42 results about "Endosome" patented technology

Provided in the present invention is a nitrogen-containing heterocycle-branched cationic lipid. The structure thereof is as represented by general formula (1), wherein the definition of each symbol is consistent with that described herein. The nitrogen-containing heterocycle-branched cationic lipid has a nitrogen-containing heterocycle as a branched core, an amino acid or an amino acid derivative as a linker arm, and a saturated or unsaturated hydrocarbon group as a tail chain; and has the advantages of low toxicity, low immunogenicity and high biocompatibility. In the new cationic lipid of the present invention, the electropositivity of the nitrogen on the nitrogen-containing heterocycle is delocalized to the whole ring, so that the cationic lipid shows higher transfection efficiency and lower cytotoxicity. The new cationic lipid of the present invention contains one or more biodegradable groups between the nitrogen-containing heterocycle and the hydrophobic tail, and the presence of the degradable groups enables a lipid nanoparticle (LNP) prepared from the cationic lipid to be timely degraded in the endosome, such that the problem in the prior art whereby LNPs prepared from a non-degradable lipid accumulate in the endosome and acidify the endosomal environment, thereby hindering the endosomal escape of a drug molecule (such as a nucleic acid) and thus the drug delivered into a cell not being able to function is solved.

The present invention belongs to the field of drug delivery. Provided is an asymmetric cationic lipid containing a branched piperazine ring and having a structure as shown in general formula (1), wherein the definition of each symbol is consistent with that described in the text. In the cationic lipid of the present invention, a degradable group is introduced at an appropriate position, and the presence of the degradable group makes an LNP-pharmaceutical composition prepared therefrom be degraded at an appropriate time in vivo and have a low cytotoxicity, which solves the problems in the prior art that an LNP-pharmaceutical composition prepared from a non-degradable lipid can accumulate in endosomes and acidify the endosomal environment, so that the endosomal escape of a drug (e.g., mRNA) is hindered, and the drug delivered into cells cannot fully function. In the cationic lipid of the present invention, a heterofunctionalized small molecule containing a piperazine ring is used as a raw material. The preparation process is simple and convenient, has a lower cost, and is more environmentally friendly. The LNP-mRNA composition prepared therefrom has the advantages of low toxicity, high biocompatibility, high cell transfection, etc.

The invention provides a carrier material for supporting a protein drug. The carrier material comprises an inner core, a calcium carbonate coating layer coating the inner core and a polyethylene glycol-polyglutamic acid diblock copolymer chain segment anchored on the coating layer. The intracellular protein delivery carrier provided by the invention can effectively support various metal ions and protein drugs with the Fenton / Fenton-like reaction catalysis effect, and after the intracellular protein delivery carrier is endocytosed by cells, the protein drugs, calcium ions and the metal ions with the Fenton / Fenton-like reaction catalysis effect are released; metal ions can catalyze hydrogen peroxide in the endosome / lysosome to generate hydroxyl radicals with high oxidation activity, lipid molecules are oxidized, and a lysosome membrane is destroyed; the released calcium ions can cause mitochondrial calcium overload, improve the level of hydrogen peroxide in cells, promote generation of hydroxyl radicals in endosome / lysosome and damage of membranes of the hydroxyl radicals, induce efficient rupture of the endosome / lysosome and deliver protein drugs into cytoplasm so as to play the functions of the protein drugs.

The present invention belongs to the field of drug delivery. Provided is an asymmetric cationic lipid containing multiple tertiary amines, of which the structure is shown as a general formula (1), wherein the definition of each symbol is consistent with that in the description. In the present invention, a degradable group is introduced into a proper position of the cationic lipid, and the presence of the degradable group enables an LNP-drug composition prepared from the cationic lipid to be degradable in endosomes at a proper time and to have small cytotoxicity, thereby solving the problem that in the prior art, LNP-drug compositions prepared from non-degradable lipids will accumulate in endosomes and acidify the endosomal environment, which hinders the endosomal escape of drugs (such as mRNAs) and causes that the drugs delivered into cells fail to sufficiently exert the therapeutic effects. The cationic lipid in the present invention uses a heterofunctionalized piperazine-containing small molecule as a raw material, involves a simple preparation process and a lower cost, and is more green and environmentally-friendly. An LNP-mRNA composition prepared from the cationic lipid has the advantages of low toxicity, high biocompatibility, high cell transfection, etc.

