62 results about "Tumor microenvironment" patented technology

The invention provides an organoid chip for screening micro-ecological drugs as well as application and a preparation method of the organoid chip, and relates to the technical field of biological medicines. The invention provides a chip integrating intestinal epithelium, a prostate cancer organ and a bladder cancer organ, which is used for researching how microecological preparations, such as probiotics, metabolites and the like, affect tumor microenvironment and immunotherapy effects. The chip can simulate interaction of intestinal tract-tumor axis, and provides an in-vitro evaluation system for precise tumor immunotherapy.

This invention discloses a composite nanodelivery system encapsulated in a fusion membrane, its preparation method, and its applications. The nanodelivery system comprises a Ti3C2 / TiO2 / CuInS2 composite material, oxaliplatin loaded thereon, and a fusion membrane encapsulating the outer layer; the fusion membrane is formed by the fusion of Fusobacterium nucleatum extravesicles and M1 macrophage membranes. This invention also discloses a method for preparing the nanodelivery system, including the steps of preparing the Ti3C2 / TiO2 / CuInS2 composite material, preparing the fusion membrane, loading oxaliplatin, and encapsulating it in the fusion membrane. The nanodelivery system prepared by this invention exhibits pH-responsive drug release characteristics, generating H2S in the tumor microenvironment and H2 under light irradiation, while also possessing photocatalytic activity. This invention combines chemotherapy, photoelectrocatalytic therapy, and the regulation of multiple active substances, and can be used to prepare drugs for treating malignant tumors of the digestive system.

The invention discloses a multifunctional double-drug delivery system based on metal collaborative treatment and application of the multifunctional double-drug delivery system, and belongs to the technical field of biological medicine. The double-drug delivery system is double-drug delivery lipidosome and comprises metal ions, a lipidosome membrane and active ingredients, the metal ions are adsorbed on the surface of the lipidosome membrane, and the active ingredients are wrapped in the lipidosome membrane; the metal ions are divalent metal ions; the active component consists of an STING agonist and a traditional Chinese medicine active monomer component. According to the double-drug delivery system, the STING agonist and the traditional Chinese medicine anti-inflammatory components are co-loaded through lipidosome, and multi-dimensional remodeling of a tumor microenvironment is achieved through the double effects of exciting tumor immunity and inhibiting inflammatory reaction; and meanwhile, by introducing metal ions, the lysosome escape efficiency of a liposome drug delivery system is effectively enhanced, so that the intracellular delivery efficiency of the drug is improved.

The invention relates to the technical field of biomedical detection, and discloses a system for detecting extracellular matrix free metalloproteinase and a soluble receptor. Comprising a polypeptide substrate nanopore sensing module used for detecting the enzyme activity of free metalloproteinase in an extracellular matrix; the electrophoretic analysis module is used for detecting a soluble receptor in an extracellular matrix, applying an electric field to a tumor microenvironment sample, determining the inter-terminal resistance of the sample by using an inter-terminal resistance detection device, and detecting the soluble receptor by comparing the resistance change according to the characteristic that the existence of the soluble receptor causes the additional resistance increase of the sample; and the data processing and judging module is electrically connected with the polypeptide substrate nanopore sensing module and the electrophoretic analysis module respectively, and is used for receiving the free metalloproteinase activity detection result and the soluble receptor detection result, and judging the time interval of cellular immune escape according to a preset rule in combination with cellular morphology observation information.

Activation of STimulator of INterferon Genes (STING) triggers cytokine production and facilitates tumor antigen cross-presentation. In an embodiment of the present invention, STING-dependent innate immune signaling pathway activators (STAVs) together with Replicants including mRNA adapted to express an antigen can be delivered to antigen presenting cells (APC's) using lipid nanoparticle formulations. In various embodiments of the present invention, the range of cancers amenable to STAV / Replicant therapy can be extended using a non-cell-based nanoparticle strategy that effectively delivers the STAV / Replicant into the Tumor Micro Environment (TME) to potently generate anti-tumor cytotoxic T cell activity together with humoral immune responses. The STAV / Replicant formulations can be introduced into solid tumors present in the subject. Alternatively, the STAV / Replicant can be introduced through direct inoculation, intramuscularly, or intravenously. The lipid nanoparticles stick to the tumor cells and are co-phagocytosed to activate STING in APCs.

