772 results about "Tumor Microenvironments" patented technology

The invention belongs to the fields of immunology and cell biology, and relates to a tumor precision T cell containing an efficient killing starting mechanism and an application of the tumor precision T cell, in particular to a CAR (chimeric antigen receptor) having moderate-affinity binding characteristic with a broad-spectrum expression membrane antigen on the tumor cell surface as well as a new-generation tumor precision T cell, namely, Baize T. T cell activation is started rapidly under the action of the CAR having the moderate-affinity binding characteristic, an activation signal of the CAR is superposed with a TCR (T cell receptor) signal with tumor antigen natural recognition capacity in a CTL (tumor-specific cytotoxic T lymphocyte), the CTL is activated to proliferate and grow in a tumor microenvironment, and a tumor cell is killed preciously by the tumor-antigen-specific TCR. The tumor precision T cell has broad anti-tumor application prospect.

The present invention relates to new compositions and methods useful for preventing, treating and diagnosing metastatic and / or invasive cancer and undesirable angiogenesis. For example, the invention relates to inhibitors of proteases that are specifically expressed in tumors, prodrugs activated in the tumor microenvironment and methods for using those inhibitors and prodrugs to inhibit angiogenesis and tumor cell invasion.

The invention relates to a hyaluronic acid-modified amphipathic chitosan derivative carrier with tumor microenvironment specificity drug release effect. The hyaluronic acid-modified amphipathic chitosan derivative carrier is characterized in that firstly, a hydrophilic group is introduced into a chitosan skeleton; then, a hydrophobic group is introduced into a specifically degradable link arm containing disulfide bonds, so as to realize the amphipathic function; the amphipathic derivative is assembled into nanomicelle by self in a waterborne medium, and is further modified by a charge adsorbing principle to target the molecular hyaluronic acid; the nanomicelle can effectively load an anti-tumor drug, and the hyaluronic acid is targeted to the tumor microstructure and then is degraded by hyaluronic acid enzyme in focus cells, so that the drug can be quickly released from the nanomicelle to act on the focal part, thereby obviously improving the concentration, therapy effect and biological utilization degree of free drug on the focal part. The hyaluronic acid-modified amphipathic chitosan derivative carrier has the advantages that the carrier which carries pharmaceutical activity or pharmacological activity molecules can be applied to internal injection of blood vessels or muscles or oral administration, so as to obviously improve the anti-tumor activity of drug; the preparation method is simple, the technology is matured, and the preparation method is suitable for large-scale production.

Disclosed are methods of making a genetically modified immune cell for modifying a tumor microenvironment (TME) and methods of modifying a tumor microenvironment (TME). In some embodiments, the method can include delivering a first vector to an immune cell, wherein the first vector comprises a nucleic acid encoding a protein that induces T-cell proliferation, promotes persistence and activation of endogenous or adoptively transferred NK or T cells and / or induces production of an interleukin, an interferon, a PD-1 checkpoint binding protein, HMGB1, MyD88, a cytokine or a chemokine. Methods of modulating the suppression of the immune response in a tumor microenvironment, minimizing the proliferation of tumor and suppressive cells, and increasing the efficiency of an anti-cancer therapy, anti-infection therapy, antibacterial therapy, anti-viral therapy, or anti-tumoral therapy are also provided.

The invention discloses a quercetin drug-loading system based on a copper sulphide-metal organic frame material. A metal organic frame zeolite imidazolate framework material (ZIF-8) is generated on the surfaces of copper sulphide nano-particles (CuS NPs) as a photothermal preparation to obtain a CuS@ZIF-8 carrier, quercetin is adsorbed into a carrier, and then is modified by a stabilizer and a targeting agent FA-BSA, and thus, a nano delivery system (FA-BSA / CuS@ ZIF-8) with a targeting active effect and pH response can be formed. The water solubility and the chemical stability of the quercetinare improved, good curative effect of treating tumors by combination of phototherapy and chemotherapy can further be played, meanwhile, drug can be rapidly released under the condition of low pH in atumor microenvironment, the tumor cell intake of a pharmaceutic preparation is further enhanced, and the quercetin drug-loading system based on the copper sulphide-metal organic frame material has low toxicity to normal cells, and is good in biological compatibility.

