254 results about "Tumor microenvironment" patented technology

The present invention is based on the seminal discovery that targeted immunomodulatory antobodies and fusion proteins can counter act or reverse immune tolerance of cancer cells. Cancer cells are able to escape elimination by chemotherapeutic agents or tumor-targeted antobodies via specific immunosuppressive mechanisms in the tumor microenvironment and such ability of cancer cells is recognized as immune tolerance. Such immuno-suppressive mechanisms include immunosuppressive cytokines (for example, Transforming growth factor beta (TGF-β)) and regulatory T cells and / or immunosuppressive myeloid dendritic cells (DCs). By conteracting tumor-induced immune tolerance, the present invention provides effective compositions and methods for cancer treatment, optional in combination with another existing cancer treatment. The present invention provides strategies to counteract tumor-induced immune tolerance and enhance the antitumor efficacy of chemotherapy by activating and leveraging T cell-mediated adaptive antitumor immunity against resistant or disseminated cancer cells.

The invention provides a lipidosome-polymer drug-loaded nanoparticle and a preparation method and application thereof. The lipidosome-polymer drug-loaded nanoparticle comprises a three-layer structure, wherein the innermost layer is the drug-loaded nanoparticles formed by taking an amphiphilic cationic polymer as a carrier-coated chemotherapeutic drug; the intermediate layer is a platelet inhibitor layer adsorbed onto the surface of the drug-loaded nanoparticles; and the outermost layer is a lipid bilayer connected with tumor microenvironment responsiveness polypeptides. The lipidosome-polymer drug-loaded nanoparticle disclosed by the invention is capable of specifically targeting tumor tissues, has tumor microenvironment responsiveness, and can achieve the effects of improving tumor vascular permeability without influencing functions of blood vessels at normal tissue or cell parts, enhancing permeability and retention of the drug-loaded nanoparticles to tumor cells, enhancing the EPR effect, improving enrichment of the drug-loaded nanoparticles at tumor location and realizing high tumor killing efficiency.

The present invention includes methods and compositions for treating cancer, whether a solid tumor or a hematologic malignancy. By expressing a chimeric antigen receptor in a monocyte, macrophage or dendritic cell, the modified cell is recruited to the tumor microenvironment where it acts as a potent immune effector by infiltrating the tumor and killing the target cells. One aspect includes a modified cell and pharmaceutical compositions comprising the modified cell for adoptive cell therapy and treating a disease or condition associated with immunosuppression.

The invention discloses a gold nanocage-manganese dioxide composite nanoparticle as well as a preparation method and application thereof, and relates to the technical field of nanoparticle photodynamic therapy. The composite nanoparticle comprises a gold nanocage inner core and a manganese dioxide shell layer. The preparation method is characterized in that potassium permanganate is reduced by a one-step reduction method; the manganese dioxide shell layer covers the surface of the gold nanocage, wherein the gold nanocage inner core achieves a photodynamic curative effect under the triggering of near-infrared light; the manganese dioxide shell layer is degraded in tumor microenvironment and releases oxygen, so that the tumor oxygen deficiency is relieved, and the photodynamic curative effect is enhanced; on the other hand, the opto-acoustic and magnetic resonance bimodule imaging can also be realized. The problem of insufficient photodynamic curative effect caused by factors such as tumor oxygen deficiency and photodynamic oxygen consumption of a nanometer photosensitizer used in the prior art is solved. The photodynamic curative effect of the gold nanocage-manganese dioxide composite nanoparticle is obvious; the gold nanocage-manganese dioxide composite nanoparticle can be applied to tumor targeted oxygenation photodynamic diagnosis and treatment integration.

The invention discloses an exosome-encapsulated nano drug-loading system for tumor treatment, and preparation thereof. The system is obtained by utilizing cell endocytosis of a drug-loading nanometermaterial and then exocytosis. The drug-loading nanometer material is loaded with an antitumor medicine including at least one of a chemotherapeutic, a medicine used for immunotherapy and a medicine used for modifying a tumor microenvironment. The composition, structure and the like of the key outer component biofilm encapsulating the nano drug-loading system are improved, and compared with the prior art, the exosome-encapsulated nano drug-loading system provides a novel route for biofilm-based biological processed nanoparticles. By utilization of the exosome-encapsulated nano drug-loading system, the composition and the structure of the exosome can be maintained greatly, and the obtained exosome-encapsulated nano drug-loading system has good stability and tumor targeting performance duringblood circulation. .

