32 results about "Lipotropic" patented technology

The invention relates to application of a topoisomerase inhibitor and a conjugate thereof. Specifically, the inventor provides a class of camptothecin derivatives, linker conjugates and antibody-drug conjugates with novel structures, and the camptothecin derivatives, linker conjugates and antibody-drug conjugates have excellent anti-tumor activity and good lipophilicity. In-vitro and in-vivo experiments show that the drug conjugate containing the camptothecin derivative disclosed by the invention has an improved anti-tumor curative effect and high safety, and has an application prospect in the field of cancer treatment.

Double-stranded ribonucleic acid (dsRNAi) agents that target exon 1 of the huntingtin (HTT) gene are provided.SOLUTION: A double-stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of huntingtin (HTT), the agent comprising a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from a certain specific nucleotide sequence, and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from another certain specific nucleotide sequence, provided are dsRNA agents wherein one or more lipophilic moieties are conjugated to one or more internal positions on at least one of the sense or antisense strands.SELECTED DRAWING: None

The present application provides an oligonucleotide conjugate and a pharmaceutical composition comprising the oligonucleotide conjugate. The oligonucleotide conjugate comprises a functional double-stranded oligonucleotide, a lipophilic moiety, and a peptide chain, wherein the functional double-stranded oligonucleotide, the lipophilic moiety, and the peptide chain are connected by means of linkers. The oligonucleotide conjugate and the pharmaceutical composition provided in the present application can effectively regulate the expression level of a target gene in vivo or in vitro, and have excellent tissue specificity. Therefore, the oligonucleotide conjugate and the pharmaceutical composition can effectively treat and / or prevent disease symptoms related to the level of mRNA expressed by the target gene. The present application holds promise.

The present disclosure provides a double-stranded siRNA with lipophilic modification. The modified siRNA molecules exhibit excellent in vivo distribution and delivery efficiency via intrathecal injection, intradermal injection, or other administration routes. The molecules effectively knock down target gene expression while maintaining good tolerability and safety. The present disclosure further provides a preparation method of siRNA with lipophilical modification, a pharmaceutical composition, and application of the same in the preparation of a medicament for treating a TNF-α-mediated disease or disorder.

One aspect of the present invention relates to a double-stranded RNA (dsRNA) agent for modulating the expression of a target gene in the central nervous system (CNS), comprising: an antisense strand complementary to the target gene in the CNS; a sense strand complementary to the antisense strand; and one or more saturated or unsaturated C RNAs conjugated onto at least one strand via a linker or carrier as appropriate. 22 The present invention relates to a dsRNA agent comprising one or more lipophilic moieties containing a hydrocarbon chain. Another aspect of the present invention relates to a pharmaceutical composition comprising a dsRNA agent. Another aspect of the present invention relates to a method for modulating the expression of a target gene in CNS cell genes and a method for treating or preventing CNS damage in a subject, comprising administering a therapeutically effective amount of a dsRNA agent to cells or a subject.

This invention provides RNAi agents, such as dsRNA agents, that target the G protein-coupled receptor 75 (GPR75) gene. It also provides methods for using such RNAi agents to inhibit the expression of the GPR75 gene in a subject, and methods for treating or preventing GPR75-related diseases such as weight disorders, e.g., obesity. [Solution] A double-stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of the GPR75 gene in cells is provided, comprising a sense strand and an antisense strand that form a double-stranded region, wherein the antisense strand comprises a region complementary to a portion of the mRNA encoding the GPR75 gene, each strand is independently 14 to 30 nucleotides long, and the sense strand or antisense strand is conjugated to one or more lipophilic portions.