The present invention relates to methods and conjugates to improve the penetrability of biological substances into the tumour microenvironment (TME) for therapeutic purposes, suitably the agent comprises at least: i a therapeutic domain; ii. a cleavable domain; and iii. a stabilisation domain.

The application provides a tumor immune microenvironment multi-cell recognition and spatial analysis system, comprising: an intrinsic signal generation module generating an initial intrinsic signal vector; a preliminary functional marker module generating a preliminary phenotype classification label map based on spatial centroid coordinates of cell objects; a functional neighborhood construction module calculating and generating a functional neighborhood feature vector; a composite feature splicing module constructing a composite state feature vector; an effective function determination module decoding to obtain a continuous value feature vector output by a function determination model representing the final function strength under the regulation of the microenvironment; and a functional map rendering module rendering to generate a cell effective function map under the regulation of the environment. The application solves the problem that, in the prior art, when interpreting cell functions, the intrinsic state information of the cells and the local functional microenvironment context information cannot be effectively fused, resulting in deviation in the description of the spatial distribution map of tumor microenvironment function heterogeneity.

The embodiment of the invention provides a TPD52 immunomodulatory effect research method and system, and the method comprises the steps: obtaining single cell transcriptome data of a breast cancer tumor microenvironment; on the basis of the data, identifying the TPD52 as the immune regulation key dangerous gene by utilizing a machine learning algorithm; verifying the association of TPD52 expression and patient prognosis in a multi-center queue; and based on the function annotation and the body appearance type experiment of the TPD52, confirming the immunomodulatory effect of the TPD52, and outputting a comprehensive evaluation report of the immunomodulatory effect of the TPD52. According to the invention, a machine learning method and scRNA-seq are utilized to explore the effect of TPD52 as a key immunomodulatory factor in BRCA, and the application has important significance on tumor behavior and patient prognosis.

The present invention describes novel drug-carrying nanoparticles called bionanocarriers capable of modulating the cellular redox system and targeting the cancerous tumor.Specifically, the invention relates to a nanomedicine strategy for combating cancerous tumor cells, a strategy that aims to target the tumor, and consists of providing quercetin-linked magnetite nanoparticles (Q): (MNPs Q), and 3,5-dimaleylbenzoic acid-linked magnetite nanoparticles (A3'5DMB): (MNPs A3'5DMB)M; both types of nanoparticles were subsequently encapsulated with chitosan (Qs) and O-carboxymethyl chitosan (O-CMQs), functionalized with 11-mercaptoundecanoic acid (MUDA), and finally the anti-ABCC3 antibody was attached to the polymer phase, which was used as a selective driver of the delivery process of the encapsulated nanoparticles, thus carrying out the construction of the bionanocarriers: BNC-1: MNPs-Q-Ab; BNC-2: MNPs-a3'5DMB-Ab.Its manufacturing method and the tests of its biological functionality, its stability, the degradation of the encapsulation for the tumor microenvironment, the controlled release profile of the drugs Q and A3'5DMB, selective cell uptake, intracellular localization, cytotoxic effect on steroids of hepatocellular carcinoma cells with altered redox balance and induction of apoptosis, as well as its safety on normal cells, are described.

The invention provides application of a GPX1 inhibitor combined with a copper death inducer in preparation of a cold tumor treatment medicine. The key node effect of GPX1 in cold tumor metabolism reprogramming is found and utilized. In a cold tumor microenvironment deficient in glutamine, tumor cells often resist a copper death inducer. Through targeted inhibition of GPX1, the sensitivity of cold tumor cells to copper ion toxicity is significantly enhanced, and the drug resistance problem caused by metabolic pressure is effectively overcome.

