Polymeric nanoparticles encapsulating inhibitory ribonucleic acids (RNAs) and methods of their manufacture and use are provided. Advantageous properties of the nanoparticles include: 1) high encapsulation efficiency of inhibitory RNAs into the nanoparticles, 2) small size of the nanoparticles that increases cell internalization, and 3) sustained release of encapsulated inhibitory RNAs by the nanoparticles that allows for administration of an effective amount of inhibitory RNAs to cells or tissues over extended periods of time. Encapsulation efficiency of inhibitory RNAs into the nanoparticles is greatly increased by complexing the inhibitory RNAs to polycations prior to encapsulation. Methods of using the polymeric nanoparticles for treating or inhibiting diseases or disorders are provided.
Yale researchers have developed biodegradable polymeric microparticles containing one or more active agents for the sustained delivery of ophthalmic drugs. Drugs include latanaprost for glaucoma, and triamcinolone for diabetic retinopathy and uveitis. Drug release has been shown over several months.
Glaucoma is the second leading cause of blindness in the world, and the risk for developing the disease increases with age. It is associated with a rise in intraocular pressure (IOP), the reduction of which can usually preserve vision. While effective IOP-lowering medications are available, they require continuous administration, up to several times per day in some cases. Non-compliance with glaucoma medications is very high among elderly patients, with frequent administration requirements strongly associated with nonadherence. This novel treatment addresses the large and growing compliance issue with a sustained delivery timolol maleate injection. With the possibility of administration once every few months at routine doctor's visits, daily compliance is negated.
Yale's technology mimics physiological antigen presentation with biodegradable nano- or microparticles constructed from poly(lactide-co-glycolic acid) (PLGA), whose safety has been established for use in humans. The modular design of our polymeric artificial Antigen-Presenting Cells (aAPCs) system involves flexible addition and subtraction of functional elements including antigen-specific and polymeric T-cell receptor activators, co-stimulatory and adhesion molecules, and cytokines for exquisite controlled release. The antigens can be tumor, viral, bacterial, parasite, allergens environmental or self antigens.
Methods for increasing the patency of biodegradable, synthetic vascular grafts are provided. The methods include administering one or more cytokines and/or chemokines that promote outward tissue remodeling of the vascular grafts and vascular neotissue formation. The disclosed methods do not require cell seeding of the vascular grafts, thus avoiding many problems associated with cell seeding. Biodegradable, polymeric vascular grafts which provide controlled release of cytokines and/or chemokines at the site of vascular graft implantation are also provided.
Yale investigators have developed a new synthetic platelet to treat hemorrhage. The synthetic platelet resembles the shape of an activated platelet (star burst) and is made from FDA-approved materials, consisting of a nanosphere core and polyethylene glycol (PEG) arms. Our synthetic platelet is capable of forming a barrier to reduce membrane permeability and enhance the sealing on a disrupted blood vessel wall, which is extremely beneficial to promote synthetic platelet aggregation at the site of injury.
Investigators at Yale have created a predominantly hydrophobic polypeptide, pHLIP (pH Low Insertion Peptide), derived from the bacteriorhodopsin C helix. This polypeptide is long enough to span a membrane lipid bilayer as a transmembrane helix, and contains two flanking sequences. One end, the C-terminus, can insert across a cell membrane into the cytoplasm spontaneously in a pH-dependant manner, and the other end remains exposed to the aqueous environment outside the cell. At neutral pH, the polypeptide binds weakly to the surface of a cell membrane without insertion. Acidic pH promotes the insertion and formation of a transmembrane alpha helix. Such insertion is driven by protonation of one or two aspartic residues located in the transmembrane part of the polypeptide. The polypeptide may be conjugated with various molecules to be delivered into or accumulated at cell membranes with low extracellular pH. Acidosis can arise locally as a result of reduced vascular supply due to inflammation or infection. In tumor cells, large amounts of metabolic acid lead to acidification of the extracellular environment. This technology may be used for imaging, diagnostics, or therapeutics.
Efficient use of an in vitro produced chimeric mRNA and other modulator RNAs to create lymphocytes with high levels of specific cytotoxicity against chosen targets.