The invention provides novel compounds of formula (I), stereoisomers and pharmaceutically acceptable salts thereof: (wherein: Q is a lipophilic, zinc chelating moiety which is selective for Zn2+ ions; L1 is a covalent bond or a C1-6 alkylene chain in which one or more -CH2- groups of the alkylene chain are optionally replaced by a group independently selected from -CO- and -NR4- (where R4 is H or C1-3 alkyl); Y is selected from the following groups: (II) and (III) (where each R5 is independently H or C1-3 alkyl; and R6 is H or C1-3 alkyl); L2 is a covalent bond or a C1-6 alkylene chain in which one or more -CH2- groups of the alkylene chain are optionally replaced by a group independently selected from -CO- and -NR7- (where R7 is H or C1-3 alkyl); R is -OH, -O-C1-6 alkyl, -O-(CH2)p-O-CO-C1-6 alkyl (where p is an integer of 1 or 2) or -O-CH(CH3)-O- CO-C1-6 alkyl; each R1 is independently selected from halogen and C1-3 alkyl; each R2 is independently selected from halogen and C1-3 alkyl; R3 is H or C1-3 alkyl; n is an integer of 0 or 1; and m is an integer of 0 or 1). The compounds according to the invention are selective zinc chelators that find use as adjuvants in the treatment of bacterial infections and / or bacterial biofilms that harbour such infections. For use in such treatment, the compounds are used in combination with an antibacterial agent, for example a β-lactam antibiotic. The invention further provides a triple combination therapy for use in the treatment of bacterial infections and / or bacterial biofilms which comprises co-administration of the compounds to a subject in combination with a β-lactam antibiotic and a serine β-lactamase inhibitor.

The invention discloses a lipophilic modified nucleic acid medicine composition and application thereof, the lipophilic modification is saturated or unsaturated C4-C30 alkyl, the composition comprises an absorption enhancer, and the method is that the lipophilic modified nucleic acid medicine is delivered to the brain through the nasal mucosa. Nucleic acid drugs are transmitted into the olfactory bulb region through a neural pathway, namely, cross-olfactory mucosa, bypass BBB and directly enter the brain, the drug concentration content of the olfactory bulb is far higher than that of other tissues of the brain, and the tissues except the olfactory bulb are uniformly distributed, so that the olfactory bulb can be used as a drug reservoir and gradually and slowly spread to the other tissues of the brain; the long-time drug effect can be maintained by one-time drug administration, so that the drug administration frequency can be reduced. Compared with intrathecal injection, by adopting the composition disclosed by the invention for nasal administration and using 1 / 2 of intrathecal administration dosage, the same intrathecal steady-state distribution as intrathecal distribution can be achieved, so that the method disclosed by the invention is safer, noninvasive and efficient.

This invention discloses a lipopeptide HIV membrane fusion inhibitor and its pharmaceutical use. The lipopeptide of this invention is of formula I: X1-EMTWEEWEK KVEELEKKIEELLK-X2-X3-X4-X5; or formula II: X1-ELTWEEWEKKVEELEKKIEELLK-X6-X7-X4-X5; wherein, X1 is an amino-terminal protecting group; X2 is a polypeptide sequence (EAAAK)n, A[(EAAAK)n]A, or (EP)n, where n represents the number of repetitions; X3 is Lys, Cys, Dap, Orn, Dab, Dah, or absent; X4 is a lipophilic compound group used to modify the C-terminus; X5 is a carboxyl-terminal protecting group; X6 is a polypeptide sequence KAEEQQKKNE; and X7 is Lys, Cys, Dap, Orn, Dab, or Dah. The lipopeptide of this invention has higher antiviral activity.

The present disclosure relates to oligonucleotides comprising lipophilic monomers and their use in non-hepatic delivery. Specifically, the present disclosure relates to an oligonucleotide comprising an antisense strand complementary to a target mRNA, a sense strand complementary to the antisense strand, and one or more nucleotides represented by Formula (I-1) or (I-2). The disclosure also relates to a pharmaceutical composition comprising the oligonucleotide, and a medical use of the oligonucleotide and / or the pharmaceutical composition.

