25 results about "Cathepsin" patented technology

The invention discloses a glucan-based MMAE conjugate as well as a preparation method and application thereof, and relates to the technical field of medicines. The conjugate takes glucan with good biocompatibility as a carrier, and is covalently connected with a cytotoxic drug MMAE through a VC peptide linker capable of being cut by cathepsin B. The conjugate has good serum stability, can specifically release drugs at a tumor site, and realizes efficient tumor uptake by virtue of the stealth effect of glucan and potential GLUT1 targeting. In-vitro and animal experiments show that the conjugate has a remarkable treatment effect on pancreatic cancer and is low in systemic toxicity.

This invention discloses an enzyme- and pH-responsive nucleic acid loading and delivery material and its preparation method. The material can be used for efficient loading and delivery of nucleic acid molecules. The preparation method uses amphiphilic zwitterionic monomers to improve the reverse emulsion polymerization system, enhancing polymerization at the two-phase interface and avoiding the extrusion effect of polymerization in the aqueous core on nucleic acid molecules, thereby improving the loading efficiency of nucleic acid molecules. Further preparation of cross-linking agents MP-CL and CB-CL, which can cleave in response to matrix metalloproteinase II or cathepsin B, endows the nanogel with the ability to respond to charge reversal in the tumor matrix and to release nucleic acid molecules from tumor cells. The acid-sensitive blocks on the amphiphilic monomers give the nanogel lysosomal escape capability. The delivery material can efficiently deliver nucleic acid molecules into cells and exhibits excellent stability and biosafety.

Compositions and methods are provided of a therapeutic nanoparticle composed of collagenase IV linked via a linker (e.g. cathepsin B cleavable linker) to ferumoxytol (iron oxide). The collagenase IV is key in the composition intended for the breakdown of the tumor wall as the collagenase. Such compositions and methods are aimed at solving at the same time two of the main challenges of current approaches in the treatment of glioblastoma multiforme (GBM) which are low specificity and poor uptake.

The inventors have prepared a novel anti-Cath-D antibody (F1M1) that can reduce tumor growth in a Cath-D secreting basal-like TNBC cell line with strong immune infiltration, without significant toxicity. The F1M1 antibody prevents recruitment of immunosuppressive M2 polarized tumor-associated macrophages (TAMs) and induces activation of natural killer cells in the tumor, and the F1M1 also enhances activation of antitumor M1 polarized TAM, recruitment and maturation of conventional cDC1 dendritic cells in the tumor to promote antigen presentation and reduce depletion marker expression of CD4 + and CD8 + T cells in the tumor and drainage lymph nodes. It is worthy of noting that the affinity of the antibody F1M1 to Cath-D is better than that of the antibody F1 prepared by the inventor in advance. The inventors also have prepared a novel Fc-optimized F1M1-Fc + human antibody which can promote ADCC induction of cancer cells and CAF, improve anti-tumor efficacy, and trigger recruitment, activation and cytotoxic activity of NK cells in tumors. The F1M1-Fc + F1M1-Fc + can inhibit the growth of MDA-MB-231 and SUM159 TNBC cell xenografts and two TNBC-PDX (one of the TNBC-PDX is resistant to neoadjuvant chemotherapy), and has no obvious toxicity. In addition, the F1M1-Fc < + > improves the treatment effect of the paclitaxel and enzalutamide combined medicine. Thus, the present invention relates to anti-cathepsin-D antibodies and their use in the treatment of cancer, in particular triple negative breast cancer.

The invention belongs to the field of biological medicine, and particularly relates to a nano-drug based on chondroitin sulfate as well as a preparation method and application of the nano-drug. Chondroitin sulfate (CS) and dasatinib (DAS) are connected through a GFLG connexon responded by cathepsin B (CTSB) to prepare the prodrug CS-GFLG-DAS (CGD), the prodrug CS-GFLG-DAS (CGD) is used for reversing the phenotype of cancer-related fibroblasts and reducing the biosynthesis of extracellular matrixes, fibrotic tumors are efficiently treated, and a new perspective is provided for optimizing the application of immunotherapy in fibrotic tumors.

The invention relates to a cathepsin B sensitive fatty acid-adriamycin prodrug as well as albumin nanoparticles, a preparation method and application thereof, and belongs to the technical field of medicines. The cathepsin B sensitive fatty acid-adriamycin prodrug is a prodrug as shown in a formula (I), a geometric isomer thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein n is equal to 0-14. The invention also relates to a combined albumin nanoparticle prepared by entrapping the cathepsin B sensitive fatty acid-adriamycin prodrug by using human / bovine serum albumin as a carrier. The albumin nanoparticles are small in particle size and uniform in form, have good placement stability and colloidal stability, can stably exist in systemic circulation and normal tissues, and release a parent drug adriamycin after being taken by tumor cells and hydrolyzed by cathepsin B; therefore, specific killing of tumor cells is realized without generation of serious toxic and side effects, and good clinical development prospects are achieved.