The application discloses a kind of nanomedicine for tumor hypoxia, which is prepared by mPEG-SS-PLGA wrapping drug IR-1048, PFOB and 4-MU.The nanomedicine of the application is constructed by wrapping perfluorooctyl bromide (PFOB), 4-methyl umbelliferone (4-MU) and IR-1048 in tumor microenvironment-responsive amphiphilic polymer mPEG-SS-PLGA, and in response to high GSH in tumor area, 4-MU, PFOB and IR-1048 are released; 4-MU makes the dense tumor extracellular matrix loose, so that tumor vessels are normalized, which is conducive to PFOB carrying oxygen into the tumor interior, long-term solution of tumor hypoxia, remodeling of tumor microenvironment, and reduction of myeloid-derived suppressor cell (MDSC) infiltration; and under the action of 980nm laser in vitro, IR-1048 responds, and the effect of photothermal therapy of tumor is improved.

There is provided the combination of Bacillus Calmette-Guérin (BCG) vaccine and β-glucan adjuvant for the treatment of a cancer characterized by the presence of protumoral T3 neutrophils in the tumour microenvironment. The β-glucan is characterized by a μ-1,3 glucose backbone. The BCG and β-glucan combination demonstrated a synergistic effect in remodeling the tumour microenvironment to resist conversion of neutrophils into the T3 phenotype. The cancer can be bladder cancer, melanoma, lung adenocarcinoma, head and neck squamous cell cancer, pancreatic adenocarcinoma, low-grade gliomas, esophageal carcinoma, and cervical squamous cell carcinoma.

The invention discloses a hypoxia activating peptide-photosensitizer-drug conjugate and a preparation method and application thereof in the technical field of medicine, the conjugate takes indocyanine with a high molar extinction coefficient as a photosensitive core, distorted conjugate units are introduced to two sides of indole, the characteristic of'limited movement in molecules' is given to the conjugate, and radiation and non-radiation energy dissipation are balanced. Meanwhile, an azo bond sensitive to hypoxia is reasonably introduced between a light treatment module and a chemotherapy module to serve as a responsive linker, and is further coupled with two-molecule integrin targeting peptide cRGD, so that the azo bond is self-assembled into nanospheres in an aqueous solution, and a triple targeting mechanism, namely multivalent integrin receptor targeting, aggregation and tumor microenvironment hypoxia selective activation, is realized. In an in-situ osteosarcoma mouse model, the conjugate realizes real-time near-infrared two-region imaging, shows potent tumor inhibition, effectively inhibits lung metastasis, and does not detect obvious systemic toxicity.

The invention discloses an inhibitor-loaded oncolytic microgel as well as a preparation method and application thereof, and the inhibitor-loaded oncolytic microgel is an oncolytic microgel (OMG) with similar activity and immune activation capability to an oncolytic peptide, and can efficiently entrap an immune checkpoint inhibitor and realize adjustable drug sustained release so as to enhance the cancer immunotherapy effect. The oncolytic microgel can effectively maintain the biological activity of entrapped drugs and antibodies, and has wide application prospects in the fields of drug controlled release and the like. Meanwhile, single injection of OMG (P1C4-OMG) loaded with anti-PD-1 and anti-CTLA-4 in a tumor can effectively reverse an inhibitory tumor microenvironment, enhance anti-tumor immune response and realize a remarkable tumor inhibition effect and outstanding survival benefits, and the oncolytic microgel with the adjustable antibody release function is a safe and unique cancer immunotherapy platform.

The invention provides a near-infrared NIR-II region fluorescence ratio probe based on tumor-associated neutrophil and application of the near-infrared NIR-II region fluorescence ratio probe. The nanoprobe is a rare earth doped down-conversion nanocrystal with a core-shell structure, the surface of the rare earth doped down-conversion nanocrystal is modified with a response unit and a targeting unit, and the response unit can release a fluorescence signal through enzymatic cleavage of neutrophil elastase; and the targeting unit is used for targeting a tumor microenvironment integrin receptor. The nanoprobe has high specificity and sensitivity, high anti-interference capability and self-calibration capability, can realize NIR-IIb region ratio imaging, provides a key basis for early curative effect judgment, achieves accurate individual stratification, fills the technical blank of cancer immunotherapy curative effect monitoring, and promotes the development of a tumor immune microenvironment molecular imaging technology.