Lanthanide complexing molecules having the following structure:wherein: R1, R2, R4, and R5 are independently selected from hydrogen atom, alkyl groups containing 1-3 carbon atoms, and hydrophilic groups containing at least one oxygen atom; R3 and R6 are independently selected from hydrogen atom, alkyl groups containing 1-3 carbon atoms, and hydrophilic groups containing at least one oxygen atom; and Ra and Rb are independently selected from hydrogen atom, methyl group, halogen atoms, and hydrophilic groups containing at least one oxygen atom; wherein at least two of R1, R2, R3, R4, R5, R6, Ra, and Rb are said hydrophilic groups. Also described is a method of separating adjacent lanthanides by use of a two-phase extractant system that includes (i) an acidic aqueous solution containing the lanthanide complexing molecule (1) along with a mixture of at least two lanthanides, and (ii) an aqueous-insoluble hydrophobic solution containing a lipophilic lanthanide extractant compound.

The invention discloses an orange fluorescent silicon nanodot, a preparation method thereof and an application of the orange fluorescent silicon nanodot in mitochondrial imaging in living cells, the method comprises the following steps: S1, dissolving tetramethyl rhodamine methyl ester in ultrapure water, then adding N-(2-aminoethyl)-3-aminopropyltrimethoxysilane, uniformly stirring, and carrying out hydrothermal reaction on the obtained mixture; and S2, cooling after the reaction is finished, purifying the product by using a chromatographic column, eluting by using an eluent, collecting the eluent, and drying to obtain the orange fluorescent silicon nanodot. The silicon nanodot provided by the invention has the advantages of good light stability, high quantum yield and the like, and can be successfully applied to positioning imaging of mitochondria in living cells; compared with common blue-green fluorescence, orange fluorescence has better tissue penetrating ability and background interference resistance; the O-SiNDs prepared by the invention also has the property similar to that of lipophilic cations, and can realize high-specificity targeted marking on mitochondria of living cells.

Preparation of cannabinoid formulations containing: Δ9-tetrahydrocannabinol (Δ9-THC), Δ8-tetrahydrocannabinol (Δ8-THC), Δ9-tetrahydrocannabinolic acid (THCa), cannabidiol (CBD), cannabidiolic acid (CBDa), cannabigerol (CBG), cannabichromene (CBC) and cannabinol (CBN), either alone or in combinations henceforth known as cannabis, have been created using an emulsification process to encapsulate cannabinoids. The aqueous-based method involves micellular encapsulation of cannabinoids, a method that has been used to increase the bioavailability of poorly permeable, lipophilic drugs. The present invention demonstrates the viability of transdermal delivery with gels and patches for consistent and sustained cannabinoid dosing.

The invention relates to the field of pharmaceutical preparations and pharmaceutical chemistry, belongs to the technical field of oral delivery of antitumor drugs, and particularly relates to an abiraterone lipophilic prodrug and application thereof. The prodrug meets the following general formula: AB-O-C (= O)-(CH2) m-S-S-(CH2) m-C (= O)-O-R, the prodrug significantly improves the fat solubility and intestinal absorption capacity of abiraterone, can be absorbed through a chylomicron-mediated lymph transport pathway, and releases a parent drug in a tumor cell high-reducibility environment. The SNEDDS preparation containing the prodrug can form a particle size of 1t in vivo; the O / W type nano emulsion droplet with the size of 100 nm can significantly improve the oral bioavailability of abiraterone and inhibit the growth of prostatic cancer tumors, and has a good application prospect.