The invention provides a nanogel with hydrophilic and hydrophobic reversal, charge reversal and intracellular redox responsiveness on the basis of pH regulation. The nanogel is prepared by cross-linking of thermo-sensitive monomer with controllable radical polymerization, amphoteric ionic monomer and amido-containing pH sensitive monomer through a disulfide-bond-containing cross-linking agent. The invention further provides a nanogel drug carrier system with smart response to tumor microenvironment and its preparation method. On the condition of blood pH 7.4, the nanogel is in a hydrophilic swelling state that is favorable for avoiding being phagocytosed by the reticuloendothelial system (RES) and accordingly, the nanogel has blood long circulation capacity; on the condition of tumor tissue subacidity, the state of the nanogel is reversed into a hydrophobic shrinking state that is favorable for the nanogel to realize effective concentration, depth penetration and be absorbed effectively by tumor cells on the tumor location. Besides, in the intracellular lysosome environment, negative charge of the nanogel is reversed into positive charge, which is favorable for the nanogel to escape from the lysosome; and then the nanogel releases drugs responsively in cytoplasm high-GSH environment, thereby achieving a good tumor inhibition effect.

The disclosed method of treating a malignant solid tumor in a subject includes the steps of administering to the subject an immunomodulatory dose of a radioactive phospholipid ether metal chelate, a radiohalogenated phospholipid ether, or other targeted radiotherapy (TRT) agent that is differentially retained within malignant solid tumor tissue, and either (a) performing in situ tumor vaccination in the subject by introducing into at least one of the malignant solid tumors one or more agents capable of stimulating specific immune cells within the tumor microenvironment, or (b) performing immunotherapy in the subject by systemically administering to the subject an immunostimulatory agent, such as an immune checkpoint inhibitor. In a non-limiting example, the radioactive phospholipid ether metal chelate or radiohalogenated phospholipid ether has the formula:wherein R1 comprises a chelating agent that is chelated to a metal atom, wherein the metal atom is an alpha, beta or Auger emitting metal isotope with a half-life of greater than 6 hours and less than 30 days, or wherein R1 comprises a radioactive halogen isotope. In one such embodiment, a is 1, n is 18, m is 0, b is 1, and R2 is —N+(CH3)3.

The invention discloses a preparation method of polysaccharide-based nanometer particles sensitive to tumor microenvironments. The preparation method comprises the steps: preparing an initiator solution by adding an initiator to a water-soluble polysaccharide solution and adjusting pH, then adding a monomer-containing solvent (or directly adding monomers) and a cross-linking agent sensitive to reducing environments for carrying out polymerization and cross-linking reaction so as to obtain nanometer particles, and finally carrying out dialysis or centrifugal treatment and freeze drying to obtain the polysaccharide-based nanometer particles sensitive to tumor microenvironments. The preparation method is green, pollution-free, high in yield, efficient and convenient in synthesis and low in cost; the prepared polysaccharide-based nanometer particles are high in solid content and uniform in particle sizes; due to introduction of the cross-linking agent sensitive to reducing environments, the nanometer particles sensitive to tumor microenvironments can be prepared and have a wide application prospect in aspects of design and application of carriers for tumor treatment.

A microfluidic device provides high throughput generation and analysis of defined three-dimensional cell spheroids with controlled geometry, size, and cell composition. The cell spheroids of the invention mimic tumor microenvironments, including pathophysiological gradients, cell composition, and heterogeneity of the tumor mass mimicking the resistance to drug penetration providing more realistic drug response. The device is used to test the effects of antitumor agents.