The application discloses a kind of liposome nanoparticles for encapsulating lysine and regulated tumor organoid model.The liposome nanoparticles are prepared by thin film hydration method with DSPC,cholesterol and mPEG-DSPE as membrane material,encapsulate lysine in internal water phase,particle size is 70-250 nm,PDI is less than 0.2,encapsulation efficiency is 8%-20%,drug loading rate is 2%-50%.Tumor organoids can effectively uptake the nanoparticles,and release lysine in response to acidic microenvironment,neutralize intracellular and microenvironment acidity,adjust pH to 7.2-7.4.Based on the liposome constructed tumor organoid model,neutral pH environment can be maintained in vitro for a long time,which is used to evaluate the true efficacy of weakly alkaline chemotherapeutic drugs and overcome the problem of underestimation of efficacy caused by traditional acidic model.The application provides a method for regulating tumor microenvironment and a new evaluation tool for pH-responsive drug screening.

The invention discloses an application of a macrophage subgroup in improving the treatment effect of AK112 (Adenosine Kinase 112). The macrophage subgroup is APOE + KRT18-CCL20-macrophages. It is found for the first time that a specific macrophage subset in a tumor microenvironment (TME) can significantly improve the AK112 double-antibody tumor killing activity, and a new target is provided for overcoming clinical drug resistance. Meanwhile, a matched flow cytometry kit is developed, the kit comprises 12 antibody combinations, and the subgroup marker is synchronously and accurately detected by a single tube through a full-spectrum flow technology. The sensitivity and the specificity are high, the AK112 treatment response can be dynamically monitored, and the disease progress can be predicted. According to the macrophage targeted synergistic mechanism and the integrated detection system, a combined treatment strategy is provided for AK112 drug-resistant patients, and a pioneering tool is provided for individualized curative effect evaluation.

The present application relates to a kind of anti-PD-L1 and HHLA2 bispecific antibody and its preparation method and application.The bispecific antibody includes PD-L1 binding domain and HHLA2 binding domain, the PD-L1 binding domain includes anti-PD-L1 monoclonal antibody, the HHLA2 binding domain includes the variable region of anti-HHLA2 nanobody;The variable region of anti-HHLA2 nanobody is connected with the N terminal or C terminal of the light chain or heavy chain of anti-PD-L1 monoclonal antibody by flexible linker.The present application constructs specific structure anti-HHLA2 and PD-L1 bispecific antibody, with high specificity and affinity, can up-regulate cell-mediated immune response, and enhance the function of T cell and NK cell in tumor microenvironment.In addition, bispecific antibody drug conjugate can be further developed, with higher efficient tumor cell specific killing ability, provide new method, new idea for treating tumor and infectious disease.

The invention provides a tumor drug evaluation method based on PBMC (peripheral blood mononuclear cells) and prostate organs and application, and belongs to the technical field of biology. The method comprises the following steps: (1) constructing a tumor organoid, namely pretreating an excision tissue to obtain a cell cluster, wrapping the cell cluster by using Matrigel, paving a plate, and adding a tumor organoid culture medium for culturing; (2) separating peripheral blood mononuclear cells; (3) co-culturing the peripheral blood mononuclear cells and the tumor organs to obtain CTL cells; and (4) co-culturing the CTL cells and the tumor organoid, treating the co-cultured mixture with the tumor drug, and judging the efficacy of the tumor drug. According to the tumor drug evaluation method based on the PBMC and the prostate organoid, the tumor microenvironment can be relatively closely reproduced by utilizing the tumor organoid, and the efficacy of the anti-cancer drug can be more accurately evaluated.

