pH-dependent structural transitions in cationic ionizable lipid mesophases are critical for lipid nanoparticle function.

Lipid nanoparticles (LNPs) are advanced core-shell particles for messenger RNA (mRNA) based therapies that are made of polyethylene glycol (PEG) lipid, distearoylphosphatidylcholine (DSPC), cationic ionizable lipid (CIL), cholesterol (chol), and mRNA. Yet the mechanism of pH-dependent response that is believed to cause endosomal release of LNPs is not well understood. Here, we show that eGFP (enhanced green fluorescent protein) protein expression in the mouse liver mediated by the ionizable lipids DLin-MC3-DMA (MC3), DLin-KC2-DMA (KC2), and DLinDMA (DD) ranks MC3 ≥ KC2 > DD despite similar delivery of mRNA per cell in all cell fractions isolated.

Quantification of magic angle spinning dynamic nuclear polarization NMR spectra.

Dynamic nuclear polarization (DNP) allows to dramatically enhance the sensitivity of magic angle spinning nuclear magnetic resonance (MAS NMR). DNP experiments usually rely on the detection of low-γ nuclei hyperpolarized from H with the use of cross polarization (CP), which assures more efficient signal enhancement. However, CP is usually not quantitative.

High Sensitivity Detection of a Solubility Limiting Surface Transformation of Drug Particles by DNP SENS.

We investigate the presence of a surface species for the active pharmaceutical ingredient (API) AZD9496 with dynamic nuclear polarization surface enhanced nuclear spectroscopy (DNP SENS). We show that using DNP we can elucidate the presence of an amorphous form of the API at the surface of crystalline particles of the salt form. The amorphous form of the API has distinguishable C chemical shifts when compared to the salt form under various acidic conditions.

Promoting intestinal lymphatic transport targets a liver-X receptor (LXR) agonist (WAY-252,623) to lymphocytes and enhances immunomodulation.

Lymphocytes play a central role in the pathology of a range of chronic conditions such as autoimmune disease, transplant rejection, leukemia, lymphoma HIV/AIDs and cardiometabolic diseases such as atherosclerosis. Current treatments for lymphocyte-associated conditions are incompletely effective and/or complicated by a range of off-target toxicities. One major challenge is poor drug access to lymphocytes via the systemic blood and this may be attributed, at least in part, to the fact that lymphocytes are concentrated within lymph fluid and lymphoid tissues, particularly in gut-associated lymphatics.

Core-Shell Structure of Organic Crystalline Nanoparticles Determined by Relayed Dynamic Nuclear Polarization NMR.

The structure of crystalline nanoparticles (CNPs) is determined using dynamic nuclear polarization (DNP) enhanced NMR spectroscopy experiments. The CNPs are composed of a crystalline core containing an active pharmaceutical ingredient (compound P), coated with a layer of PEG (DSPE-PEG 5000) located at the crystal surface, in a DO suspension. Relayed DNP experiments are performed to study H-H spin diffusion and to determine the size of the crystalline core as well as the thickness of the PEG overlayer.

Nanocrystal formulations of a poorly soluble drug. 2. Evaluation of nanocrystal liver uptake and distribution after intravenous administration to mice.

A stabilized high drug load intravenous formulation could allow compounds with less optimal pharmacokinetic profiles to be developed. Polyethylene glycol (PEG)-ylation is a frequently used strategy for particle delivery systems to avoid the liver, thereby extending blood circulation time. The present work reports the mouse in vivo distribution after i.

Nanocrystal formulations of a poorly soluble drug. 1. In vitro characterization of stability, stabilizer adsorption and uptake in liver cells.

In the present work, milled nanocrystals of a poorly soluble compound using different stabilizers were prepared and characterized. The aim of the study was to evaluate a fundamental set of properties of the formulations prior to i.v.

Amorphous drug nanosuspensions. 3. Particle dissolution and crystal growth.

In the present paper, we have studied particle dissolution and crystal growth of the poorly water soluble drug felodipine, using fluorescence as a probe for the amount of crystalline material. Dissolution kinetics is essentially diffusion-controlled, while the rate of crystal growth is significantly slower compared to the diffusion-controlled limit. The deviation from diffusion control was characterized by the effective length, lambda, related to the kinetics of a surface integration process.

A formulation comparison, using a solution and different nanosuspensions of a poorly soluble compound.

The pharmacokinetic parameters of AZ68 administered as a solution have been compared with those from an amorphous and a crystalline nanosuspension using rats as in vivo specie. All formulations were administered intravenously (i.v.

Amorphous drug nanosuspensions. 2. Experimental determination of bulk monomer concentrations.

A simple turbidimetric method was developed to measure the bulk concentration of drug in nanosuspensions. The bulk concentrations measured were in the range from 1 microM to 1 mM. The accuracy of the method was checked by determination of the bulk concentration of crystalline nanosuspensions, i.

Amorphous drug nanosuspensions. 1. Inhibition of Ostwald ripening.

Amorphous drug nanosuspensions are prone to particle growth due to Ostwald ripening. By incorporating a second component of extremely low aqueous solubility, Ostwald ripening can be inhibited. These studies indicate that to inhibit ripening, the drug/inhibitor mixture (in the particles) must form a single phase.