The invention discloses a metal organic framework material for enhancing combination of chemodynamic therapy and hunger therapy as well as a preparation method and application thereof, wherein the material can decompose excessive glutathione in a tumor microenvironment to generate metal ions capable of catalyzing Fenton-like reaction. A pH-responsive metal-organic framework material ZIF-8 is usedfor in-situ growth and is coated with a substance capable of decomposing glucose, and the surface of the material is modified with a metal oxide, so that a composite material system is obtained. The metal oxide can react with glutathione to generate metal ions, ZIF-8 is decomposed to release drugs or biological enzymes under the condition of low pH, glucose can be decomposed to generate hydrogen peroxide, and the metal ions subjected to Fenton-like reaction catalyze hydrogen peroxide to generate toxic .OH, so that the effect of combining chemodynamic therapy and hunger therapy is achieved. Thematerial system is good in biocompatibility, reduces the toxic effect of traditional chemical drug therapy on normal cells, and is expected to be applied to cancer treatment in the future.

The invention discloses a programmed multi-target tree-shaped macromolecular assembled body medicine conveying system as well as a preparation method and application thereof and belongs to the field of biomedical materials. The medicine conveying system taking an amphipathic tree-shaped macromolecular assembled body as a carrier is used for realizing programmed multi-target through responding a tumor micro-environment, so that main biological obstacles met in a process of transferring the medicine carrier in a body are overcome, and finally, medicines are conveyed to the destination. The obtained self-assembled body has a multi-target effect through the functionalization effect of a plurality of types of terminal groups. On one hand, tree-shaped molecules are used as the medicine carrier and have the advantages of good stability, high mechanical strength, multivalent terminal groups, hyper-branched structures, and intracellular conveying of echoviruses; on the other hand, a multi-element cooperated self-assembling policy is integrated with the advantages of all functional groups on a tree-shaped macromolecular self-assembled unit, so that the assembled body can be conveyed by the multifunctional and efficient medicine system. The system is particularly suitable for conveying anti-tumor medicines.

The invention discloses a gene for encoding anti-BCMA chimeric antigen receptor. The nucleotide sequence of the gene is represented by SEQ ID NO:2. The invention also discloses a recombinant expression vector containing the gene, and a myeloma BCMA antigen-targeted transgenic T cell. The transgenic T-cell is a primitive cell containing the recombinant expression vector and knocked out of a PD1 gene or / and a CTLA4 gene, or is a primitive cell with the chromosome being integrated with the gene for encoding anti-BCMA chimeric antigen receptor and knocked out of tbe PD1 gene or / and the CTLA4 gene.A preparation method of the transgenic T-cell comprises the following steps: mixing of gRNA, CRISPR-cas9 mRNA and HDR mix, and electrotransformation recombination of the T cell. The invention furtherdiscloses an application of the myeloma BCMA antigen-targeted transgenic T cell in the preparation of drugs for treating multiple myeloma. In the construction process of carT of, a recognition sequence of EGFR is introduced, EGFR monoclonal antibody Cetuximab is used to eliminate a carT cell if necessary, and PD1 and CTLA4 genes are knocked out to relieve the inhibition effect of the PD1 and CTLA4 genes on the carT cell and enhance the overcoming effect of the carT cell on the inhibition of the tumor microenvironment on immune cell functions.

The invention relates to an extracorporal building method of a tumor microenvironment and an application of the method. By using the method, a three-dimensional stent similar with a cell internal microenvironment is built and total cells of tumor tissues are inoculated to promote recovery of physiological activity of all cells, so that a tumor microenvironment is built for drug screening for individual-based tumor treatment.

The invention discloses a branched polyHPMA copolymer-DOX conjugate, and the preparation method and the application thereof, and belongs to the field of biological materials. According to the invention, the branched polyHPMA copolymer-DOX conjugate is successfully prepared through one step of RAFT polymerization. DOX in the conjugate is connected with a branched polyHPMA copolymer through a pH sensitive key, and biodegradable fragments are contained in a branched polyHPMA copolymer framework. The conjugate is excellent in biocompatibility, has dual sensitive characteristics of pH sensitivity and enzyme sensitivity, and serves as an intelligent drug delivery system to form nano particles to intensively gather in tumor sites, quickly release drug under a tumor microenvironment and be degraded to be low molecular weight fragments, therefore, excellent biosecurity is ensured while the antineoplastic effect is improved, and the branched polyHPMA copolymer-DOX conjugate has a wide application scope in tumor therapy.

