38 results about "Hypoxia response" patented technology

The invention discloses a hypoxia response prodrug and a preparation method and application thereof.The hypoxia response prodrug comprises a compound shown in the formula I, pharmaceutically acceptable salt of the compound and solvate: # imgabs0 #. According to the hypoxia response prodrug and the preparation method and application thereof, azo bonds serve as a functional connecting group and a hypoxia response group, and then fluorescence and biological activity of a photosensitizer are temporarily closed; the photosensitizer and the chemotherapeutic drug can be selectively broken and released under the hypoxia condition, OFF-ON (off-on) fluorescence and biological activity of hypoxia stress response can be achieved, the selectivity to tumor cells is further improved, the fluorescence characteristic of the prodrug OFF-ON is expected to be used for tumor diagnosis and curative effect monitoring, and integration of diagnosis and treatment is expected to be achieved.

The invention discloses a universal mononuclear / macrophage delivery system for enhancing fibrosis part drug accumulation and application, and the universal mononuclear / macrophage delivery system comprises the following steps: (1) preparation of a carrier: adding a low-oxygen response element HRE fused MMP14 plasmid into an aqueous phase solution, then preparing an RMR-LNP suspension from the aqueous phase solution and an oil phase solution by adopting a microfluidic technology, and purifying to obtain the carrier; then, DSPE-PEG2000-TriArg is added into the purified system, incubation is carried out, and RMR-L-TriArg is obtained; and (2) transfecting the mononuclear / macrophage: co-incubating the RMR-L-TriArg and the mononuclear / macrophage, and then transfecting to obtain the mononuclear / macrophage delivery system for enhancing the drug accumulation at the fibrosis part. By constructing MMP14 high-expression macrophages, delivery to the hepatic fibrosis site can be increased, accumulation of drugs is increased, and the treatment effect is enhanced.

The invention is applicable to the technical field of single-soldier breathing equipment for emergency rescue personnel in plateau anoxic areas, and provides an air oxygenation type respirator which is mainly applied to the field of single-soldier breathing protection for emergency rescue in plateau anoxic areas and comprises a mask, an oxygen bottle and an oxygenation structure assembly. An automatic air oxygenation structure is designed in the air supply assembly structure of the air oxygenation type respirator, when a user wears the air oxygenation type respirator, oxygenation can be automatically conducted on inhaled low-oxygen-content air, and the oxygen supply amount is achieved through cooperation of the oxygenation structure assembly. According to the technical scheme, the portable oxygen supply device has the advantages that the portable oxygen supply device is portable, long-endurance automatic oxygen supply is provided, the oxygen deficit problem that the oxygen content of air is insufficient during breathing in an existing plateau oxygen deficit area is solved in an atmosphere air and oxygen increasing mode, and emergency rescue workers in the plateau oxygen deficit area do not suffer from oxygen deficit during breathing through technical innovation; therefore, the problem of hypoxia reaction when low-altitude rescue workers enter a high-altitude area to carry out rescue is solved, the rescue efficiency is improved, and the device can be used for carrying out oxygen therapy first aid on persons in distress at the first time when medical workers do not arrive.

The invention discloses a method for constructing a transgenic zebrafish model of hypoxia response. The method comprises the following steps: firstly assembling an sv40mp promoter after a hypoxia response element HRE sequence and cloning the promoter into a pT2AL200R150G plasmid carrying green fluorescent protein (GFP), then microinjecting the recombinant plasmid and transposase mRNA into zebrafish embryos, and inserting the recombinant sequence into the genome of F0 generation zebrafish by Tol2 transposon technology; raising the F0 generation fish to adult fish, hybridizing with wild-type zebrafish to produce F1 generation, hybridizing the F1 generation with the wild-type fish again to produce single-copy transgenic zebrafish F2 generation, self-pollinating male and female sibling zebrafish of the F2 generation, and screening out transgenic zebrafish Tg (HRE-sv40mp:GFP) of hypoxia response of F3 generation that can be stably inherited. The transgenic zebrafish Tg(HRE‑sv40mp:GFP) constructed in the present invention can be used as a simple and efficient hypoxia response model for biological research in hypoxia-related fields, as well as for screening molecular targeted drugs for HIF‑1α, providing a living animal screening model for the development of anti-tumor drugs.

