44 results about "Transcytosis" patented technology

A pharmaceutical composition comprises a GPCR agonist fusion protein in which a GPCR agonist peptide is covalently coupled to albumin via a linker in a manner that is resistant to a retro-Michael addition. Advantageously, compositions presented herein avoid decoupling of the agonist form the albumin while retaining the agonist in a steric relationship to the albumin that allows for effective binding and activation of the GPCR while also enabling gp60-mediated transcytosis and FcRn-mediated albumin recycling. These properties enable ultra-low dosages for the GPCR agonist fusion protein to give a therapeutic effect while substantially reducing or even entirely avoiding adverse effects otherwise commonly associated with unbound agonists. Such retro-Michael resistant composition is generally achieved by conformational modification of the albumin, resulting in stereoselective coupling of the linker to the albumin.

A pharmaceutical composition comprises a GPCR agonist fusion protein wherein the GPCR agonist peptide is covalently conjugated to an albumin via a linker in a manner that is resistant to a reverse Michael addition. Advantageously, the compositions presented herein avoid uncoupling of the agonist to the albumin while maintaining the agonist and the albumin in a spatial relationship that allows efficient binding and activation of the GPCR while also enabling gp60-mediated endocytosis transport and FcRn-mediated albumin recirculation. These characteristics enable ultra-low doses of GPCR agonist fusion proteins to produce therapeutic effects while significantly reducing or even completely avoiding side effects that would otherwise be typically associated with unbound agonists. Such reverse Michael resistant compositions are typically achieved by conformationally modifying an albumin, resulting in a stereoselective coupling of a linker to the albumin.

A pharmaceutical composition comprises a GPCR agonist fusion protein in which a GPCR agonist peptide is covalently coupled to albumin via a linker in a manner that is resistant to a retro-Michael addition. Advantageously, compositions presented herein avoid decoupling of the agonist form the albumin while retaining the agonist in a steric relationship to the albumin that allows for effective binding and activation of the GPCR while also enabling gp60-mediated transcytosis and FcRn-mediated albumin recycling. These properties enable ultra-low dosages for the GPCR agonist fusion protein to give a therapeutic effect while substantially reducing or even entirely avoiding adverse effects otherwise commonly associated with unbound agonists. Moreover, these properties also enable transport of the GPCR agonist fusion protein across the blood brain barrier and therefore allow treatment of neural disorders.

The disclosure provides the structure of an MFSD2A-SYNC2 complex together with functional data that revealed important molecular aspects of MFSD2A transport cycle, receptor-mediated cell-cell fusion, and pharmacology and resulted in the identification of two novel allosteric modulators of MFSD2A, which are two soluble fragments of SYNC2, namely SYNC2su-co and SYNC2su-co-2, representing first-in-class molecules to inhibit MFSD2A LPCs uptake and increase transcytosis rate.

Antibodies can treat neurodegenerative disorders (NDs) caused by misfolded proteins. Still, the blood-brain-barrier (BBB) resists their entry, a barrier that can be reduced by scFv instead of whole antibody and conjugating it with transferrin protein to induce transcytosis. While the scFv binds variable heavy and light chains with a non-cleavable linker, a cleavable linker between the scFv and transferrin protein can reduce exocytosis, enhancing the activity of the scFv.

The invention discloses application of a gene editing virus interfering expression and secretion of enzyme prototype cathepsin D in brain trauma, belongs to the field of gene functions and application, and finds that brain injury is aggravated and nerve dysfunction is aggravated due to the fact that the level of the enzyme prototype cathepsin D in plasma is increased due to the brain trauma through detection. The mechanism is as follows: the enzyme prototype cathepsin D enhances the transendocytosis effect of cerebral vascular endothelial cells after brain trauma, so that plasma inflammatory factors are gathered in damaged brain tissues; meanwhile, the expression of cerebrovascular endothelial cells VCAM-1 is also up-regulated, and neutrophil infiltration in an injured brain region after brain trauma is intensified. Research finds that down-regulation of plasma enzyme prototype cathepsin D can alleviate inflammatory factor concentration and neutrophil density in a brain injury area after trauma, and alleviate neurological function impairment of mice. Aiming at the functions of the plasma prototype cathepsin D, a strategy for reducing the plasma level of the plasma prototype cathepsin D by a gene editing technology for interfering the prototype cathepsin D is provided for treating the cerebral trauma.