The invention discloses a cationic lipid capable of being ionized and application of the cationic lipid. According to the ionizable cationic grease, adsorption is formed by the structural design of the head and biological drugs such as nucleic acid, and the encapsulation efficiency is improved; the tail part adopts a saturated or unsaturated aliphatic chain to form a branch structure, and the head part and the tail part are connected by an ester bond, so that in-vivo degradation is facilitated to reduce toxicity; due to the design of the unsaturated aliphatic chain, the membrane flowability during release of the endosome is improved, and the release efficiency of the biological medicine is effectively improved; moreover, the ionizable cationic grease provided by the invention has good temperature stability, not only can the product quality be improved, but also the accessibility of the product is expanded. In a word, the ionizable cationic lipid disclosed by the invention has the advantages of high encapsulation efficiency, low toxicity, high endosome release efficiency, good temperature stability and the like, the quality and the treatment effect of lipid nanoparticle drugs can be improved, and a new scheme and a new choice are provided for biological drug delivery.

Described herein is a DNA nanotechnology-based platform for the delivery of nucleic acids into cells. The delivery platform relies on compacting cargo mRNA and / or ssDNA into single folded nanostructures that act as the primary structural vehicle material for nanoparticle delivery to cells. The described compositions and methods provide an alternative to packaging mRNA or ssDNA into lipid nanoparticle vehicles, which have complex formulation properties. Also described herein are strategies for protecting mRNA and / or ssDNA cargo and helping these nucleic acid molecules escape the endosome into the cytoplasm using a cationic peptide-PEG coating.

The invention provides an amino acid skeleton ionizable lipid as well as a preparation method and application thereof, the amino acid skeleton ionizable lipid is modified by taking amino acid as a core, has more ester groups and peptide bonds, and can be quickly hydrolyzed by enzyme after RNA is effectively released in vivo; the transfection body is provided with four tail structures, the cross sectional area of the lipid tail can be increased, drugs such as RNA are helped to escape from an endosome, and then the transfection effect is enhanced; the charge capable of ionizing the lipid is electrically neutral under physiological conditions, so that the cytotoxicity caused by excessive positive charges is reduced, the stability of the lipid nanoparticles is further improved, the cycle time of the loaded nucleic acid medicine is prolonged, and the pharmacokinetic characteristics are improved. The LNP prepared from the ionizable lipid, auxiliary phospholipid, cholesterol and PEG lipid provided by the invention has more excellent nucleic acid carrier performance, and can effectively deliver nucleic acid drugs such as siRNA, mRNA, pDNA and the like into cells to play a role.

Described herein are compositions and methods for selective depletion of target molecules using a recyclable CDP-receptor-binding mediated complex to elicit endocytosis and cellular degradation of the target. Exemplary compositions containing a peptide, such as a CDP peptide, that bind a transferrin receptor can be linked to a peptide that binds a target molecule. Such compositions can be used to selectively recruit the target molecule to endosomes via transferrin receptor-mediated endocytosis of the composition and the bound target molecule. Once inside the endosome, the acidic pH can lead to release of the target molecule from the composition due to pH-dependent binding of the composition for the target molecule, and the transferrin receptor portion is recycled back to the cell surface for “reloading”. The target molecule can then be trafficked into lysosomes wherein it is degraded.

The invention discloses a protein degradation agent based on an endosome-phagosome connection assembly and application of the protein degradation agent, and belongs to the technical field of protein degradation and nano biological medicine. According to the endosome-phagosome connecting assembly, by inserting an endosome membrane and marking endosome degradation protein, a special degradation technology strategy enables the endosome-phagosome connecting assembly to expand an autophagy degradation target spectrum in traditional cytoplasm to various target proteins outside a cell membrane / cell, and the current development situation of a current targeted protein degradation tool can be thoroughly changed possibly. The preparation method is simple, raw materials are easy to obtain, the method is suitable for research and application transformation, the traditional degradation thought is broken through by utilizing an endosome-phagosome connecting assembly, most target proteins can be degraded through an endosome-autophagy-lysosome approach, the design is novel, the application range is wide, the cost is low, the efficiency is high, a very good degradation effect can be achieved, and the method is suitable for popularization and application. The method can be applied to the field of various complex diseases and has huge potential development and transformation prospects.