The invention discloses a preparation method and application of a PD-1 / CTLA-4 (programmed death-1 / cytotoxic T lymphocyte antigen-4) bispecific antibody. The preparation method comprises the following steps of using a single-chain antibody gene as a template and introducing disulfide bond into a variable region of the antibody by a particular high-efficiency amplification primer through PCR (polymerase chain reaction) and Overlap PCR through a gene engineering technique, so as to prepare a PD-1 / CTLA-4 bispecific antibody fragment; cloning the gene fragment to a chronic virus expression carrier, and transfecting 293T cells to package the virus; transducing a CIK (cytokine induced killer) cell, separating PBMC (peripheral blood mononuclear cell) from peripheral blood of a health person, using CD3 / CD28 magnetic beads to stimulate the growth of the T cell, and co-culturing the chronic virus and the T cell, so as to obtain a novel anti-tumor T cell which can block an immunosuppression signal of the tumor and tumor micro environment source, and enhance the function of killing cancer cells.

The invention belongs to the field of organic synthesis or pharmaceutical preparations and relates to a synthesis method of a hyaluronic acid-photosensitizer / antitumor drug with synergistic anti-tumor efficacy and a preparation method of a nano drug delivery system. Conjugates are amphiphilic by connecting a photosensitizer and an indissolvable antitumor drug on a hyaluronic acid skeleton by ester bonds and are self-assembled in water to obtain a nanomicelle. The synthesis method and the preparation method are characterized by comprising the synthesis method of covalent linkage of hyaluronic acid and a photosensitizer / antitumor drug and a method for self-assembling the nano drug delivery system by the hyaluronic acid-photosensitizer / antitumor drug. The system is expected to have good biocompatibility and active targeting property of tumors in a body; the solubility of the indissolvable antitumor drug can be improved, the phagocytosis of a reticuloendothelial system is avoided, and the cycle time in the body is prolonged; after the system reaches a lesion location, the ester bonds of the system are fractured in a tumor microenvironment under the condition of a low pH value and releases the photosensitizer and the antitumor drug; the system is excited by near-infrared light to generate heat and fluorescence; on one hand, tumor cells are killed and wounded by a phototherapy and chemotherapy combined mode; on the other hand, distribution conditions of the tumor cells in the body can be characterized.

The invention discloses a carrier-free co-assembled tumor targeting anti-cancer nano medicine as well as a preparation method and application thereof. The carrier-free dual anti-cancer nano medicine is prepared from a hydrophobic medicine, namely ursolic acid, together with board-spectrum anti-tumor medicines such as doxorubicin in water through co-assembling, in addition, a fluorescence labeling nucleic acid aptamer, a molecular target, an antibody or polypeptide and the like with tumor targeting functions are adsorbed to the surface of the medicine through mutual electrostatic functions, then the carrier-free co-assembled tumor targeting anti-cancer nano medicine with tumor targeting and tumor microenvironment response is prepared, a synergic anti-tumor function is achieved, diagnosis and treatment integration is achieved, particularly the medicine has outstanding functions in preventing tumor transfer, and more importantly the problems that a conventional nano carrier is complex in system, indefinite in in-vivo metabolism and the like are solved.

The invention provides a multi-nuclide multi-frequency resonance synchronous imaging system which is used for detecting the tumor ion dynamic balance, the energy metabolism, the molecular target change and the tumor microenvironment change. The system can simultaneously transmit radio frequency pulse signals corresponding to four nuclides of 1H, 23Na, 31P and 19F and synchronously receive the nuclear magnetic resonance load signals of the four nuclides. The multi-nuclide multi-frequency resonance synchronous imaging system comprises a signal excitation system, a multi-nuclide multi-frequency signal excitation and acquisition system, a magnetization system and an imaging system. The multi-nuclide multi-frequency signal excitation and acquisition system comprises four nuclide channel modules of 1H, 23Na, 31P and 19F, and each nuclide channel module comprises a signal excitation power amplifier submodule and a signal acquisition submodule. The magnetization system comprises magnets and radio frequency transmitting coils. The imaging system comprises a signal preamplifier, a signal acquisition command module, an image reconstruction module, an image post-processing and display module and an image database.