The present disclosure provides engineered mesenchymal stem cells (MSCs), a pharmaceutical composition containing the same, and use thereof in the manufacture of a medicament for treating cancer. The mesenchymal stem cells (MSCs) comprise an introduced NQO1 protein-coding sequence and / or an introduced hypoxia response element (HRE), and a nucleic acid encoding one or more immunostimulatory cytokines.

The invention provides a light-promoted release supramolecular diagnosis and treatment prodrug as well as a preparation method and application thereof, and belongs to the technical field of biological medicines. The light-promoted release supramolecular diagnosis and treatment prodrug provided by the invention consists of a calixarene prodrug and a photosensitizer included in the calixarene prodrug, and has the advantages of simple preparation method, breast cancer hypoxia response targeted therapy, real-time near-infrared fluorescence imaging tracing, light-promoted drug release and the like. The light-promoted release supramolecular diagnosis and treatment prodrug provided by the invention not only can realize accurate diagnosis and targeted treatment of breast cancer in vivo, but also can cause local hypoxia of a tumor microenvironment by virtue of photodynamic characteristics of the photosensitizer, realizes light-promoted drug release, and provides a new way for accurate and controllable diagnosis and treatment requirements of breast cancer.

This invention discloses a method for assessing hypoxia response based on dynamic evaluation of heart rate deceleration force and HRV, belonging to the field of biomedical signal processing. The method simultaneously acquires electrocardiogram (ECG) signals and environmental and blood oxygen parameters to dynamically correct the risk baseline; extracts frequency domain, time domain, and heart rate deceleration force features from the ECG signals and establishes a dual-channel cross-judgment logic; inputs the judgment results with the current blood oxygen saturation into a lightweight neural network inference output risk stratification; controls a wearable actuator to initiate multi-target stratified sequential stimulation including heat and vibration based on the stratification results, and adaptively updates the individualized hyperthermia prescription based on the intervention efficacy index, ultimately achieving dual-channel synergistic control of oxygen therapy and hyperthermia. This invention effectively solves the shortcomings of traditional methods, such as delayed early warning and inability to dynamically correct in non-networked environments, constructing a closed loop from precise monitoring to multi-target synergistic intervention, significantly improving the body's adaptability and resilience to hypoxia.

The invention relates to hypoxia response therapeutic VEGFA (vascular endothelial growth factor A) mRNA (messenger Ribonucleic Acid) and application thereof. The mRNA comprises a 5'end cap, a 5 'UTR (Untranslated Region) containing a Kozak sequence, VEGFA ORF (Open Region Fragment), a 3' UTR containing an RNA (Ribonucleic Acid) binding protein HuR binding site, a RhoBAST fluorescent aptamer at the tail end of the 3 'UTR and a PolyA tail. According to the design, through a HuR hypoxia-dependent nuclear plasma transport mechanism, the stability of mRNA in hypoxic cells is improved by 2.5 times, the protein expression quantity is improved by 2 times, and proliferation of endothelial cells is remarkably promoted. Further disclosed is a VEGFA mRNA delivery system based on engineered extracellular vesicles (EVs): EVs surface modified kidney targeting peptide LTH. The system is efficiently accumulated in ischemic kidneys, VEGFA expression is remarkably enhanced, and abnormal vascular hyperplasia of external renal organs is avoided. Animal experiments prove that the survival rate of a renal ischemia-reperfusion injury model can be increased to 100% by intravenous injection of drug-loaded EVs, and the capillary density is remarkably increased 7 days after treatment. The invention is suitable for treating ischemic diseases, organ ischemia reperfusion injury or chronic wounds and the like, and has the advantages of accurate targeting, hypoxia response, high stability and safety.

The present invention discloses a pretreatment method and device for improving high-temperature anoxic reaction, the method comprising pre-treating materials that need to undergo high-temperature anoxic reaction, so that the materials after pre-treatment are more in line with the expected effect of the high-temperature anoxic reaction. The pre-treatment method comprises concentration, dehydration, dissociation, drying, batching, homogenization, and molding, and the physical and chemical properties of the materials entering the high-temperature anoxic reaction are optimized after pre-treatment. In practice, different combinations of links can be selected according to the different physical and chemical properties of the materials to achieve the purpose of optimizing the physical and chemical properties of the materials, so as to achieve better high-temperature anoxic reaction effects for different materials. The present invention can make the materials to be treated use less reaction energy in the high-temperature anoxic reaction and obtain a faster reaction speed; the entire high-temperature anoxic process can be made more controllable through homogenization and molding, greatly reducing the blind spots of the high-temperature anoxic reaction and reducing the residues of harmful substances.