Cells engineered with custom-designed receptors can efficiently transfer membrane-associated macromolecules into recipient cells upon contact, which can be freed from endosomes in recipient cells and optionally functionalized in a trogocytosis-like manner via pH-responsive membrane fusion. A variety of configurations, payload proteins and donor and recipient cells are possible with the methods descried herein.

The invention relates to the technical field of biological medicine, in particular to application of TOMM40 in preparation of a medicine for treating breast cancer. The invention finds that TOMM40 overexpression promotes the increase of the content of DDR1 in lipid rafts instead of early-stage endosomes; a co-immunoprecipitation experiment shows that TOMM40 and PHB2 interact with DDR1 and SRC, and DDR1 and SRC also interact with each other; the combination of TOMM40 and PHB2 can promote phosphorylation activation of DDR1, the activated DDR1 further promotes activation of SRC interacting with the activated DDR1, activation of a downstream MAPK signal channel is caused, and meanwhile, the activated DDR1 can directly activate an AKT / mTOR channel; furthermore, the invention finds that the killing ability of tumor cells can be obviously enhanced by further utilizing Flurizoline and DDR1-IN-1 to treat the breast cancer cells, and the method is expected to become a new strategy for breast cancer treatment.

The present disclosure features compositions and methods for the treatment of actinomycete (e.g., Corynebacteriales) infections caused by mycobacterial cells residing within a host cell (e.g., a mammalian cell, such as an immune cell, e.g., a macrophage or dendritic cell). The compositions and methods involve delivering a mixture of lytic enzymes to specifically target the cell envelope of a group of related bacterial species within intracellular compartments (endosomes, phagosomes, lysosomes, or cytosol) where bacteria of the aforementioned orders infect, grow, hide, and rest.

The invention provides esterase-responsive ionizable cationic lipid and application thereof in improving the delivery efficiency of nucleic acid drugs. The lipid provided by the invention is electrically neutral under physiological conditions, has excellent biological safety, is positively charged in a meta-acidic endosome / lysosome environment, promotes escape of a carrier and a nucleic acid drug through a proton sponge effect, is hydrolyzed under the action of intracellular esterase and then is converted into an electrically neutral or electronegative compound, and is used for preparing a drug carrier. Dissociation with nucleic acid drugs with negative charges is completed, and the biological functions of the nucleic acid drugs are played to the maximum extent. Therefore, the lipid provided by the invention can be used for efficient delivery of in-vivo and in-vitro nucleic acid drugs, and has a wide application prospect.

The invention belongs to the field of drug delivery, and provides a piperazine ring-containing branched asymmetric cationic lipid, the structure is shown as a general formula (1), and the definition of each symbol is consistent with that described in the specification. A degradable group is introduced to a proper position of the cationic lipid, and the existence of the degradable group enables the LNP-pharmaceutical composition prepared from the cationic lipid to be timely degraded in vivo and small in cytotoxicity, so that the problems that in the prior art, the LNP-pharmaceutical composition prepared from non-degradable lipid can be stored in the vivo, the endosome environment is acidified, and the toxicity of the LNP-pharmaceutical composition is reduced are solved. The endosome escape of the medicine (such as mRNA) is blocked, and the medicine delivered into the cells cannot fully play a role. The cationic lipid provided by the invention adopts the heterofunctionalization piperazine ring-containing small molecules as raw materials, the preparation process is simple and convenient, the cost is lower, the cationic lipid is greener and more environment-friendly, and the LNP-mRNA composition prepared from the cationic lipid has the advantages of low toxicity, high biocompatibility, high cell transfection and the like.

Described herein are block copolymers, and methods of making and utilizing such copolymers. The described block copolymers are disruptive of a cellular membrane, including an extracellular membrane, an intracellular membrane, a vesicle, an organelle, an endosome, a liposome, or a red blood cell. Preferably, in certain instances, the block copolymer disrupts the membrane and enters the intracellular environment. In specific examples, the block copolymer is endosomolytic and capable of delivering an oligonucleotide (e.g., an mRNA) to a cell. Compositions comprising a block copolymer and an oligonucleotide (e.g., an mRNA) are also disclosed.