Antibodies can treat neurodegenerative disorders (NDs) caused by misfolded proteins. Still, the blood-brain-barrier (BBB) resists their entry, a barrier that can be reduced by scFv instead of whole antibody and conjugating it with transferrin protein to induce transcytosis. While the scFv binds variable heavy and light chains with a non-cleavable linker, a cleavable linker between the scFv and transferrin protein can reduce exocytosis, enhancing the activity of the scFv.

This invention discloses nanoparticles based on transcytosis-activating ligands, their preparation method, and applications, particularly in the treatment of fundus diseases. The nanoparticles comprise an enzyme protein core and a polymer shell grown in situ on the protein surface. The polymer shell contains positively charged monomers, transcytosis-activating ligands, and neutral monomers. The nanoparticles can enhance the hydrolytic resistance of enzyme proteins (e.g., antioxidant enzymes), protecting them from degradation during transport and improving delivery stability. Simultaneously, the nanoparticles can also promote the efficient delivery of proteases (especially to the posterior segment of the eye), exhibiting good safety and showing excellent application prospects in the medical field.

This invention discloses an oral frameshift peptide neoantigen vaccine, its preparation method, and its application, relating to the field of biomedical technology. The preparation method includes: 1) synthesizing a sea urchin-like metal-organic framework (MOF) via a hydrothermal method using zinc ions and 3,3''-dihydroxy-2',5'-dimethyl-[1,1':4',1''-terphenyl]-4,4''-dicarboxylic acid; 2) loading the sea urchin-like MOF with a frameshift peptide and a Toll-like receptor 9 agonist via electrostatic interactions and / or van der Waals forces to prepare the oral frameshift peptide neoantigen vaccine. This vaccine not only promotes antigen endocytosis and transcytosis via intestinal microfold cells by activating cyclin 42, but also alleviates immune tolerance mediated by the goblet cell-regulatory T cell immunosuppressive axis and activates specific CD8+. + T cells help prevent the development of Lynch syndrome-related colorectal cancer.

Delivery of a payload across a cytoplasmic membrane includes providing a population of cells, contacting the population of cells with a volume of an aqueous solution. The aqueous solution includes an effective load and an alcohol at a concentration greater than 5%. The volume of the aqueous solution may be a function of the exposed surface area of the cell population, or a function of the number of cells in the cell population. Related compositions, instruments, systems, techniques, and articles are also described herein.

A pharmaceutical composition comprises a GPCR agonist fusion protein in which a GPCR agonist peptide is covalently coupled to albumin via a linker in a manner that is resistant to a retro-Michael addition. Advantageously, compositions presented herein avoid decoupling of the agonist form the albumin while retaining the agonist in a steric relationship to the albumin that allows for effective binding and activation of the GPCR while also enabling gp60-mediated transcytosis and FcRn-mediated albumin recycling. These properties enable ultra-low dosages for the GPCR agonist fusion protein to give a therapeutic effect while substantially reducing or even entirely avoiding adverse effects otherwise commonly associated with unbound agonists. Moreover, these properties also enable transport of the GPCR agonist fusion protein across the blood brain barrier and therefore allow treatment of neural disorders.

Antibodies can treat neurodegenerative disorders (NDs) caused by misfolded proteins. Still, the blood-brain-barrier (BBB) resists their entry, a barrier that can be reduced by scFv instead of whole antibody and conjugating it with transferrin protein to induce transcytosis. While the scFv binds variable heavy and light chains with a non-cleavable linker, a cleavable linker between the scFv and transferrin protein can reduce exocytosis, enhancing the activity of the scFv.

