65 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 invention provides an LPC liposome preparation for brain-targeted delivery of chemotherapeutic drugs as well as a preparation method and application of the LPC liposome preparation. The LPC liposome preparation comprises L-alpha-lysophosphatidylcholine, egg yolk lecithin and cholesterol, and the mass of the L-alpha-lysophosphatidylcholine is 5%-30% of the total mass of the L-alpha-lysophosphatidylcholine, the egg yolk lecithin and the cholesterol. The constructed LPC lipidosome can accelerate endocytosis of the lipidosome in bECs, and the lipidosome is transferred to an endosome recovery way by up-regulating p62, so that the lipidosome is prevented from entering a lysosome degradation way, and the transendocytosis efficiency is remarkably improved.

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 present disclosure relates to methods and compositions useful for measuring the transcytosis of a molecule. In particular, the present disclosure relates to in vitro receptor-dependent transcytosis assays for evaluating the clearance rates of therapeutic antibody molecules and Fc-fusion proteins in humans and animals.

Disclosed is a linear or cyclic peptide having an amino acid sequence represented by the formula (1): XN-X5- X6-X7-X8-X9-X10-X11-X12-X13-X14-X15 (1), or a pharmaceutically acceptable salt thereof. The peptide, when bound to LRP1, can deliver any drug to brain tissues by transcytosis mediated by LRP1.

The invention relates to an insulin-loaded hybrid nano-vesicle as well as a preparation method and application thereof. The hybrid nano-vesicle is obtained by hybridizing a milk-derived exosome and an insulin-loaded liposome. The milk-derived exosome and the liposome are creatively hybridized and used for co-loading and delivering insulin, the hybridized nano-vesicle can survive in a severe environment of gastrointestinal tracts and protect wrapped insulin, in intestinal tracts, the hybridized nano-vesicle interacts with FcRn on intestinal epithelial cells through surface IgG and triggers transendocytosis, and in addition, the exosome and the liposome can be used for co-loading and delivering insulin. The hybridized nano-vesicles have the advantages that a lysosome degradation pathway is avoided, then the hybridized nano-vesicles are effectively accumulated in the liver through portal veins, insulin is released in the liver to regulate blood sugar, and the hybridized nano-vesicles can be used for preparing insulin oral preparations.

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.

The invention belongs to the field of functional nano materials, and particularly relates to pH-responsive nano gel with mechanical property conversion and application of the pH-responsive nano gel. The deformability of the nanogel is measured by using the ratio SD-pH of the diameter Dswoln of the nanogel at a first temperature T1 lower than the critical phase transition temperature of the nanogel to the diameter Dswoln of the nanogel at a second temperature T2 higher than the critical phase transition temperature of the nanogel. The SD-pH1 of the nanogel when the pH1 is 4.5-6 is greater than the SD-pH2 of the nanogel when the pH2 is 6.8-7.4, and the ratio of the SD-pH1 to the SD-pH2 is greater than or equal to 1.6. Compared with a control group, the nanogel disclosed by the invention is proved to have a remarkable pH-responsive mechanical property transformation effect and optimal active transendocytosis efficiency, and has optimal deep penetrating power and anti-tumor effect at a tumor part.

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 invention relates to the fields of molecular medicine and targeted delivery of therapeutic or diagnostic agents to cells outside the vascular system and into the parenchymal tissue of organs within the body. More specifically, the present invention relates to improved TfR-binding moieties capable of crossing the blood brain barrier (BBB) and capable of carrying and releasing cargo specifically targeted to the parenchymal tissue of the brain. The present invention relates to a transcytosis selection method to obtain VNARs against mammalian blood brain barrier (BBB) receptors using phage display libraries as well as against receptors found in other directional cell barrier systems like the gastrointestinal tract and other organs. The VNARs may be used alone or as components in compositions or as conjugates that target the particular receptor transport systems for delivery of therapeutics or diagnostics to the brain (in the case of BBB receptors) or other tissues.

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.

The present invention relates to a transporter peptide capable of binding to a transferrin receptor. The transporter peptide can be covalently or non-covalently conjugated with an effector to form a transporter peptide conjugate, or the transporter peptide and an effector form a recombinant transporter peptide conjugate in a manner that represents a nucleic acid encoding the transporter peptide and the effector. The transporter peptide and the recombinant transporter peptide transport the effector to a target by binding to a transferrin receptor. Binding of the transporter peptide to a transferrin receptor on a cell of a tissue barrier induces transendocytosis of the cell to transport the transporter peptide conjugate through the tissue barrier. The transport peptide can be used as a drug delivery system and can be used for related treatment of central nervous system (CNS) diseases.

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 present disclosure relates to isolated non-naturally occurring delivery constructs comprising a bacterial toxin-derived delivery construct coupled to a biologically active therapeutic cargo; wherein the delivery construct is capable of delivering the biologically active cargo via transcytosis transport across an epithelial cell; and wherein the delivery construct does not comprise a bacterial toxin-derived translocation domain or a bacterial toxin-derived catalytic (cytotoxic) domain.

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.