The application discloses application of cathepsin E in preparation of a drug for treating or preventing lung cancer, relates to the technical field of biological medicine, and first proves that CTSE is highly expressed in lung adenocarcinoma tissues and has the biological function of inhibiting lung cancer cell proliferation through clinical sample analysis, cell function experiment and animal experiment. Mechanism research shows that CTSE plays the anticancer role by down-regulating the expression of cathepsin B (CTSB) and promoting the degradation of STING protein through a lysosome pathway and inhibiting the cGAS-STING natural immune pathway. The application clarifies the application value of CTSE as a new target for treating lung adenocarcinoma, provides a theoretical basis and experimental basis for developing a novel lung cancer treatment drug, and has an important clinical application prospect.

This invention provides an activatable semiconductor polymer, its preparation method, and its applications. The activatable semiconductor polymer of this invention can efficiently accumulate at tumor sites. Due to the presence of electron-withdrawing groups on its side chains, the polymer's fluorescence is quenched. Upon response to tumor markers—biothiols, reactive oxygen species, and cathepsin B—the polymer's fluorescence recovers, enabling precise imaging and sonodynamic therapy at the tumor site. Simultaneously, the activatable semiconductor polymer of this invention can label immune cells (such as dendritic cells and macrophages) and track their metastasis from the tumor to the draining lymph nodes.

Anti-VEGF proteins including the VEGF trap protein aflibercept can be produced to have a low level of an aspartyl protease (e.g., a low level of cathepsin D), such as less than 1 ppm of the aspartyl protease.

This invention discloses a molecular marker for identifying the body size of bighead carp and its application, belonging to the field of molecular breeding technology for aquatic animals. The molecular marker is a SNP site on the cathepsin Bb gene, whose nucleotide sequence exhibits a G / C polymorphism at position 1907, named g.1907.G>C. This SNP site is located on intron 4 of the cathepsin Bb gene. The genotype of this SNP site is significantly correlated with the body weight of bighead carp, and individuals with the CC genotype have significantly higher body weights than those with the GC genotype. This invention can rapidly and accurately screen for bighead carp individuals with superior body size, providing technical support for marker-assisted breeding of bighead carp and improving breeding efficiency.

The application discloses a cell-penetrating peptide modified enzyme-sensitive PDC type PROTAC as well as a preparation method and application thereof, and belongs to the technical field of tumor targeted therapy. The cell-penetrating peptide modified enzyme-sensitive PDC type PROTAC is obtained by modifying a cell-penetrating peptide and an enzyme-sensitive linker (GFLG) to a PROTAC of an anti-tumor drug target protein ligand, has the ability to release the PDC type PROTAC under catalysis of cathepsin B, has a smaller influence on cell viability of U251 cells, U87 cells and HEK293 cells, has proliferation inhibition activity on the U251 cells and the U87 cells, can degrade target proteins in the U251 cells and the U87 cells, can induce apoptosis of the U251 cells and the U87 cells, has an influence on U251 cell cycles, can be used for preparing an anti-tumor drug (target protein degradation and membrane penetration), has a good application prospect in preparation of a drug for targeting human brain glioma cells, and can be used as another important field for PROTAC drug development.

The invention relates to the technical field of biological medicine, in particular to application of glucosylceramide level as a diagnosis and treatment target of heart failure. According to the invention, key pathological cascade reactions such as lysosomal membrane permeabilization, cathepsin leakage, mitochondrial dysfunction and the like in the occurrence and development process of heart failure are blocked from the source by reducing the level of glucosylceramide in myocardial tissues. By inhibiting synthesis of glucosylceramide or enhancing degradation in lysosome of glucosylceramide, glucosylceramide abnormally accumulated in myocardial cells is removed, organelle structures and energy metabolism states are remarkably improved, and then myocardial contraction and relaxation functions are improved. In an animal model, the strategy can reverse ventricular remodeling, improve ejection fraction and relieve cardiac hypertrophy and fibrosis. In addition, the glucosylceramide detection method provided by the invention can be used for assisting in evaluating metabolic abnormalities related to heart failure, so that disease judgment is more accurate.

This invention relates to a cathepsin B-sensitive fatty acid-doxacin prodrug, its albumin nanoparticles, preparation method, and application, belonging to the field of pharmaceutical technology. The cathepsin B-sensitive fatty acid-doxacin prodrug is defined as the prodrug shown in general structural formula (I), its geometric isomers, and its pharmaceutically acceptable salts, hydrates, and solvates; where n = 0-14. Further, the cathepsin B-sensitive fatty acid-doxacin prodrug is encapsulated using human / bovine serum albumin as a carrier to prepare bound albumin nanoparticles. These albumin nanoparticles have a small and uniform particle size, exhibiting good placement and colloidal stability. They remain stable in systemic circulation and normal tissues. However, after being taken up by tumor cells, they are hydrolyzed by cathepsin B to release the parent drug doxacin, thereby achieving specific killing of tumor cells without producing serious toxic side effects, showing promising clinical development prospects.