The application discloses a two-photon fluorescent probe and uses the same for tumor microenvironment monitoring. The application opens the two-photon fluorescent characteristics of the material by responding to the overexpression of SO2 and H2O2 at the tumor site in stages, monitors and indicates the changes of cell oxidative stress and homeostasis balance, and is further used for early diagnosis of diseases caused by internal environment homeostasis imbalance. The application regulates the cancer cell uptake capacity of the molecule by introducing suitable lipophilic and hydrophilic groups, increases the recognition site of biological thiols by introducing conjugated olefin bonds, and further realizes the step-by-step recognition of endogenous signal molecules by using the easiness of substitution reaction, enhances the fidelity of the signal, and is expected to realize the in-situ activated two-photon fluorescence, early and accurate diagnosis of a series of diseases such as cardiovascular diseases, Alzheimer's disease and the like induced by internal environment homeostasis imbalance.

The application belongs to the technical field of biological diagnosis, and relates to a subcellular organelle active targeting imaging probe and a preparation method thereof. The subcellular organelle active targeting imaging probe of the application is formed into nanoparticles (NPs) by coupling a fluorescent imaging probe with a special sequence of bombesin peptide and a derivative thereof; on one hand, the NPs can be surface-functionalized with lipophilic cations related to the NPs; on the other hand, the NPs can be passively targeted to tumor sites, and have high permeability and retention effect for solid tumors.

The invention discloses a floxuridine phosphamide ester prodrug and application thereof in preparation of a medicine for treating liver cancer, and belongs to the technical field of medicine. The invention designs and synthesizes a series of 5-FdU phosphamide ester derivatives which are subjected to specific esterification modification at 3 '-site. Different aromatic acyl, fatty acyl or amino acid residues are introduced to the 3 '-site, so that the lipophilicity of molecules is further adjusted to enhance liver tissue distribution, and the enrichment and activation process of the medicine in the liver is optimized by utilizing the steric hindrance or metabolic lysis characteristic of the 3'-site. Experiments prove that the series of compounds show excellent anti-hepatoma cell proliferation activity and good pharmacokinetic characteristics, and a new choice is provided for clinical treatment of liver cancer.

This invention presents a method for co-encapsulating and targeting curcumin and anthocyanins based on functionalized probiotic extracellular vesicles, achieving highly efficient oral targeted delivery of curcumin and anthocyanins. This method uses probiotic-derived extracellular vesicles as the basic carrier, both of which exhibit good biocompatibility, digestive stability, and loading capacity. Secondly, to enhance carrier function, this invention synthesizes EGCp with an amphiphilic structure and embeds it into the vesicle membrane through self-assembly, thereby endowing the carrier EGC with inherent antioxidant and anti-inflammatory activities. Furthermore, to endow the carrier system with highly efficient targeting capability against inflammatory cells, the surface of the engineered vesicles is modified with octenyl succinic anhydride grafted with hyaluronic acid to obtain a functional formulation capable of co-delivering curcumin and anthocyanins. EGCp and OSA-HA work synergistically to construct a co-delivery system that can simultaneously and efficiently load lipophilic curcumin and hydrophilic anthocyanins and actively target inflammatory sites.

The application provides an application of auro-thio-pan in preparation of a drug for treating a USP6 gene rearrangement and abnormal activation disease, and the auro-thio-pan is a lipophilic gold-based compound. Researches of the application show that in addition to the USP6 gene rearrangement disease, tumors such as osteosarcoma, RUNX1 gene rearrangement and CBFbeta gene rearrangement leukemia, synovial sarcoma and the like also have abnormal activation of USP6, and are clinical application scenarios of USP6 inhibitors. It is further found that the compound auro-thio-pan can effectively combine with a catalytic domain of USP6 and inhibit the deubiquitination enzyme activity of USP6, and inhibit the growth of RUNX1 rearrangement tumors at the cell and animal levels. The application opens up a new direction for the development of a drug for treating the USP6 gene rearrangement and abnormal activation tumor and the like, and expands the application range of auro-thio-pan in the treatment of clinical diseases, and provides a possibility for improving the prognosis and survival of corresponding clinical disease patients.