Nanoparticle compositions including one or more active agents, and strategies for enhanced delivery of the active agents, are provided. In preferred embodiments, the nanoparticles are composed of block copolymers of one or more hydrophobic polymers that form the core, and a hyperbranched polymer that forms a shell or corona. In some embodiments, the particles include an acid-sensitive, poly(amine-co-ester) (PACE) that can increase release of the active agent in acidic environments, for example within endosomes. The compositions can include one or more targeting moieties. Preferred targeting moieties include adenosine agonists and pHLIP which can enhance delivery to tumor cells. Methods of using the compositions to treat diseases and disorders of the central nervous system, for example, brain cancers such as glioma, are also provided.

The invention provides an anti-serum albumin single-domain antibody and application thereof. Specifically, the single-domain antibody provided by the invention can specifically target serum albumin of human, monkey and mouse, does not influence the combination of HSA and FcRn, and can still maintain the combination activity in an endosome acidification environment. The single-domain antibody can be used for prolonging the half-life period of a medicine.

Guanosine-targeted nanocarriers for encapsulating an active agent and delivering it to extracellular guanosine and DNA are provided. The nanocarriers, for example, polymeric particles, liposomes, and multilamellar vesicles have targeting moiety that targets guanosine attached, linked, or conjugated thereto. The targeting moiety that targets guanosine is typically an antibody, or variant, fragment, or fusion protein derived therefrom that binds to guanosine. The targeting moiety can be a circulating autoantibody that binds guanosine such as those commonly found in patients with SLE. Cytoplasmic delivery vehicles that do not localize into endosomes or lysosomes are also provided. The delivery agent is typically an antibody, or variant, fragment, or fusion protein derived therefrom that binds to guanosine. In some embodiments, the targeting moiety or delivery agent is antibody 4H2 or a variant, fragment, or fusion protein derived therefrom. Pharmaceutical compositions, methods of use, and dosage regimens are also provided.

The invention provides a multi-antigen loaded, active lymph node targeting and ultrasonic response senescence nano vaccine based on artificial vesicles as well as a preparation method and application of the senescence nano vaccine, and belongs to the technical field of vaccines. The invention relates to a modular two-component senescence nano vaccine based on click chemistry, which comprises DSPE-PEG-DBCO and azide functionalized senescence cell-derived artificial nano vesicles (N3-SCAVH / R) co-carrying a sound sensitive agent and a TLR7 / 8 receptor agonist, and the N3-SCAVH / R carries abundant SAAs. According to the vaccine, a DBCO target is pre-marked on a lymph node through subcutaneous injection of DSPE-PEG-DBCO, and N3-SCAVH / R which is continuously delivered can be anchored to the lymph node through a click chemical reaction; and then ultrasonically irradiating the lymph node to activate the sound-sensitive agent to assist the antigen in escaping from the endosome and enhance DC cross presentation. The nano vaccine can effectively remove plaque senescence cells and delay disease progression, and is good in safety.

The invention lies in the field of delivery of nucleic acids into a cell. In particular, disclosed herein is a nucleic acid that is polyplexed with a polymeric scaffold, which is provided in combination with an endosomal escape-enhancing saponin that is covalently bound either to the polymeric scaffold or to a cell targeting ligand by a linker configured to release the saponin from the scaffold under conditions present in an endosome. The disclosed herein compositions and methods may be exploited in the treatment of various diseases and / or conditions by systemic delivery.

The invention relates to the technical field of microneedle patches, in particular to a tremella polysaccharide microneedle patch carrying magnetic endosomes and a preparation method and application of the tremella polysaccharide microneedle patch, the microneedle patch comprises a microneedle body and a base backing layer, the needle body takes a high polymer material and tremella polysaccharide as main components and carries the magnetic endosomes, and the magnetic endosomes are arranged on the substrate backing layer. The needle body is attached to the surface of the substrate backing layer and can be completely separated when dissolved. According to the tremella polysaccharide microneedle patch carrying the magnetic endosome, the needle body has enough mechanical strength to pierce a skin cuticle to deliver effective components to a corium layer, and the back lining layer is low in dissolution speed and convenient to disassemble completely. According to the tremella polysaccharide microneedle patch carrying the magnetic endosome, the tremella polysaccharide serves as natural polysaccharide, preparation is easy, components are safe, and the tremella polysaccharide microneedle patch has anti-inflammatory activity for adjuvant therapy. The tremella polysaccharide microneedle patch carrying the magnetic endosome contains the magnetic endosome, has good biocompatibility, and plays a dual role in resisting oxidation and promoting blood vessels.