This invention discloses an enzyme-sensitive PDC-type PROTAC modified with a human leukemia cell-targeting transmembrane peptide, its preparation method, and its applications, belonging to the field of tumor targeted therapy technology. This PDC-type PROTAC is composed of a hypoxia-inducible factor 1α (HIF-1α) protein fragment linked to imatinib via dodecanoic acid, and further modified with the human leukemia cell-targeting transmembrane peptide Cyclo-C9C-R and the cathepsin B-sensitive sequence GFLG. The modified PDC-type PROTAC can release the original drug under the catalysis of cathepsin B, with minimal impact on THP1 cell viability, but effectively inhibits the proliferation of K562 and KU812 cells, degrades target proteins, induces apoptosis, and affects the cell cycle. This gives the PDC-type PROTAC significant advantages in the preparation of anti-tumor drugs, particularly showing promising application prospects in the development of drugs targeting human chronic myeloid leukemia cells and human peripheral blood basophilic leukemia cells, opening up a new field for PROTAC drug development.

The present invention generally relates to compounds that are useful for inhibiting one or more trypsin-like S1 serine proteases, HGFA, matriptase, hepsin, KLK5 and / or TMPRSS2 as well as cysteine proteases including trypsin-like cysteine proteases (e.g. Cathepsin B). The present invention also relates to various methods of using the inhibitor compounds to treat or prevent viral infections, including those caused by coronaviruses and influenza, conditions associated with KLK5, various malignancies, pre-malignant conditions, and cancer.

Disclosed are compounds of Formulas (I), (la), (lb), (II), (Ila), (III), (Illa), and (Illb), as well as pharmaceutical compositions thereof. The compounds can be used to improve proteostasis and enhance clearance of protein accumulation events by positively modulating the autophagy-lysosomal pathway, including augmenting the activity of cathepsin enzymes, and / or to treat neurological diseases, disorders and conditions, such as, but not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, mild cognitive impairment, frontotemporal dementia, amyotrophic lateral sclerosis, Lewy body dementias, chronic traumatic encephalopathy, traumatic brain injury, and α-synucleinopathies.

The invention discloses an enzyme response near-infrared two-region fluorescence / computed tomography dual-mode imaging probe based on a gold nano-cluster and a preparation method and application of the enzyme response near-infrared two-region fluorescence / computed tomography dual-mode imaging probe. The probe comprises: a gold nanocluster capable of simultaneously providing near-infrared two-region fluorescence and computed tomography imaging signals; the polypeptide molecule is modified on the surface of the material. The polypeptide comprises a cathepsin B response sequence, biotin with a targeting function and a click reaction unit 2-cyanobenzothiazole. The probe disclosed by the invention is subjected to enzyme digestion and trigger click reaction under the action of highly expressed CTSB in liver cancer cells, so that the gold nanoclusters are subjected to cross-linked aggregation at tumor parts, the retention time of the probe is prolonged, NIR-II fluorescence and CT imaging effects are remarkably enhanced, and high-sensitivity detection on liver cancer is realized.

The invention discloses a macrophage targeting probe, a preparation method and application, the probe is based on blood platelets coupled with a CD41 antibody, and the surfaces of the blood platelets are further modified with phospholipid compounds coupled with a cathepsin substrate peptide fragment-fluorophore structure. The probe has the advantages of good macrophage targeting property, low immunogenicity and capability of crossing a biological membrane barrier. Meanwhile, the cathepsin substrate peptide fragment-fluorophore structure in the probe can generate fluorescence only after being cut by cathepsin K in the macrophage, real-time fluorescence tracking imaging of the functional state and position of the macrophage can be effectively achieved, and then early diagnosis of diseases and guidance of disease treatment are achieved.

Provided herein are methods of diagnosing, monitoring and treating a disease or disorder using cathepsin K as a biomarker. The disease or disorder may be an inflammatory disease, an autoimmune disease, or sepsis. Also, provided herein are compositions for treating the disease or disorder diagnosed by the described methods.