The invention discloses design and synthesis of a novel lipophilic Fe (III) complex. The chemical formula of the complex is [Fe-5NO2-8HQ]. The Fe (III) complex shows strong in-vitro anticancer activity on various human tumor cells (including cis-platinum sensitive type and cis-platinum resistant type ovarian cancer cells); particularly, the compound still has a remarkable growth inhibition effect on platinum-resistant tumor cells, and shows the advantage of overcoming the drug resistance of cis-platinum. In addition, the [Fe-5NO2-8HQ] shows effective antibacterial activity on different strains of gram-positive pathogenic bacteria such as staphylococcus aureus and the like. Compared with a free ligand, the complex has the advantages that the antibacterial effect is greatly improved, and the complex is also applicable to drug-resistant strains. The preparation method of the complex is simple and efficient, and the product is stable and easy to separate. The complex can be used as an active pharmaceutical ingredient for preparing anti-cancer drugs and antibacterial drugs, and has potential application value in the aspects of anti-tumor treatment (especially aiming at drug-resistant tumors) and drug-resistant bacterial infection resistance.

Disclosed herein are polynucleic acid conjugate compositions comprising a polynucleic acid molecule and one or more targeting moiety such as an asialoglycoprotein receptor targeting moiety and a lipophilic moiety, for targeted delivery of the polynucleic acid molecule to a target cell. Disclosed herein are also pharmaceutical compositions comprising polynucleic acid conjugate composition. Further, provided herein are methods and / or uses of polynucleic acid conjugate composition and pharmaceutical composition comprising polynucleic acid conjugate composition described herein.

A lipophilic nucleotide analogue of the following formula: where Y is a hydroxyl protecting group, R1 is a C1-6 alkyl or a halogen-substituted C1-6 alkyl, R2 is a C1-6 alkyl or a halogen-substituted C1-6 alkyl, L is a lipophilic group; and Base is a nucleotide base. A preparation of the nucleotide analogue from is provided. A method for enhancing the in-vivo delivery of nucleic acid drugs with the nucleotide analogue is also provided.

Disclosed herein are compositions and pharmaceutical formulations that comprise a binding moiety conjugated to a polynucleic acid molecule linked to a lipophilic moiety. Also described herein include methods for treating a disease or disorder which utilize a composition or a pharmaceutical formulation comprising a binding moiety conjugated to a polynucleic acid molecule linked to a lipophilic moiety.

The present invention provides a method of treating a bacterial infection, the method comprising co-administering to a subject in need thereof an effective amount of each of the following agents: (A) a selective zinc chelating agent comprising one or more lipophilic zinc chelating moieties covalently linked to one or more hydrophilic moieties, wherein the zinc chelating moiety is selective for Zn2 + ions, and wherein the hydrophilic moiety is selected from the group consisting of hydrophilic monomer, oligomer, and polymer groups; (B) a [beta]-lactam antibiotic selected from the group consisting of penicillins, monocyclic [beta]-lactams, and carbapenems; and (C) a serine beta-lactamase inhibitor. Also provided are pharmaceutical compositions and kits comprising a combination of agents (A), (B) and (C).

The invention provides a cyclic polypeptide, which is characterized in that a neuronal targeting peptide Tet1 is used as a basic peptide chain, cysteine is respectively introduced to the C terminal and the N terminal of the basic peptide chain, and sulfydryl of the cysteine reacts with a cross-linking agent to form a cyclic structure; the cross-linking agent is selected from one of 4, 4 '-di (bromomethyl) biphenyl, decafluorobenzene or a maleimide functional aliphatic derivative. The invention also provides a preparation method of the cyclic polypeptide and application of the cyclic polypeptide in preparation of a drug delivery carrier for treating neurodegenerative diseases. Cysteine is introduced to the C end and the N end of the neuron targeting peptide Tet1, sulfydryl reacts with different cross-linking agents to construct an annular polypeptide library with the lipophilicity regulation and control function, an endocytosis path mediated by a cavette is triggered to break through age-dependent blood-brain barrier delivery obstacles, blood-brain barriers are efficiently penetrated, neurons are accurately targeted, and the neuronal targeting peptide Tet1 has the advantages of being high in targeting ability, good in targeting effect and the like. And a novel drug delivery carrier is provided for treatment of neurodegenerative diseases.