The invention relates to a single domain antibody that binds Heparin-binding EGF-like growth factor (HB-EGF) for use in preventing, treating and / or diagnosing e.g. a brain disease, wherein the single domain antibody is in combination with a therapeutic compound and / or a diagnostic / imaging compound. The single domain antibody may in particular be a Variable domain of a Heavy chain only (VHH) antibody of camelid origin or an engineered single-domain antibody (sdAb) of other mammalian and be capable of transporting cargo such as peptides or other molecules into the brain across the blood-brain barrier (BBB) by receptor-mediated transcytosis (RMT). The brain disease may for example be Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, brain tumor, or Hunter syndrome.

Antibodies can treat neurodegenerative disorders (NDs) caused by misfolded proteins. Still, the blood-brain-barrier (BBB) resists their entry, a barrier that can be reduced by scFv instead of whole antibody and conjugating it with transferrin protein to induce transcytosis. While the scFv binds variable heavy and light chains with a non-cleavable linker, a cleavable linker between the scFv and transferrin protein can reduce exocytosis, enhancing the activity of the scFv.

The present disclosure is directed to nanobody-siRNA conjugates and methods of producing and using same. The nanobody-siRNA conjugates include a nanobody that may direct the conjugate to a target cell. The nanobody-siRNA conjugates are delivered into the target cell via receptor-mediated transcytosis, where the siRNA is delivered to the cell cytoplasm after it exits the endosome. To treat diseases and conditions, such as cancers and autoimmune diseases, the siRNA can be efficiently passed through the BBB to modulate an immune response. The small size of nanobodies allows more efficient targeted delivery than typical antibody systems, while conjugation strategies involving click chemistry permit the multiplexed loading of siRNA to nanobodies for increased therapeutic effects.

The present invention relates to a method of enhancing transendocytosis comprising modulating the expression of vesicle-associated membrane protein 3 (VAMP3) and syntaxin 4 (syntaxin 4, STX-4). Compositions for increasing VAMP3 and / or STX-4 expression in HBMEC, and compositions comprising a target molecule in a form suitable for transendocytosis across the blood brain barrier.

Antibodies can treat neurodegenerative disorders (NDs) caused by misfolded proteins. Still, the blood-brain-barrier (BBB) resists their entry, a barrier that can be reduced by scFv instead of whole antibody and conjugating it with transferrin protein to induce transcytosis. While the scFv binds variable heavy and light chains with a non-cleavable linker, a cleavable linker between the scFv and transferrin protein can reduce exocytosis, enhancing the activity of the scFv.

A pharmaceutical composition comprises a GPCR agonist fusion protein wherein the GPCR agonist peptide is covalently conjugated to an albumin via a linker in a manner that is resistant to a reverse Michael addition. Advantageously, the compositions presented herein avoid uncoupling of the agonist to the albumin while maintaining the agonist and the albumin in a spatial relationship that allows efficient binding and activation of the GPCR while also enabling gp60-mediated endocytosis transport and FcRn-mediated albumin recirculation. These characteristics enable ultra-low doses of GPCR agonist fusion proteins to produce therapeutic effects while significantly reducing or even completely avoiding side effects that would otherwise be typically associated with unbound agonists. In addition, these properties also enable GPCR agonist fusion proteins to transport across the blood-brain barrier, and thus allow for the treatment of neurological disorders.