The application provides a tumor immune microenvironment multi-cell recognition and spatial analysis system, comprising: an intrinsic signal generation module generating an initial intrinsic signal vector; a preliminary functional marker module generating a preliminary phenotype classification label map based on spatial centroid coordinates of cell objects; a functional neighborhood construction module calculating and generating a functional neighborhood feature vector; a composite feature splicing module constructing a composite state feature vector; an effective function determination module decoding to obtain a continuous value feature vector output by a function determination model representing the final function strength under the regulation of the microenvironment; and a functional map rendering module rendering to generate a cell effective function map under the regulation of the environment. The application solves the problem that, in the prior art, when interpreting cell functions, the intrinsic state information of the cells and the local functional microenvironment context information cannot be effectively fused, resulting in deviation in the description of the spatial distribution map of tumor microenvironment function heterogeneity.

The present invention belongs to the technical field of biochemistry; and specifically relates to an anti-tumor prodrug, and a preparation method therefor and the use thereof. The anti-tumor prodrug is composed of the tail of nervonic acid and the head of a hydrophilic chemotherapeutic drug. The hydrophilic chemotherapeutic drug is gemcitabine, and the tumor is glioma. An acid-sensitive amphiphilic prodrug compound is synthesized on the basis of using a nutrient nervonic acid capable of penetrating the blood-brain barrier and a chemotherapeutic drug as raw materials. Once the prodrug compound reaches a tumor site, an acid-sensitive bond is automatically cleaved due to the low pH in the tumor microenvironment, causing the prodrug compound to separate into the nervonic acid and the chemotherapeutic drug to perform respective functions thereof, wherein the chemotherapeutic drug kills glioma cells, and the nervonic acid repairs nerve tissues, thereby fundamentally solving the toxic side effects of the chemotherapeutic drug, and integrating therapeutic and rehabilitative effects.

A Tumor Micro-Environment (TME) responsive expression vector including a nucleic acid sequence of a synthetic promoter, comprising two or more promoter-response-elements inducing expression of an immune-effector gene.

The invention provides a nano-drug delivery system based on a chemotherapy-photothermal-photodynamic synergistic effect, which is characterized in that graphene oxide is used as a substrate material, and a nano-drug carrier GO-HA-Ce6-GNRs constructed by a composite nano-micelle HA-Ce6 and a photothermal transduction agent gold nanorod is modified through an amide bonding reaction; and loading an anti-cancer drug doxorubicin hydrochloride through pi-pi interaction to obtain the nano-drug compound GO-HA-Ce6-GNRs (at) DOX. The nano-drug delivery system disclosed by the invention has excellent photo-thermal / photodynamic performance and good stability in a physiological environment, can realize targeted delivery of an anti-cancer drug to cervical cancer tissues, and can controllably release the drug under dual response of an acidic tumor microenvironment / NIR; the efficient chemotherapy-photothermal-photodynamic combined cervical cancer treatment effect and the relatively strong fluorescence imaging capability are shown.

This invention provides a method and application for evaluating tumor drugs based on PBMCs and prostate organoids, belonging to the field of biotechnology. The method includes the following steps: (1) Construction of tumor organoids: pre-treating excised tissue to obtain cell clusters, encapsulating the cell clusters with Matrigel, plate-coating, and adding tumor organoid culture medium for culture; (2) Isolating peripheral blood mononuclear cells; (3) Co-culturing peripheral blood mononuclear cells with tumor organoids to obtain CTL cells; (4) Co-culturing CTL cells with tumor organoids, treating the co-culture mixture with tumor drugs, and judging the efficacy of tumor drugs. The tumor drug evaluation method based on PBMCs and prostate organoids provided by this invention utilizes the fact that tumor organoids can more closely reproduce the tumor microenvironment, and more accurately evaluate the efficacy of anticancer drugs.

Monoclonal antibodies that specifically bind CD25, as well as conjugates of the anti-CD25 antibodies, are described. The CD25-specific monoclonal antibodies and conjugates thereof do not block binding of IL-2 to CD25 and induce little to no antibody-dependent cellular cytotoxicity (ADCC). The anti-CD25 antibodies and conjugates can be used, for example, to target photoimmunotherapy to T regulatory (Treg) cells in tumor beds to enhance the local host immune response to the tumor.