This invention relates to the field of tracer preparation technology, and specifically discloses a method for preparing a positron emission tomography (PET) tracer that penetrates the blood-brain barrier and targets hypoxia-inducible factor (HIF). The tracer is a compound with HIF targeting and rapid brain tumor enrichment capabilities, and comprises the following parts: a) a short-half-life radionuclide portion for PET imaging; b) a HIF-1α protein-binding domain; and c) a lipophilic linker / regulatory domain for modulating intracranial pharmacokinetics. This method for preparing a PET tracer that penetrates the blood-brain barrier and targets HIF integrates high-affinity targeting and tumor microenvironment response mechanisms, giving it excellent targeting specificity, rapid brain penetration and enrichment capabilities, and ideal rapid systemic clearance characteristics, thereby obtaining high-contrast, low-background, high-quality images.

The application discloses a gamma-glutamyltransferase and mitochondrial viscosity dual-responsive fluorescent probe and a preparation method and application thereof. The gamma-glutamyltransferase and mitochondrial viscosity dual-responsive fluorescent probe structure is shown as formula I. The fluorescent probe provided by the application takes coumarin and cyanine dye as two different emitting fluorophore parents, constructs a gamma-glutamyltransferase and viscosity dual-target recognition site through two strategies of hydroxyl protection-deprotection and introduction of a molecular rotor, and introduces a lipophilic cationic molecule to realize mitochondrial targeting by using the negative electricity of a mitochondrial inner membrane, has the advantages of anti-spectral crosstalk, mitochondrial targeting and simultaneous imaging of two analytes, and can effectively monitor the proliferation and invasion of liver cancer cells in the process that a liver precancerous lesion deteriorates into early hepatocellular carcinoma. The fluorescent probe can be applied to the medical technical field of diagnosis of liver precancerous lesion patients and the like, and creates conditions for the gamma-glutamyltransferase and mitochondrial viscosity dual-responsive fluorescent probe in diagnosis of liver precancerous lesions.

The application discloses a novel mitochondrion-targeting photosensitizer and application thereof in photodynamic and photothermal combined treatment, and belongs to the field of biomedical materials. The photosensitizer has a D-pi-A type molecular structure and a strong intramolecular charge transfer (ICT) effect. Under near-infrared laser irradiation, the photosensitizer can simultaneously and efficiently generate reactive oxygen species (ROS) and undergo photothermal conversion, and the photothermal conversion efficiency is high. With the near-infrared fluorescence emission characteristics, the material can realize photodynamic and photothermal synergistic treatment under fluorescence imaging guidance, and is suitable for diagnosis and treatment integration of tumors and removal of subcutaneous superficial tumors. As a positively charged salt molecule, the photosensitizer has lipophilic cation characteristics, can precisely target mitochondria of tumor cells through electrostatic interaction, and thus effectively kills cancer cells.

The invention provides a cubic gold-iron nano preparation, a preparation method and application of the cubic gold-iron nano preparation in tumor multi-mode imaging, and belongs to the technical field of biomedical nano materials. The particle size of the nano preparation is 30-300 nm, the nano preparation comprises gold, iron and oxygen elements, the content of the gold element is 1-10%, and the content of the iron element is 0.3-10%. The nano preparation is a carrier and is loaded with at least one functional molecule selected from lipophilic fluorescent molecules and small molecular chemotherapeutic drugs. And the lipophilic fluorescent molecule is DID. Based on a multi-modal imaging strategy of a gold-iron nano platform, high spatial resolution of CT, soft tissue contrast advantages of MRI and high sensitivity of photo-thermal and fluorescence imaging can be integrated, and precise visualization of a tumor microenvironment is realized.