The invention discloses ultrasonic response ZnS (at) Lf piezoelectric nanoparticles as well as a preparation method and application thereof, and relates to the technical field of piezoelectric materials. The ultrasonic response ZnS (at) Lf piezoelectric nano-particle comprises a ZnS nano-particle and lactoferrin loaded on the surface of the ZnS nano-particle. According to the invention, lactoferrin is used as a potent brain-targeting ligand, and passes through a blood-brain barrier to be accumulated in brain parenchyma under the cell transfer action of brain capillary endothelial cells. ZnS nano particles release charges under the ultrasonic action, an electric signal activates a voltage-gated calcium ion channel and extracellular calcium ion influx, calcium ion / calmodulin kinase induces tyrosine hydroxylase (TH) phosphorylation, the activity of tyrosine hydroxylase is enhanced, tyrosine hydroxylase is a key enzyme for generating dopamine, and the activity of the tyrosine hydroxylase is enhanced. Therefore, more tyrosine in vivo is converted into neurotransmitter dopamine under the action of the enzyme. Finally, the regeneration of dopaminergic neurons is realized, so that the Parkinson's disease is effectively improved.

Anti-VEGF (Vascular Endothelial Growth Factor) (RNAT82) is a single chain variable fusion protein comprising fragment antibody variable light and variable heavy chains with binding domains conjugated with transferrin protein to induce transcytosis across the blood-retina barrier to treat neovascular (wet) age-related macular degeneration (AMD) by systemic administration instead of intravitreal administration, and binding and transcytosis to cancer cells to treat cancer. The present invention can be manufactured by recombinant process or by encoding in vivo as mRNA.

The invention discloses a synthesis method of monoatomic manganese-doped amino-rich PEG (polyethylene glycol) carbon quantum dots, and belongs to the technical field of biomedical materials.The synthesis method comprises the following steps: 1) adding manganese chloride into PEG400, and uniformly mixing to form a uniform mixed solution A; 2) adding ethylenediamine hydrochloride into the mixed solution A obtained in the step 1), and uniformly mixing to form a uniform mixed solution B; and (3) carrying out hydrothermal reaction on the mixed solution B obtained in the step (2), after the reaction is finished, cooling to room temperature, washing, purifying and drying to obtain the monoatomic manganese-doped amino-enriched PEG carbon quantum dots. The synthesized Mn (at) NH2-CDs can efficiently inhibit ferroptosis by removing active oxygen and ferrous ions, and the inhibition effect of the Mn (at) NH2-CDs on the cellular level is obviously higher than that of existing common active oxygen removing drugs and iron ion chelating agents; and the surface of the material is rich in amino groups, so that the material carries a large number of positive charges, and can penetrate through a blood brain barrier to enter brain tissues to inhibit ferroptosis through adsorption-mediated transendocytosis, thereby realizing treatment of shock wave brain injury.

Antibodies can treat neurodegenerative disorders (NDs) caused by misfolded proteins. Still, the blood-brain-barrier (BBB) resists their entry, a barrier that can be reduced by scFv instead of whole antibody and conjugating it with transferrin protein to induce transcytosis. While the scFv binds variable heavy and light chains with a non-cleavable linker, a cleavable linker between the scFv and transferrin protein can reduce exocytosis, enhancing the activity of the scFv.

Methods for enhancing transcytosis comprising modulating expression of Vesicle-associated membrane protein 3 (VAMP3) and syntaxin 4 (STX-4). Composition for increasing expression of VAMP3 and / or STX-4 in HBMECs and compositions comprising target molecules in a form suitable for transcytosis across the blood brain barrier.

The application discloses a transcytosis DNA nanoframework material, a preparation method and application thereof, and the transcytosis DNA nanoframework material is assembled through a hybridization chain reaction of a DNA-containing polymer as a skeleton and DNA hairpins; the skeleton is prepared from at least acrylamide-modified DNA, diethylaminoethyl methacrylate and 3-methacrylamidophenylboronic acid as raw materials through polymerization and oxidation. The transcytosis DNA nanoframework material integrates transcytosis function and gene silencing function, and can be used for precise delivery and treatment of pancreatic cancer and other solid tumors rich in dense matrix barriers.