The present invention relates to a lipid complex for the nasal delivery of nucleic acid molecules comprising ionized lipids, structural lipids, cholesterol, and lysoPC as active ingredients. The lipid complex of the present invention can be usefully utilized for the local and intensive delivery of therapeutic nucleic acid molecules specifically to nasal epithelial cells by efficiently being compatible with the microenvironment unique to nasal tissue, easily penetrating the mucus layer barrier, and effectively escaping endosomes. Furthermore, the lipid complex of the present invention can be applied as a combination administration platform that induces a synergistic therapeutic effect by two pharmacological components by loading additional drugs into internal compartments of the lipid complex, as well as improving dispersibility by loading the target nucleic acid molecule externally.

The invention provides a nitrogen-containing heterocyclic ring branched cationic lipid, the structure is shown as a general formula (1), and the definition of each symbol is consistent with that described in the specification. The nitrogen-containing heterocyclic ring branched cationic lipid takes a nitrogen-containing heterocyclic ring as a branched core, amino acid or an amino acid derivative as a connecting arm and saturated or unsaturated alkyl as a tail chain, and has the advantages of low toxicity, low immunogenicity and high biocompatibility. The positive electricity of nitrogen on the nitrogen-containing heterocyclic ring in the novel cationic lipid is delocalized to the whole ring, so that the cationic lipid shows higher transfection efficiency and lower cytotoxicity. One or more biodegradable groups are contained between the nitrogen-containing heterocyclic ring and the hydrophobic tail part of the novel cationic lipid, and due to the existence of the biodegradable groups, the prepared lipid nano-particles LNP can be timely degraded in an endosome, so that the problems that in the prior art, the LNP prepared from non-degradable lipid can be stored in the endosome, the endosome environment is acidified, and the lipid nano-particles LNP cannot be degraded are solved. Endosome escape of drug molecules (such as nucleic acid) is blocked, and the problem that drugs delivered into cells cannot play a role is solved.

The invention discloses a signal peptide, a polypeptide-nucleic acid conjugate and a synthesis method and application thereof, and belongs to the technical field of molecular biology. The signal peptide is one of NPXY, YXXphi, [DE] XXX [LI] and DXXLL; wherein X is any amino acid, phi is any large-volume hydrophobic side chain amino acid, [DE] represents one of D and E, and [LI] represents one of L and I. In addition, the invention also provides application of the signal peptide in preparation of a compound capable of penetrating through a cell membrane or a body tissue barrier by being connected with a nucleic acid fragment. The invention also provides a polypeptide-nucleic acid conjugate which is a conjugate of any one of the signal peptides and siRNA (small interfering Ribonucleic Acid). After several signal peptides provided by the invention are coupled with the siRNA, the siRNA can be promoted to escape into cytoplasm from an endosome, so that the siRNA drug transfection efficiency is improved.

The present invention relates to: an antibody constant region in which an endosome escape motif having activity under the slightly acidic conditions of an endosome is introduced into the constant region of an antibody, thereby imparting the ability of an immunoglobulin G (IgG) antibody to actively translocate from outside a cell to the cytoplasm; an antibody comprising the same; a method of producing the same; and uses thereof. More particularly, the present invention provides a highly efficient cytosol penetrating antibody (cytotransmab) having improved endosome escape ability by introducing an endosome escape motif into a CH3 domain, which is a heavy chain constant region of an IgG antibody, and / or a CL domain, which is a light chain constant region of an IgG antibody, and relates to a pharmaceutical composition for the treatment, prevention, or diagnosis of cancer comprising the same.