The invention relates to an albumin-stabilized MnO2 nanomaterial as well as a preparation method and an application. The albumin-stabilized MnO2 nanomaterial is a multi-component BMnNSs-HPPH nanocomposite. The nanomaterial is a multi-component nanocomposite (BMnHNCs) with good water dispersity and is formed by loading a photosensitizer HPPH in a BSA-MnO2 nanosheet. By the aid of high reactivity and high specificity of MnO2 for endogenous H2O2 under the acid condition, BMnHNCs can realize NIRF and MRI bimodal imaging response to the tumor microenvironment and tumor microenvironment enhanced photodynamic therapy. The nanocomposite has good biocompability and biodegradability and safe and efficient diagnosis and treatment capacity, will provide a new idea for comprehensively regulating the tumor microenvironment and improving tumor diagnosis and treatment capacity and has greater potentials in the aspects of clinical conversion.

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 present disclosure relates to an Extra Cellular Matrix composition specific for cancer type and a tumor microenvironment platform for long term culturing of tumor tissue, wherein said culturing provides human ligands and tumor tissue micro-environment to mimic physiologically relevant signalling systems. The present disclosure further relates to the development of a Clinical Response Predictor and its application in the prognostic field (selection of treatment option for the patient) and translational biology field (development of anticancer drugs). The disclosure further relates to a method of predicting clinical response of a tumor patient to drug(s). The disclosure further relates to a method for screening tumor cells for the presence of specific markers for determining the viability of said cells for indication of tumor status.

The invention discloses an internally and externally refined composite nano photosensitizer as well as a preparation method and application thereof and belongs to the technical field of nanometer biomedicine. The preparation method disclosed by the invention comprises the following steps: removing a surface ligand from rare-earth upconversion nanoparticles, and modifying by a photosensitizer to obtain an upconversion nano photosensitizer; and coating luminescence molecules and the upconversion nano photosensitizer by virtue of hydrophobic-hydrophobic interactions by adopting amphiphilic polymers, thereby obtaining the composite nano photosensitizer. The composite nano photosensitizer is capable of simultaneously responding to stimulus of a tumor microenvironment so as to realize internal photodynamic force and external photodynamic force under near-infrared light excitation. By combining the characteristic that hydrogen peroxide and the like is highly expressed in the tumor microenvironment with the characteristic of upconversion emission of near-infrared light excitation, tumors are inhibited in both modes in an internally and externally refined manner. After a covalent or chemical coordination manner on the surface of the rare-earth upconversion nanoparticles is combined with the photosensitizer, the energy transfer efficiency can be improved, the singlet oxygen yield is increased, and the photodynamics therapy effect under external excitation can be effectively improved.

The invention relates to a micromolecular conjugate based on RGD polypeptide-chemotherapy drug and a self-assembly nanometer prodrug system thereof, and belongs to the technical field of biological medicine and nanometer medicine. The nanometer prodrug system has the main advantages that (1) the system is formed by RGD polypeptide and an anti-tumor drug through direct covalent connection via micromolecular connecting arms, and the drug loading capacity of the system is improved; (2) the conjugate is self-assembled into a nanometer prodrug using the drug as a hydrophobic inner core and the RGD polypeptide as a hydrophilic outer shell, the active targeting on tumor cells and tumor new vessels is realized through the ligand-receptor mutual action, and the endocytosis is promoted; (3) the stability of the nanometer prodrug system in the body circulation can be ensured through thioether bonds, reduction sensitive bonds and cathepsin B sensitive bonds, and the cytotoxic drug is released when the nanometer prodrug system reaches the tumor microenvironment; and (4) the micromolecular conjugate instead of a macromolecular material is used as a carrier, so that the nanometer prodrug system can favorably and better penetrate into the tumor tissues and cells to achieve better anti-tumor effects.