The invention discloses a transferrin-mediated near-infrared two-region fluorescent probe, which is characterized in that a structural group of N, N-dimethylaminobenzene or N-ethyl-9, 9-dimethyl-9, 10-dihydroacridine is used as an electron donor (D), a vinyl bond is used as a pi conjugate bridge, and an imidazolone skeleton similar to green fluorescent protein is used as a first electron acceptor (A1); a quinoline salt structure is used as a second electron acceptor (A2), a benzyl bromide group is introduced to the tail end of a molecule, and the compound has a typical D-pi-A1-A2 type structure. The transferrin-mediated near-infrared two-region fluorescent probe can be subjected to nucleophilic substitution reaction with sulfydryl of transferrin to form a transferrin-covalently coupled near-infrared two-region fluorescent probe, so that active crossing of a blood brain barrier is realized by utilizing a TRF receptor-mediated transendocytosis pathway on the blood brain barrier; and efficient enrichment and stable NIR-II imaging are realized in brain tissues, and the imaging signal-to-noise ratio and the imaging definition are remarkably improved.

Antibodies can treat neurodegenerative disorders (NDs) caused by misfolded proteins. Still, the blood-brain-barrier (BBB) resists their entry, a barrier that can be reduced by scFv instead of whole antibody and conjugating it with transferrin protein to induce transcytosis. While the scFv binds variable heavy and light chains with a non-cleavable linker, a cleavable linker between the scFv and transferrin protein can reduce exocytosis, enhancing the activity of the scFv.

Antibodies can treat neurodegenerative disorders (NDs) caused by misfolded proteins. Still, the blood-brain-barrier (BBB) resists their entry, a barrier that can be reduced by scFv instead of whole antibody and conjugating it with transferrin protein to induce transcytosis. While the scFv binds variable heavy and light chains with a non-cleavable linker, a cleavable linker between the scFv and transferrin protein can reduce exocytosis, enhancing the activity of the scFv.

The invention relates to the technical field of biological medicine, and particularly discloses an organophosphorus hydrolase central targeting delivery strategy based on receptor mediation and fusion protein and application of the organophosphorus hydrolase central targeting delivery strategy. The fusion protein ANG-OPHDS5 comprises a targeting peptide Angiopep-2, a connecting fragment and organophosphorus hydrolase, and the amino acid sequence of the fusion protein ANG-OPHDS5 is as shown in SEQ ID NO: 1. The fusion protein can realize efficient central targeting delivery through transendocytosis mediated by an LRP1 receptor highly expressed on a blood brain barrier. Experiments show that the fusion protein can effectively degrade organophosphorus toxicants, retain high enzyme activity, remarkably relieve brain tissue damage in an animal model, and show good brain targeting and detoxification effects. The invention further relates to nucleic acid for coding the fusion protein, an expression vector, a recombinant host cell microorganism, a preparation method of the fusion protein and application of the fusion protein in preparation of drugs for relieving or treating organophosphorus poisoning.

Antibodies can treat neurodegenerative disorders (NDs) caused by misfolded proteins. Still, the blood-brain-barrier (BBB) resists their entry, a barrier that can be reduced by scFv instead of whole antibody and conjugating it with transferrin protein to induce transcytosis. While the scFv binds variable heavy and light chains with a non-cleavable linker, a cleavable linker between the scFv and transferrin protein can reduce exocytosis, enhancing the activity of the scFv.

The present invention relates to a nucleic acid molecule comprising a nucleotide sequence encoding a metabolic protein or a portion thereof, or a sequence having at least 90% sequence identity to said metabolic protein or a portion thereof, a human insulin-like growth factor II (IGFII) gene sequence, and a nucleotide sequence encoding at least one peptide that promotes cellular uptake or transcytosis inserted into said IGFII gene sequence between the nucleotides encoding amino acids 28 and 42 of mature IGFII. The invention further relates to related viral particles, fusion proteins, and uses thereof.