization of nanoparticle formulations.

Small-volume lipid digestion measurements for assessing drug dissolution in lipid-based formulations using SAXS.

Lipid-based formulations improve the absorption capacity of poorly-water-soluble drugs and digestion of the formulation is a critical step in that absorption process. A recent approach to understanding the propensity for drug to dissolve in digesting lipid-based formulations couples an pH-stat lipolysis model to small-angle X-ray scattering (SAXS) by means of a flow-through capillary. However, the conventional pH-stat apparatus used to measure the extent of lipid digestion during such experiments requires digest volumes of 15-30 mL and drug doses of 50-200 mg, which is problematic for scarce compounds and can require excessive amounts of formulation reagents.

Clofazimine-Loaded Mucoadhesive Nanoparticles Prepared by Flash Nanoprecipitation for Strategic Intestinal Delivery.

Purpose: This study was undertaken to develop novel mucoadhesive formulations of clofazimine (CFZ), a drug candidate for the treatment of cryptosporidiosis, with the aim of strategic delivery to the small intestine, the main site of the disease parasites.

Methods: CFZ-loaded nanoparticles (nCFZ) coated with non-biodegradable anionic polymer (nCFZ/A) and biodegradable anionic protein complex (nCFZ/dA) were prepared by Flash NanoPrecipitation (FNP) and evaluated for their physicochemical and biopharmaceutical properties.

Results: The mean diameters of nCFZ/A and nCFZ/dA were ca.

Tween Preserves Enzyme Activity and Stability in PLGA Nanoparticles.

Enzymes, as natural and potentially long-term treatment options, have become one of the most sought-after pharmaceutical molecules to be delivered with nanoparticles (NPs); however, their instability during formulation often leads to underwhelming results. Various molecules, including the Tween polysorbate series, have demonstrated enzyme activity protection but are often used uncontrolled without optimization. Here, poly(lactic-co-glycolic) acid (PLGA) NPs loaded with β-glucosidase (β-Glu) solutions containing Tween 20, 60, or 80 were compared.

Microfluidic Technology for the Production of Hybrid Nanomedicines.

Microfluidic technologies have recently been applied as innovative methods for the production of a variety of nanomedicines (NMeds), demonstrating their potential on a global scale. The capacity to precisely control variables, such as the flow rate ratio, temperature, total flow rate, etc., allows for greater tunability of the NMed systems that are more standardized and automated than the ones obtained by well-known benchtop protocols.

Transient Electric Birefringence of Linear and Circular DNA: A Comparison of Kinetic Theory Predictions.

The use of monodisperse DNA and restriction enzyme modification allows the preparation of model samples of polymer rings and linear chains with a precision that is not possible by conventional synthetic routes. These samples allow direct comparisons of the predictions of polymer kinetic theories. Transient electric birefringence allows rapid imposition or forces (∼100 ns) and monitoring of conformational changes (∼0.