The invention belongs to the field of biological medicine, and provides an active compound for treating prostatic cancer and a preparation method thereof. A-B-C-D-P five-module linear connection design is adopted, wherein the A module is a prostate specific membrane antigen targeting binding unit, the B module is a prostate specific antigen enzyme digestion recognition sequence HSSKLQ, the C module is a cathepsin B-responsive Val-Cit-p-aminobenzyl self-destruction unit, the D module is a reduction-responsive disulfide bond connecting arm, and the P is an anti-tumor pharmacodynamic fragment. A coupling reaction is accurately controlled through a continuous flow microchannel technology, controllable self-assembly of the 20-60-nanometer nano aggregate is achieved, the average hydration diameter dispersion coefficient is not larger than 0.20, and the nano aggregate stably exists in plasma and selectively releases drugs in a tumor microenvironment. Multiple contradictions among prodrug system process manufacturability, intracellular response release and stable dispersion of the preparation are solved, and wide clinical application value is achieved.

The invention relates to a cathepsin B sensitive fatty acid-avitecan prodrug, albumin nanoparticles thereof, a preparation method and application, and belongs to the technical field of medicines. The cathepsin B-sensitive fatty acid-avitecan prodrug is a prodrug as shown in a formula (I), a geometric isomer of the prodrug, and pharmaceutically acceptable salts, hydrates and solvates of the prodrug, wherein n is equal to 0-14. The invention also relates to a combined albumin nanoparticle prepared by using human / bovine serum albumin as a carrier to encapsulate a cathepsin B sensitive fatty acid-etiotecan prodrug. The albumin nanoparticles are small in particle size and uniform in form, have good placement stability and colloidal stability, can stably exist in systemic circulation and normal tissues, and release a parent drug, namely avixetecan after being taken by tumor cells and hydrolyzed by cathepsin B, so that the albumin nanoparticles can be used for treating tumor tumors. Therefore, specific killing of tumor cells is realized without generation of serious toxic and side effects, and good clinical development prospects are achieved.

The invention discloses an antibody coupling medicine for targeting colorectal cancer cells and a preparation method of the antibody coupling medicine, and belongs to the technical field of biological medicine. The antibody coupling drug is formed by connecting cetuximab, atorvastatin or a derivative thereof and a specific connexon through covalent bonds and is constructed by adopting a site specific coupling technology, the average drug-antibody ratio is 3.13, and the monomer purity is greater than or equal to 97%. The connexon can be broken in response to acidity, high reducibility or high cathepsin expression conditions of a tumor microenvironment, so that accurate release of the effective load is realized. The invention also discloses a preparation method of the antibody coupling drug, which comprises the steps of antibody reduction, active intermediate preparation, coupling, quenching and purification, and the yield is greater than or equal to 85%. The antibody coupling drug can specifically target EGFR high-expression KRAS mutant colorectal cancer cells, reverses the drug resistance of tumors to an EGFR inhibitor by inhibiting a mevalonic acid pathway, remarkably reduces the systemic toxicity of atorvastatin, and has excellent curative effect and safety.

The invention relates to the technical field of biomedical detection, in particular to a cathepsin B-based biomarker detection product and application thereof. The cathepsin B-based biomarker detection product comprises an active substrate probe, a standard substance solution, a reaction buffer solution and a detection chip. The active substrate probe is a fluorescence labeled polypeptide chain, and a specific cleavage site is composed of arginine-arginine-lysine; the surface of the detection chip is modified with an affinity ligand to fix a target enzyme molecule. The invention further provides a detection method and application. The detection method is suitable for early diagnosis of cancers, activity monitoring of inflammatory diseases and prognosis evaluation of neurodegenerative diseases. Efficient and accurate detection is realized through a microfluidic device and an automatic control system, the sensitivity and the specificity are remarkably improved, and diversified clinical requirements are met.

The application belongs to the field of biological medicine, and provides a fluorescent probe which is specifically responsive to cathepsin B. The probe is a biological fluorescent probe with a fluorescent 'on' response which is developed based on an aggregation-induced emission effect, and the amino acid sequence is Ac-rrrr-AEEA-GIVRAK(Gl-TPE)-COOH. The probe is synthesized by a solid-phase synthesis method, cathepsin B specifically cuts the recognition site GIVRAK, after cutting, the part containing tetraphenyl ethylene is aggregated, the aggregation-induced emission effect is triggered, a strong fluorescent signal is generated, and the specific recognition and monitoring of the probe to cathepsin B are realized. Meanwhile, the probe introduces four D-arginines to help the probe enter cells, and the monitoring of cathepsin B at the cell level is realized. The fluorescent probe has high practical application value, and has the advantages of strong monitoring specificity of cathepsin B, simple method and mild conditions.

The application discloses a high-efficiency fluorescein probe and a preparation method and application thereof, and relates to the field of fluorescein probes. The high-efficiency fluorescein probe prepared by the application has an extremely low detection limit for cathepsin B, has excellent fluorescence performance and good biocompatibility, is suitable for detection of tumor-related cathepsin B, and has important application significance in early diagnosis of tumors.