The invention discloses a nano-drug with hypoxia responsiveness and a photoisomerization function as well as preparation and application thereof, and belongs to the technical field of biological medicines. The 4, 4 '-diacyl chloride azobenzene is used as a low-oxygen response unit and is covalently linked with the 10-hydroxycamptothecine and the drug carrier mPEG to form the size-controllable nano-drug, and the nano-drug has a proper particle size, is more beneficial to enrichment and curative effect exertion of the drug at a tumor site through blood circulation, and has a good application prospect. When the nano-drug reaches a hypoxia tumor site, the azo group in the nano-drug is reduced by the special azo reductase in a hypoxia environment, so that the structure of the nano-drug is disintegrated, the 10-hydroxycamptothecine is released to play a role in chemotherapy, and the toxic and side effects of the drug on normal tissues are reduced; besides, the nano-drug is high in utilization rate and has better biocompatibility, so that the nano-drug has a better application prospect in preparation of antitumor drugs.

The invention relates to a hypoxia targeting hyaluronic acid nano delivery system and a construction method and application thereof, the construction method comprises the following preparation method: S1, dissolving 2-nitroimidazole and K2CO3 in dimethylformamide, carrying out high temperature alkali treatment, adding N-Boc-bromoethylamine, and carrying out high temperature reaction to obtain Boc-NIH; s2, dissolving the Boc-2-NIH in dichloromethane, adding trifluoroacetic acid for deprotection, and adjusting the pH value to be neutral, so as to obtain 2-NIH; s3, dissolving HA in deionized water, sequentially adding EDC and NHS to activate carboxyl, then adding 2-NIH, reacting at room temperature, and dialyzing to obtain a hypoxic targeting hyaluronic acid nano delivery carrier HA-NIH; s4, HA-NIH loads a drug, and the hypoxia targeted hyaluronic acid nano delivery system is formed. According to the invention, a bifunctional nano system with CD44 active targeting and hypoxia response release is successfully constructed, a dynamic regulation and control mechanism of HA molecular weight on a targeting-permeation-retention effect is provided, and a synergistic effect of tumor stem cell microenvironment specific response and drug space-time release is realized.

This invention belongs to the field of nanomedicine technology, specifically relating to a pH / hypoxia dual-responsive polymer, nanomicelles, their preparation method, and applications. The pH / hypoxia dual-responsive polymer is a hydroxyethyl deacetylated chitosan modified with p-nitrobenzyl chloroformate and cinnamaldehyde. Ropivacaine is loaded onto it and prepared into nanomicelles for use as a drug delivery system after tumor surgery. Due to its acid sensitivity and hypoxia response, it can intelligently identify the tumor microenvironment, achieving precise drug delivery.

The invention relates to an application of a multifunctional supramolecular nano-platform drug, in particular to an application of a multifunctional supramolecular nano-platform in preparation of a drug for treating liver ischemia reperfusion injury. The multifunctional supramolecular nano platform is a GalAC4A supramolecular carrier loaded with naringenin NAR. The multifunctional supramolecular nano platform is prepared from naringenin NAR, galactose Gal and CAC4A in azo calixarene. The multifunctional supramolecular nano platform is a nano compound of NAR (at) GalAC4A. The multifunctional supramolecular nano platform realizes specific targeting of hepatocytes through endocytosis mediated by an asialoglycoprotein receptor. The invention provides a novel'receptor recognition-hypoxia response-collaborative treatment ', a three-party design strategy is provided, a GalAC4A supermolecular carrier loaded with naringenin (NAR) is successfully constructed, and the NAR-coated GalAC4A nano-composite is formed.

A system includes an enclosed tent or chamber or a breathing apparatus, a hypoxia induction system and a device for measuring arterial oxygen saturation in a subject breathing air within the enclosed tent or chamber or from the breathing apparatus. The hypoxia induction system delivers oxygen-depleted air having between 5 to 20% O2 to the enclosed tent or chamber or breathing apparatus. The system adjusts the oxygen content of the oxygen-depleted air being delivered to the enclosed tent or chamber or the breathing apparatus based upon the arterial oxygen saturation measured by the device such that oxygen saturation in the subject is maintained within a range of 50% to 90%.