The invention discloses gene sets and a scoring model for evaluating a tumor microenvironment, and application of the gene sets, and belongs to the field of biological information. It is proved for the first time that the gastric cancer has remarkable tumor microenvironment typing, and prognosis difference of gastric cancer patients with different typing is remarkable. According to a constructionmethod of the multi-gene scoring model for evaluating the gastric cancer tumor microenvironment, 44 gene sets capable of representing different microenvironment types are screened out, and the prediction efficiency of the tumor microenvironment multi-gene scoring model corresponding to the gene sets is remarkably better than that of other existing models; and the model is not only a prognostic marker of a gastric cancer patient, but also has a quite remarkable prediction effect in pan-cancer. The model provided by the invention not only can be used as a good prognosis biomarker, but also can be used for predicting checkpoint inhibitor immunotherapy response of various tumors by effectively evaluating the tumor microenvironment, and has important significance and clinical application valuefor better screening immunotherapy benefiting people.

Dysfunctional or exhausted T cells arise in chronic diseases including chronic viral infections and cancer, and express high levels of co-inhibitory receptors. Therapeutic blockade of these receptors has clinical efficacy in the treatment of cancer. While co-inhibitory receptors are co-expressed, the triggers that induce them and the transcriptional regulators that drive their co-expression have not been identified. The immunoregulatory cytokine IL-27 induces a gene module in T cells that includes several known co-inhibitory receptors (Tim-3, Lag-3, and TIGIT). The present invention provides a novel immunoregulatory network as well as novel cell surface molecules that have an inhibitory function in the tumor microenvironment. The present invention further provides the novel discovery that the transcription factors Prdm1 and c-Maf cooperatively regulate the expression of the co-inhibitory receptor module. This critical molecular circuit underlies the co-expression of co-inhibitory receptors in dysfunctional T cells and identifies novel regulators of T cell dysfunction.

The invention belongs to the field of preparation of nanomaterials and particularly relates to a preparation method of a degradable silicon dioxide particle internally doped with a polyphenol-metal mesh. According to the preparation method, a silicon dioxide polycondensation network system is doped with a metal-polyphenol coordinated and complexed network structure, so that porosity of silicon dioxide is increased; and the polycondensation degree of silicon dioxide is further weakened by virtue of a hydrogen-bond interaction between hydroxyl and silanol, so that the hydrolytic degradation of silicon dioxide is accelerated. The metal-polyphenol coordinated and complexed network structure can be dissociated under faintly-acid and high-glutathione environments so as to induce the collapse of a silicon dioxide skeleton structure, nano-particles are degraded into smaller fragments, and then silicic acid molecules, polyphenol molecules and metal ions are further degraded and extracted, so that the self-degradation of a drug carrier in a tumor microenvironment is realized.

Methods and compositions for improving the delivery and / or efficacy of a therapy (e.g., an anti-cancer, anti-fibrotic or anti-inflammatory therapy) are disclosed. The invention is based, at least in part, on the discovery that metformin, a widely prescribed anti-diabetic drug, can affect the tumor microenvironment (e.g., directly, i.e., independent of its effects on cancer cells themselves or tumor metabolism). In embodiments described herein, metformin has been shown to reduce the amount of extracellular matrix, including collagen 1 and hyaluronan, in the fibro-inflammatory tumor microenvironment in a subject (e.g., a subject with a desmoplastic tumor).