The invention discloses a transgenic T cell of a targeted CD30 antigen. The transgenic T cell is a primary cell which is integrated with a gene shown as SEQ ID NO:2 and encoding the targeted CD30 antigen, and knocks out a PD1 gene and / or CTLA4 gene, or is a primary cell containing a recombinant lentivirus expression vector (including a gene which is shown as SEQ ID NO:2 and encodes the targeted CD30 antigen and shRNA of a targeted PD1 gene or / and shRNA of a targeted CTLA4 gene); the primary cell is CD4+T cell or CD8+T cell. A preparation method comprises the following steps: firstly, carryingout lentivirus infection on the CD4+T cell or the CD8+T cell; secondly, mixing gRNA, CRISPR-cas9mRNA and HDR, and carrying out electroporation recombination on the T cell to obtain a finished product.According to the transgenic T cell disclosed by the invention, a recognition sequence of an EGFR (Epidermal Growth Factor Receptor) is introduced in carT construction; if necessary, a carT cell can be eliminated by using EGFR monoclonal antibody Cetuximab, the PD1 gene and the CTLA4 gene are knocked out or silenced, inhibition of the gene to the carT cell is eliminated, and the function of overcoming a tumor microenvironment and inhibiting immune cells by the carT cell are enhanced.

The invention relates to the technical field of biomedicine, in particular to a hydrogen peroxide-responsive liposomal nanoprobe and a preparation method and application thereof. The liposomal nanoprobe comprises a liposome, HRP and ABTS, wherein a hydrophilic cavity of the liposome is loaded with HRP, and a hydrophobic layer of the liposome is loaded with ABTS. The hydrogen peroxide-responsive liposomal nanoprobe prepared by the invention has very good hydrogen peroxide responsiveness, and can realize the detection of nano hydrogen peroxide. Compared with the traditional method for detecting hydrogen peroxide by fluorescence or bioluminescence, the photoacoustic imaging detection can significantly improve the depth of penetration of tissues to achieve the hydrogen peroxide imaging of deep tissues; the photoacoustic imaging of the liposome nanoprobe can monitor the occurrence and development of inflammation in real time, and the liposome nanoprobe can react with hydrogen peroxide in a tumor microenvironment to achieve the photoacoustic imaging of tumors.

Compositions comprising CD80-targeted therapeutics and methods of using these compositions are provided for the treatment of a disease or disorder in which CD80-expressing cells or regulatory T cell function contribute to or exacerbate the associated pathology.

Methods for treating, preventing or delaying onset of tumor formation and other forms of cancer are disclosed. The methods involve administration of a complement inhibitor to inhibit C5a receptor signaling in the tumor microenvironment.

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 polydopamine nano diagnosis and treatment preparation and a preparation method thereof. The nano diagnosis and treatment agent is prepared by the following steps: taking mesoporous polydopamine as a carrier, respectively supporting rhodium nanoparticles in the hole and on the surface of the mesoporous polydopamine by virtue of a hydrothermal synthesis reaction, and adsorbing a photosensitizer dihydroporphin (Ce6) onto the polydopamine and rhodium nanoparticles, thereby obtaining the polydopamine nano diagnosis and treatment agent with excellent dispersion property. Byutilizing photothermal effects of the carrier mesoporous polydopamine and the rhodium nanoparticles, the temperature of the tumor site is locally raised. By combining with catalytic characteristics of the rhodium nanoparticles, hydrogen peroxide in a tumor microenvironment is catalyzed to decompose so as to produce oxygen, and aims of producing singlet oxygen and effectively killing cancer cellsare achieved under the conditions of the photosensitizer Ce6 and applied laser. Meanwhile, by combining with photoacoustic imaging characteristics of the polydopamine, the aim of guiding photothermaltherapy and photodynamic synergistic therapy by photoacoustic imaging can be achieved, and the tumor treatment effect is expected to be improved. Moreover, the polydopamine nano diagnosis and treatment agent is excellent in biocompatibility, and has clinical application potential.

The invention discloses an in-vitro construction method of a liver cancer organ model. Liver cancer cells, hepatic stellate cells and liver sinusoidal endothelial cells are suspended in a culture medium A in a specific proportion; on the fourth day of culture, half of culture liquid is replaced, and culture is maintained; from the seventh day, the culture medium A is replaced with a culture mediumB, and then culture is continuously conducted for seven days; amplification subculture is conducted on the fourteenth day. On the basis of complex cellularity in a tumor microenvironment, the 3D liver cancer organ in-vitro model which is uniform in size, stable in structure, capable of being used for detecting the effectiveness of anticancer drugs and capable of achieving multiplication culture is quickly constructed. The constructed liver cancer organ model is simple in method, quick to construct, high in operability and suitable for researching a liver cancer generation and development mechanism, high-throughput screening of liver cancer drugs and the like, and has industrialization significance.