The invention belongs to the technical field of biological medicine, and particularly relates to preparation of a hypoxia response albumin supramolecular nano drug delivery system and application of the hypoxia response albumin supramolecular nano drug delivery system in hypoxia tumor treatment. The nano drug delivery system comprises an albumin supramolecular nano carrier taking an azo calix [4] arene derivative as a drug carrying main body, a mitochondrial targeting photosensitizer and an autophagy inhibitor. The system is prepared through a light click chemical reaction between double bonds of azo calixarene and albumin subjected to reduction treatment, and has the hypoxia response characteristic. Meanwhile, the nano drug delivery system can initiate an active oxygen storm effect and inhibit the growth of hypoxic tumors in a hypoxic environment and under external stimulation of red light, and has a fluorescence imaging function. In addition, the novel drug delivery system is mild in preparation process, can load multiple drug combinations at the same time, has a diagnosis and treatment integrated function, and has a wide application prospect in the field of hypoxia tumor treatment.

The present invention relates to a membrane-bound IL-15 fusion protein expressed on TIL cells. Specifically, the present invention uses a hypoxia response element HRE to induce the expression of a membrane-bound IL-15 (mIL-15) fusion protein, so that the TIL cell group expressing the fusion protein maintains the memory stem cell phenotype for a long time and enhances its anti-tumor activity; in the construction of the fusion protein, the CD86 transmembrane region and intracellular domain are used to further increase the proportion of stem cells in the TIL cells; in the molecular construction, truncated hEGFRt is used as a molecular switch to further improve its safety. The stemness and persistence of TIL cells expressing the fusion protein of the present invention are significantly improved, and long-lasting immune monitoring and treatment capabilities can be provided.

The invention relates to a biomarker of periapical cells and application of the biomarker, and belongs to the technical field of biological detection. The objective of the invention is to solve the problem that a conventional periodontal cell marker has expression overlap with other interstitial cells under an anoxic condition, cannot accurately distinguish tip periodontal cell subgroups, and hinders functional research and targeted therapy development thereof. The method comprises the following steps: screening 15 specific genes (including Adamts9, Cd93, Ctla2a, Fkbp1a, Angpt2 and the like) as periapical cell biomarkers by adopting machine learning according to brain single cell sequencing data of a high-altitude hypoxia mouse; and constructing a logistic regression prediction model to realize cell identification. According to the biomarker combination and the biomarker model, the false detection rate (lt; 5%). A new molecular marker for accurately identifying periapical cells is developed through a machine learning method based on a big data set, and a brand new breakthrough is provided for developing hypoxia response type periapical cell specific markers and functional targets.

The invention provides cyclic peptides that are able to disrupt the typical response to hypoxia and which have particular utility in the treatment of cancers and von Hippel-Lindau disease.

The invention provides an SNP (Single Nucleotide Polymorphism) genetic marker for predicting hypoxia reaction risk and a detection kit thereof. The kit is based on a Rea l-t time PCR (Polymerase Chain Reaction) technology, performs targeted detection on three core SNP (Single Nucleotide Polymorphism) sites (such as chr1.40149875T and chr6.89858851A) related to hypoxia sensitivity, and evaluates the hypoxia tolerance of an individual in combination with a genetic risk scoring model. The kit disclosed by the invention is suitable for low-oxygen reaction risk layering in scenes such as plateau operation, exercise training, clinical anesthesia and the like, and has relatively high sensitivity and practicability.

The application discloses a urine detection method based on platinum ultra-nanoparticles responding to hypoxia and application thereof. The platinum ultra-nanoparticles PNCA are formed by covalently connecting the ultra-small platinum nanoclusters after amination with 4,4'-dicarboxylic azobenzene azo responding to hypoxia through EDC / NHS reaction, and after wrapping the nanoparticles with a layer of hyaluronic acid HA, the nanoparticles can specifically target tumor sites. Then, under the action of the hypoxia environment reductase in the tumor site, the PNCA nanoparticles can be reduced and degraded into many small PtNCs, re-entering the blood circulation, and since the particle size is less than the critical value 5.5 nm that can be removed by the kidney, the nanoparticles can be excreted from the kidney to the urine for disease state detection. Due to the excellent hypoxia response effect of the PNCA nanoparticles and the high kidney removal effect of the PtNCs, the application has obvious advantages in in vivo application.