A three-dimensional cell culture system is provided comprising one or more cell types of interest incorporated in a natural or synthetic hydrogel. An apparatus for high-throughput drug screening is also provided comprising a plurality of three-dimensional cell culture systems and a dispenser for placing at least one three-dimensional cell culture system into a pre-determined well of a multiwell plate. A method for high-throughput drug screening is also provided that comprises providing a test agent, providing a three-dimensional cell culture system, determining a first cellular response of the cell of interest before culturing in the presence of the agent, culturing the cell of interest in the cell culture system in the presence of the agent, determining a second cellular response of the cell of interest after culturing in the presence of the agent, and comparing the first and second cellular responses.

The invention belongs to the field of biological medicines, and relates to application of nanoparticles, in particular to application of the nanoparticles as tumor microenvironment responsive drugs orimaging agents. The nanoparticle comprises a chelate shell formed by tannic acid and ferric ions, and chemotherapeutic drugs are entrapped in the chelate shell. In a tumor microenvironment, the nanoparticle can slowly release a chemotherapeutic drug entrapped in the nanoparticle and slowly release iron ions in the nanoparticle to enhance the nuclear magnetic resonance imaging effect. The technical scheme can be applied to medical practice of tumor imaging and tumor treatment.

The invention discloses an 18F-labeled compound and a pod protease targeted PET imaging probe, which relates to the technical fields of radiopharmaceuticals and nuclear medicine. The invention provides a compound shown as a formula (I), asparagine site shearing and disulfide bond reduction are carried out in a tumor microenvironment with high expression of pod protease, and a radioactive dimer 18F-1-dimer is formed by virtue of a biocompatible CBT-Cys click condensation reaction, so that the tumor imaging effect is improved. The compound with a structure shown in the formula (I) is synthesizedby adopting a one-step ion exchange 18F labeling method, the method is simple to operate, and preparative HPLC for further purification is not needed. The invention further provides the pod proteasetargeted PET imaging probe which is a compound shown in (I). The PET imaging probe has the advantages of high stability, high sensitivity, strong specificity, good safety and the like.

Development of a physiologically relevant 3D model system for cancer research and drug development represents quite a challenge. We have adopted a 3D culture system based on a transglutaminase-crosslinked gelatin gel (Col-Tgel) to mimic tumor 3D microenvironment. The system has several unique advantages over other alternatives which include cell-matrix interaction sites provided by collagen derived peptides, a 3D construct suitable for reproducing the solid tumor microenvironment including multicellular tumor spheroids and metabolic gradients. In addition the controllable gel stiffness provides a wide range of mechanical restrictions; and compatibility with imaging based screening due to its transparent properties. In addition the Col-Tgel provides a cure-in-situ delivery vehicle for tumor xenograft formation in animals with a high take rate. Overall, this unique 3D system could provide a platform to accurately mimic in vivo situations to study tumor formation and progression both in vitro and in vivo, as well as for screening antineoplastic drugs and assessing the occurrence of drug resistance related to cancer cell stress.

The invention relates to a charge reversal Pulullan derivative and a synthesis method and application thereof. The Pulullan derivative is composed of a Pulullan framework, a multi-amino modified group and a beta-carboxylic acid amide modified group, has remarkable liver / liver cancer targeting property, and can quickly respond to a faintly acid tumor microenvironment and a cell endosome / lysosome so as to achieve reversal from electronegativity to electropositivity. By modifying poly(beta-amino ester) (PBAE) / polylactic acid-polyglycolic acid copolymer (PLGA) composite nanoparticles with the Pulullan derivative, liver cancer targeted delivery of nanoparticles can be mediated efficiently, effective release of a carried drug at the tumor position is achieved, and the charge reversal Pulullan derivative is a liver / liver cancer targeted carrier material with excellent performance for drugs, genes and image contract agents and has broad application space.

The invention relates to a targeted CSF1R chimeric antigen receptor modified NK92MI cell, a T cell, and a preparation method and application of the cells. Specifically, the invention provides a chimeric antigen receptor CAR, the chimeric antigen receptor CAR comprises an antigen binding structure domain, and the antigen binding structure domain combines with a CSF1R antigen. A fusion protein can kill M2 type tumor related macrophage in the tumor microenvironment so as to damage the tumor (particularly a solid tumor) microenvironment, and the fusion protein can be used together with other medicines for treating cancers or tumors to treat the cancers or the tumors.