The invention provides a CAR-T cell capable of efficiently and stably expressing an inhibiting antibody and application thereof. Specifically, the invention provides a transgenic T cell, and the genome of the transgenic T cell is stably integrated with expression cassettes containing nucleic acid sequences coding chimeric antigen receptors and immune checkpoint inhibiting antibodies, wherein two ends of the expression cassettes contain inverted terminal repeats of transposons. In the genome of the pluripotent CAR-T cell, the expression cassettes of the inhibiting antibodies are stably integrated via a transposon system, so the CAR-T cell has the activity of stably and efficiently expressing the inhibiting antibodies on the premise that original killing activity of the T cell is maintained, transfer-back CAR-T cells are prevented from inhibition by a tumor microenvironment, and residual tumor-specific T cells can be activated in situ. Meanwhile, a molecular brake system is introduced to ensure the security of CAR-T cell therapy, and transfer-back pluripotent CAR-T cells can be timely removed if necessary.

The invention discloses a tumor microenvironment response nanoparticle based on peptides dendrimer modified fluorescence carbon dots. A preparation method of the tumor microenvironment response nanoparticle comprises the following steps: (1) preparation of nanometer fluorescence carbon dots; (2) surface sulfhydrylation modification of the fluorescence carbon dots; (3) preparation of second-generation peptides dendrimer grafted by arginine-lysine; (4) surface modification of the second-generation peptides dendrimer with fluorescence carbon dots; (5) preparation of a zwitterionic polymer polycarboxylate betaine methacrylate; (6) preparation of drug-loading carbon dots; (7) preparation of a drug-loading nanoparticle. The drug-loading nanoparticle prepared with the method has the specific fluorescent property of the carbon dots and dual high-sensitive responsiveness for an acid environment of a tumor site and high-concentration glutathione, high-selectivity rapid drug release in tumor cells can be achieved, and the drug-loading nanoparticle is high in anti-tumor efficiency and good in safety; in addition, integration of diagnosis and treatment of tumors is expected to achieve.

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.

Embodiments of the disclosure include compositions and methods effective for immunotherapy, such as for cancer. The embodiments include cells that recognize a combination of two signals or three signals present at the tumor microenvironment. In certain embodiments, the signals for antigen stimulation, co-stimulation, and cytokine signaling act through separate molecules, although in certain embodiments the signals for antigen stimulation and co-stimulation are transmitted through the same molecule.

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 PH-sensitive targeted LPNs (lipid poly-L-histidine hybrid nanoparticles) for encapsulating anti-tumor drugs. The LPNs comprise raw materials in percentage by mass as follows:50%-80% of PHIS (poly-histidine) and 20%-50% of lipid (including lipid-PEG), wherein the lipid PEG accounts for 1%-100% of the total mass of lipid. A hydrophobic core consists of PHIS, and the surfaceis modified with polyethylene glycol and tumor targeted peptide. The PEGylated lipid surface has the characteristics of good biocompatibility, high stability and long in-vivo circulation. A histidinecore can encapsulate the hydrophobic anti-cancer drugs under the neutral condition, histidine is protonized in the tumor microenvironment to mediate the carrier potential to change from negative to near neutral, intake and endocytosis of a carrier arepromoted, the carrier mediates the lysosome to escape after endocytosis, the drugs are released rapidly, tumor cells are effectively killed, and accordingly, the problems that the PEGylated nano-carrier endocytosis efficiency is low and cannot release the drugs in cells effectively after endocytosis are solved. The surface of the carrier can bemodified with a tumor-specific antibody or ligand, the tumor targeting property is further improved, and the therapeutic effect is improved.

The invention relates to a cell co-culture micro-fluidic chip and application thereof. The cell co-culture micro-fluidic chip comprises culture channels and a microchannel, wherein the culture channels are connected through the microchannel; the height of the culture channels is 100-300 microns; the height of the microchannel is less than or equal to 5 microns. The micro-fluidic chip disclosed by the invention is used for constructing a nerve microenvironment of a tumor, so as to provide a platform for studying the tumor microenvironment and basic research on nerve-cancer interaction, further can be used for pharmaceutical detection based on the action between the cells to screen the antitumor effect of the related nerve drugs, and provides a novel approach for analysis to discover the antitumor drugs.