The invention provides an anoxia response promoter element and application thereof, and belongs to the technical field of biological medicine. The hypoxia response promoter element disclosed by the invention is obtained by transforming a whole sequence of a 1000bp region of an HAND1 gene promoter into a sequence as shown in SEQ ID NO.10 or SEQ ID NO.11. The hypoxia response promoter element disclosed by the invention is a hypoxia response promoter element disclosed by the invention. According to the invention, the HAND1 gene promoter region is analyzed and modified, and the modified promoter shows stronger transcriptional activation ability under an anoxic condition, and is a powerful tool for transcriptional regulation of engineered cardiac fibroblasts.

The application discloses a kind of group and individualized respiratory process modeling method based on sensitivity optimization, belong to biomedical engineering and physiology technical field, including the following steps: S1, data preparation;S2, model construction and parameter optimization;S3, model verification.The application adopts the above-mentioned group and individualized respiratory process modeling method based on sensitivity optimization, which realizes the accurate simulation of blood oxygen saturation, respiratory rate and tidal volume, captures the hypoxic response characteristics, avoids the influence of low-quality signals, and makes the daily difference simulation have higher fitting accuracy.

The invention discloses a chimeric antigen receptor for enhancing tumor recognition specificity and application thereof, and belongs to the technical field of cell therapy. The invention provides a chimeric antigen receptor for enhancing tumor recognition specificity. The chimeric antigen receptor comprises a CD8 alpha signal peptide, an anti EGFR (epidermal growth factor receptor) scFv, a tag, a CD28Hinge, a CD28TM, a CD28 costimulatory domain, a P2A shearing peptide, a CD8 alpha signal peptide, a tag, an anti CD133scFv, a CD8 alpha Hinge, a CD8 alpha TM, CD3 zeta and ODD which are sequentially connected in series. The invention also provides a hypoxia response type double-target gene engineering immune cell. The hypoxia response double-antigen recognition immune cells prepared by the invention can be activated and play a role in killing tumor cells only under the conditions of hypoxia and simultaneous recognition of two antigens, damage to normal tissues caused by an off-target effect is avoided, and the hypoxia response double-antigen recognition immune cells have higher safety.

The application belongs to the technical field of biological medicine, and particularly relates to a beta-carboline quinoline azo oxonium based on hypoxia response and a preparation method and application thereof. The application constructs a brain ischemia activated beta-carboline quinoline azo oxonium shown in the following formula. The beta-carboline quinoline azo oxonium realizes focal specific release of NO through reduction and fracture of an azo bond, and can integrate near-infrared fluorescence imaging function to provide real-time visual monitoring for treatment response.

The invention belongs to the field of new auxiliary materials and new dosage forms of pharmaceutical preparations, and particularly relates to a core-shell structure sequential drug release system for cascade deep penetration and induced differentiation treatment, construction of the core-shell structure sequential drug release system and application of the core-shell structure sequential drug release system in a drug delivery system. The system is of a shell-core structure, an inner core is nanoparticles which encapsulate an induced differentiation agent and have hypoxia response capability, and a shell is an acid response reversible polymer loaded with chemotherapeutic drugs. According to the invention, a pulse drug release strategy is utilized to overcome penetration obstacles of solid tumors, programmed drug release is carried out aiming at heterogeneity distribution of different cells in the tumors, a tumor microenvironment characterized by chemotherapy drug resistance and immune escape is effectively remodeled, and comprehensive inhibition of the tumors is realized.

The present application relates to a kind of expression secretory IL-2 fusion protein of engineered TIL cell and its application.It is specifically, the present application provides the fusion protein of IL-2 and CD25, and is designed using the double hypoxia response element (HRE) and oxygen-dependent degradation domain (ODD) element group hypoxia sensing safety switch, control fusion protein only expresses in hypoxic environment, on the one hand, realizes the specific concentration expression of IL-2 in tumor microenvironment, enhances tumor local concentration, can effectively maintain the anti-tumor activity of TIL in tumor tissue;On the other hand, the security risk brought by IL-2 system exposure is minimized.Meanwhile, the endogenous TIM-3 expression of TIL cell is silenced, so as to effectively reduce TIL exhaustion, further enhance the anti-tumor activity of TIL cell.