The invention discloses a tumor specific microbial antigen epitope recognition method, and belongs to the technical field of bioinformatics and tumor immunology. The identification method comprises the following steps: based on whole transcriptome sequencing data of a sample, obtaining a high-quality non-host microorganism sequence, and carrying out species classification screening; the method comprises the following steps: defining a microorganism transcription programming region and a target sample specific microorganism transcription reprogramming region, calculating to obtain a microorganism transcription reprogramming index MiTRI, obtaining microorganisms which generate high transcription reprogramming activity in a target sample, and quantitatively analyzing the transcription adaptability change (namely transcription reprogramming) of the microorganisms in a tumor microenvironment, so as to obtain the high transcription reprogramming activity of the microorganisms. Therefore, the precise recognition of the tumor-specific microbial epitope with high immunogenicity is realized. And a new method is provided for screening and identifying the microbial epitope with tumor specificity and immunogenicity.

The present invention relates to methods and conjugates to improve the penetrability of biological substances into the tumour microenvironment (TME) for therapeutic purposes, suitably the antibody-drug-conjugate comprises an engineered agent conjugated to one or more payloads, wherein the agent comprises: i a therapeutic domain; ii. a cleavable domain; and iii. a stabilisation domain. The cleavable domain is positioned between the therapeutic domain and the stabilising domain.

The application provides a preparation method and application of a dual-indocyanine green diagnosis and treatment integrated compound with a stimulus response, provides a micro-nano structure formed by self-assembly of a compound with a structure shown in formula (I) or an isomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof in an aqueous solution, and preparation of a pharmaceutical composition and application thereof in preparation of a fluorescent probe, a phototherapy drug, a drug for diagnosis and / or treatment of cancer, and stimulus-responsive drug release. The compound provided by the application can accumulate at a tumor site, and can realize aggregation structure conversion and optical performance regulation by responding to a unique redox stimulus of a tumor microenvironment, realize precise photothermal / photodynamic combined treatment of the tumor in an aggregated state under irradiation of a specific excitation wavelength, and realize long-acting fluorescence imaging of a low background at the tumor after disaggregation of the aggregation. The tumor treatment effect is good, the trauma is small, the fluorescence imaging precision is high, the time is long, the biological safety is excellent, and diagnosis and treatment integration at the tumor site is realized.

The application discloses a combined immunization drug, a temperature-sensitive gel composition, a chemotactic factor particle and application thereof, and uses a mixed solution of an injectable temperature-sensitive polymer PLGA-PEG-PLGA, a chemotactic factor particle and an immune checkpoint inhibitor PD-1 monoclonal antibody to form a temperature-sensitive hydrogel beside a solid tumor at body temperature, and long-term controllable release of the chemotactic factor and aPD1, so as to enhance the targeting of adoptive T cells to the solid tumor and the resistance to immunosuppression in the tumor microenvironment. Through combination of the immunoregulatory temperature-sensitive gel and a tumor-penetrating peptide iRGD, the infiltration of the adoptive T cells to the solid tumor is enhanced, so that the solid tumor is efficiently treated. The chemotactic factor particle is constructed by using a distearoyl phosphoethanolamine-polyethylene glycol-N-hydroxysuccinimide modified chemotactic factor and an albumin carrier.

This invention relates to polymer microspheres supported by active metal nanoparticles, their manufacturing method, and applications, and belongs to the technical field of tumor embolization therapy. The polymer microspheres supported by active metal nanoparticles described in this invention include a polymer microsphere skeleton and active metal nanoparticles distributed inside the polymer microsphere skeleton. This invention mainly produces the target microspheres by a reversed-phase microemulsion method. The polymer microspheres supported by active metal nanoparticles produced in this invention are used in transarterial tumor embolization, embolizing tumor blood vessels and blocking nutrient supply to the tumor site, while also gradually and continuously releasing hydroxides within the epithelium to adjust the tumor microenvironment to a weakly acidic state, releasing hydrogen gas to activate the immune response, inducing hydrogen gas therapy, and amplifying the effect of embolization therapy. This demonstrates a superior combined therapeutic effect compared to embolization therapy using only polymer microspheres.