The invention relates to an anti-PD-L1 nano antibody as well as a derivative and an application thereof. Specifically, the invention provides an anti-PD-L1 nano antibody, and the antibody has a function of blocking binding of PD-L1 and a receptor PD-1. Moreover, the invention provides a gene sequence for encoding the nano antibody, a corresponding expression vector, a host cell capable of expressing the nano antibody, and a production method of the nano antibody. Meanwhile, the invention also provides a fusion protein with the PD-L1 nano antibody and an immunomodulatory molecule part, which can inhibit a PD-1 / PD-L1 pathway on the basis of targeting and neutralizing TGF-beta of a tumor microenvironment, can restore the activity of T cells, enhances immune response, and more effectively improves the effect of inhibiting tumor generation and development.

Provided herein are activatable anti-human CTLA-4 antibodies comprising a heavy chain comprising a VH domain and a light chain comprising a masking moiety (MM), a cleavable moiety (CM), and a VL domain. Such activatable anti-human CTLA-4 antibodies have CTLA-4 binding activity in the tumor microenvironment, where the masking moiety is removed by proteolytic cleavage of the cleavable moiety by tumor-specific proteases, but exhibit greatly reduced binding to CTLA-4 outside the tumor. In this way, the activatable anti-human CTLA-4 antibodies of the present invention retain anti-tumor activity while reducing the side effects associated with anti-CTLA-4 activity outside the tumor.

The invention discloses a preparation method of drug-loaded microspheres with tumor microenvironment responsiveness. The microspheres are mainly prepared based on a silica colloidal crystal microsphere template and a hydrogel, and loading and encapsulation of a drug are realized respectively through the physical adsorption of the drug and the wrapping of a tumor microenvironment responsive material. The drug-loaded microspheres are prepared by the microfluidic technology, have a three-dimensional penetration nano-porous structure, and can realize loading with a large amount and slow-release ofthe drug. In addition, the tumor-responsive material wrapped on the surface of the microspheres can protect the drug from being degraded until the drug reaches the tumor site. The drug-loaded microspheres prepared by the method of the invention have good biocompatibility and biological functionality, and exhibit great value in the field of tumor drug delivery.

The invention relates to a fusion protein of an IFN and an anti-PD-L1 antibody, a pharmaceutical composition containing the fusion protein and a kit as well as an application of the fusion protein intumor treatment. The fusion protein can be targeted to PD-L1 and IFN receptors at the same time. An IFN signal in a tumor microenvironment is activated by inducing more powerful T cell activation to enhance PD-1 / PD-L1 treatment on tumors; meanwhile, the anti-PD-L1 antibody can be used for specifically transferring immunoregulation molecules to tumor tissues. The fusion protein acts to generate multiple feedforward responses, so that the targeting effect is increased and the toxicity is reduced, and response to IFN treatment is enhanced, so that the anti-tumor effect is maximized.

The invention relates to the technical field of a biomedical nano material, and more particularly to a tumor microenvironment responsive diagnosis and treatment integrated nano probe and a preparationmethod thereof. The nano probe uses bovine serum albumin as a template and a sulfur source to construct nanoparticles having uniform dispersion and uniform particle size with Bi2S3 and MnO2 by a biomineralization mode, and an activated carboxyl group of bovine serum albumin is cross-linked with an amino group of a peptide chain to link a matrix metalloproteinase-responsive peptide chain to provide the nano probe with multimodal imaging and treatment. The material is subjected to matrix metalloproteinases in the tumor microenvironment, and the peptide chain is sheared to promote the hydrophobic chain exposure, which results increase in the hydrophobic properties of the nanoparticles, the degree of enrichment of the material in the tumor site is enhanced, which can effectively improve the imaging and therapeutic performance of the nano probe.