The invention relates to an engineered TIL cell for expressing secreting type IL-2 fusion protein and application of the engineered TIL cell. Specifically, the invention provides a fusion protein of IL-2 and CD25, and a double-hypoxia induction safety switch design consisting of a hypoxia response element (HRE) and an oxygen dependent degradation domain (ODD) element is adopted to control the fusion protein to be expressed only in a hypoxia environment, so that on one hand, the specific centralized expression of IL-2 in a tumor microenvironment is realized, and the local concentration of tumors is enhanced; the anti-tumor activity of TIL in tumor tissue can be effectively maintained; on the other hand, potential safety hazards caused by exposure of the IL-2 system are reduced to the maximum extent. Meanwhile, endogenous TIM-3 expression of the TIL cells is silenced, so that TIL depletion is effectively reduced, and the anti-tumor activity of the TIL cells is further enhanced.

Application of a multifunctional supramolecular nanoplatform drug: The application of a multifunctional supramolecular nanoplatform in the preparation of drugs for liver ischemia-reperfusion injury. The multifunctional supramolecular nanoplatform is a GalAC4A supramolecular carrier loaded with naringenin (NAR). The multifunctional supramolecular nanoplatform is prepared from naringenin (NAR), galactose (Gal), and CAC4A from azocalixarene. The multifunctional supramolecular nanoplatform is a NAR@GalAC4A nanocomposite. The multifunctional supramolecular nanoplatform achieves hepatocyte-specific targeting through desialyl glycoprotein receptor-mediated endocytosis. This invention proposes a novel "receptor recognition-hypoxia response-synergistic therapy" three-pronged design strategy, successfully constructing a GalAC4A supramolecular carrier loaded with naringenin (NAR) to form a NAR@GalAC4A nanocomposite.

The invention relates to genetically engineered bacteria for synthesizing a CD47 antibody through hypoxia response, construction of the genetically engineered bacteria and application of the genetically engineered bacteria in preparation of a tumor immune checkpoint blocking preparation, and belongs to the technical field of tumor immune checkpoint blocking preparations. The genetically engineered bacterium contains a hypoxic promoter, an expression sequence of a pelB secretion signal, an expression sequence of a CD47 antibody and a terminator which are sequentially connected in series from upstream to downstream. Wherein the hypoxic promoter has the capability of sensitively promoting expression of a target gene at a low oxygen concentration, and a pelB secretion signal can effectively promote the extracellular action concentration of a CD47 antibody. The genetically engineered bacterium is different from the design principle of traditional genetically engineered bacteria, in-situ synthesis of therapeutic drugs is triggered on the basis of tumor microenvironment oxygen concentration, remote regulation and control can be carried out on bacterial gene expression of tumor parts, and space-time control over therapeutic bacteria is enhanced.

The invention discloses a nanometer diagnosis and treatment preparation for hypoxia accelerated drug release and a preparation method thereof, and belongs to the technical field of biomedicine. In order to solve the problems existing in photodynamic therapy in an existing hypoxia tumor microenvironment, the nano diagnosis and treatment preparation for accelerating drug release in hypoxia, disclosed by the invention, comprises an aggregation-induced emission (AIE) molecule probe TPA-TT, a hypoxia response prodrug, DSPE-PEG-2000 and an immune cell membrane; an aggregation-induced emission molecule (AIE) probe TPA-TT and a hypoxia response prodrug are jointly wrapped in DSPE-PEG-2000, and finally the surface of the DSPE-PEG-2000 is wrapped with an immune cell membrane. Preparing an aggregation-induced emission molecular probe; preparing a nano diagnosis and treatment preparation loaded with an aggregation-induced emission molecular probe and a hypoxia response prodrug; the surface of the nano diagnosis and treatment preparation is covered with an M1 macrophage immune cell membrane. The invention provides a scheme for killing tumor cells and promoting apoptosis of cancer cells under the guidance of accurate imaging, and has tumor near-infrared fluorescence imaging and photodynamic and chemical dynamic synergistic treatment performance while specifically targeting the cancer cells.