The present invention relates to the field of methods for providing pharmaceutical compositions comprising poorly water-soluble drugs. In particular the present invention relates to compositions comprising stable, amorphous hybrid nanoparticles, comprising at least one protein kinase inhibitor and at least one polymeric stabilizing and matrix-forming component, useful in pharmaceutical compositions and in therapy.

Network materials which exhibit both shear thinning and self-healing properties are disclosed. The networks contain particles and gel-forming compounds. The networks are useful for a variety of biomedical uses, including drug delivery.

The invention relates to compositions including polynucleotides encoding polypeptides which have been chemically modified by replacing the uridines with 1-methyl-pseudouridine to improve one or more of the stability and/or clearance in tissues, receptor uptake and/or kinetics, cellular access by the compositions, engagement with translational machinery, mRNA half-life, translation efficiency, immune evasion, protein production capacity, secretion efficiency, accessibility to circulation, protein half-life and/or modulation of a cell's status, function, and/or activity.

Methods for preparing particles and related compositions are provided. In some embodiments, the particles include at least one polynucleotide (e.g., mRNA), and in certain embodiments, the particles may include at least one ionizable molecule (e.g., a lipid). A method for preparing a suspension including the particles may comprise one or more filtration steps. In some such embodiments, prior to or during filtration, one or more properties of the particles (e.g., surface charge) and/or one or more properties of the suspension (e.g., pH) may be altered. In some embodiments, altering one or more properties of the particles and/or suspension may improve yield, improve a characteristic of the resulting composition, and/or prevent or reduce certain problems, such as fouling during the filtration process.

α-Bi.sub.2O.sub.3 NPs exhibit not only potent broad-spectrum antibacterial activity of killing both Gram-negative (MIC=0.75 μg/mL vs. P. aeruginosa) and Gram-positive (MIC=2.5 μg/mL vs. S. aureus) bacteria, but they are also effective against Ag-resistant and carbapenem-resistant bacteria (MICs=1.0 μg/mL and 1.25 μg/mL, respectively), and they are able to sensitize bacteria towards meropenem (mero), acting synergistically and thus allowing for its continued use with smaller therapeutic doses (fractional inhibitory concentration=0.45). Importantly, unlike other technologies that have been considered as effective metal antimicrobials, α-Bi.sub.2O.sub.3 NPs do not contribute to the generation of antimicrobial resistant phenotypes with no resistance observed after 30 passages. The Bi-based materials represent a critical tool against multidrug resistant bacteria.

Described herein is a nanoparticle system including a multivalent nanoparticle core having a plurality of β-hairpin peptides conjugated thereto. Also included are pharmaceutical compositions and methods of making the nanoparticle system. Further included are immunotherapy methods including administering the nanoparticle system to a subject in need thereof, such as a human cancer patient.

The disclosure features immune cell delivery lipid nanoparticle (LNP) compositions that allow for enhanced delivery of agents, e.g., nucleic acids, such as therapeutic and/or prophylactic RNAs, to immune cells, in particular T cells, as well as B cells, dendritic cells and monocytes. The LNPs comprise an effective amount of an immune cell delivery potentiating lipid such that delivery of an agent by an immune cell delivery LNP is enhanced as compared to an LNP lacking the immune cell delivery potentiating agent. Methods of using the immune cell delivery LNPs for delivery of agents, e.g., nucleic acid delivery, for protein expression, for modulating immune cell activity and modulating immune responses are also disclosed.

A nanoparticulate composition including particles comprising at least one active ingredient, wherein the particles have an effective average particle size is in the range of about 70 nm to about 220 nm measured by laser light scattering method, wherein at least 50% of said active agent particles have a particle size, by weight (volume based), of less than the effective average particle size; and (b) at least one surface stabilizer and/or at least one polymeric stabilizer, wherein the composition includes (aa) particles of at least one active ingredient selected from the group consisting of (Z)-2-cyano-3-cyclopropyl-3-hydroxy-N-(3-methyl-4-(trifluoromethyl)phenyl) prop-2-enamide, (Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]hept-2-en-6-ynamide, 2-cyano-3-cyclopropyl-N-(4-fluorophenyl)-3-hydroxyacrylamide, derivatives thereof, salts thereof and pro-drugs thereof, wherein the particles have an effective average particle size of less than about 2000 nm; and (bb) at least one surface stabilizer and/or at least one polymeric stabilizer.

The subject invention provides materials and methods for intracellular deliver of molecules and/or therapeutic agents. The subject invention also provides methods for synthesizing polymeric systems and nanomaterials that enhance or assist the passage of molecules and/or therapeutic agents across biological membranes. The compound, polymer or nanoparticle of the subject invention comprises a modified guanidine moiety in a plurality of repeating units of a polymer or on the surface of a nanoparticle where the guanidine moiety comprises, for example, a carbamoyl or thiourea modification. The polymer or nanoparticle can be used in a cancer treatment formulation.

Disclosed herein are compounds which inhibit the kinase activity of dual leucine zipper (DLK) kinase (MAP3K12), pharmaceutical compositions, and methods of treatment of DLK-mediated diseases, such as neurological diseases that result from traumatic injury to central nervous system and peripheral nervous system neurons (e.g. stroke, traumatic brain injury, spinal cord injury), or that result from a chronic neurodegenerative condition (e.g. Alzheimer's disease, frontotemporal dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinocerebellar ataxia, progressive supranuclear palsy, Lewy body disease, Kennedy's disease, and other related conditions), from neuropathies resulting from neurological damage (chemotherapy-induced peripheral neuropathy, diabetic neuropathy, and related conditions) and from cognitive disorders caused by pharmacological intervention (e.g. chemotherapy induced cognitive disorder, also known as chemobrain).