Described herein are compositions and methods for selective depletion of EGFR target molecules using a recyclable receptor-binding mediated complex to elicit uptake or endocytosis and cellular degradation of the target molecule. Exemplary compositions containing a peptide, such as a CDP peptide that binds a transferrin receptor, can be linked to a peptide that binds an EGFR target molecule. Such compositions can be used to selectively deplete EGFR from the cell surface or selectively recruit EGFR to endosomes via transferrin receptor-mediated endocytosis of the composition and the bound target molecule. Once inside the endosome, the acidic pH can lead to release of the EGFR from the composition due to pH-dependent binding of the composition for the target molecule, and the transferrin receptor portion is recycled back to the cell surface for "reloading". The EGFR can then be trafficked into lysosomes wherein it is degraded.

The present application relates to pH-sensitive polymersomes. The polymersomes are capable of degradation at endosomes' mild acidic pH into resorbable materials, which also allows avoiding liposome premature degradation of the payload once internalised inside the cells. The polymersomes can thus be used in methods for the treatment or prevention of diseases.

This application relates to the field of pharmaceutical technology, and particularly to a polypeptide conjugate drug, its preparation method and application. The polypeptide conjugate drug of this application includes at least one compound of Formula I-1 and Formula I-2 in the specification or a pharmaceutically acceptable salt thereof. Based on the polypeptide conjugate drug with a unique molecular structure provided by this application, it can bind to tumor cells through the integrin receptor-binding peptide via blood circulation or remain in the tumor tissue after intratumoral injection, activate the TLR7 and TLR8 receptors in the tumor tissue, and the level of inflammatory factors in the blood after injection is further reduced compared with the payload molecule 78A1, and the safety is significantly improved. Therefore, the polypeptide conjugate drug of this application has tumor tissue targeting, can activate the TLR7 and TLR8 receptors on the cytoplasmic endosomes in the tumor tissue, exert an anti-tumor immune stimulation effect, and at the same time has lower blood and non-specific organ immune toxicity.

The present application belongs to the field of drug delivery. Provided is a new cationic lipid with a nitrogen-containing heterocyclic head group, which has a structure as shown in general formula (1), wherein the definition of each symbol is consistent with that described in the text. The cationic lipid of the present application contains a nitrogen-containing heterocyclic head group, a linker arm, a degradable linkage group, and multiple hydrophobic hydrocarbon tail chains, wherein the multiple hydrophobic hydrocarbon tail chains increase the cross-section area of the lipid tail region, thereby facilitating the formation of a cone-shaped structure. The structure can effectively promote the fusion and disruption of LNPs with an endosome membrane, thereby promoting the escape of drugs such as nucleic acids from an endosome into the cytoplasm to exert the functions. The degradable linkage group enables an LNP-pharmaceutical composition prepared therefrom to be degraded in the endosome in a timely manner, thereby promoting the endosomal escape of LNPs. The cationic lipid of the present application can also have an amino acid or a derivative thereof as a linker arm, wherein the raw materials are simple and readily obtainable. An LNP-mRNA composition prepared therefrom has the advantages of low toxicity, high biocompatibility, a high cell transfection efficiency, etc.

The invention relates to application of endosomal membrane labeled nanoparticles in targeted degradation of extracellular proteins, and belongs to the technical field of nano biological medicines. The endosomal membrane labeled nanoparticle provided by the invention takes a high-molecular organic material as a carrier, the surface of the endosomal membrane labeled nanoparticle is modified with extracellular protein targeting peptide and endosomal anchoring phagosome targeting peptide consisting of endosomal membrane insertion polypeptide and phagosome targeting peptide, and the constructed nanoparticle can specifically recognize extracellular target protein, so that the endosomal membrane labeled nanoparticle has the advantages of high specificity and high specificity. According to the present invention, the target protein enters the endosome through the endocytosis mechanism of the target protein, the membrane insertion polypeptide is inserted into the endosome lipid membrane, the phagosome targeting peptide at the terminal is anchored on the endosome surface, the cytoplasm phagosome is recruited to perform phagocytosis, and finally the target protein is degraded through the endosome-phagosome-lysosome approach; the preparation method of the endosomal membrane labeled nanoparticles is simple and convenient, and the endosomal membrane labeled nanoparticles have good biological safety and efficient delivery capacity and have huge potential in the fields of biomedical research and clinical treatment.