CN112546025A - 一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备方法 - Google Patents
一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备方法 Download PDFInfo
- Publication number
- CN112546025A CN112546025A CN202011448169.5A CN202011448169A CN112546025A CN 112546025 A CN112546025 A CN 112546025A CN 202011448169 A CN202011448169 A CN 202011448169A CN 112546025 A CN112546025 A CN 112546025A
- Authority
- CN
- China
- Prior art keywords
- dsp
- ipi549
- cmcs
- delivery system
- tumor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 40
- 229940079593 drug Drugs 0.000 claims abstract description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 30
- 239000008367 deionised water Substances 0.000 claims abstract description 25
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 25
- 239000002105 nanoparticle Substances 0.000 claims abstract description 25
- 229940002612 prodrug Drugs 0.000 claims abstract description 15
- 239000000651 prodrug Substances 0.000 claims abstract description 15
- 230000009471 action Effects 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- XUMALORDVCFWKV-IBGZPJMESA-N 2-amino-N-[(1S)-1-[8-[2-(1-methylpyrazol-4-yl)ethynyl]-1-oxo-2-phenylisoquinolin-3-yl]ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical group C[C@H](NC(=O)C1=C2N=CC=CN2N=C1N)C1=CC2=CC=CC(C#CC3=CN(C)N=C3)=C2C(=O)N1C1=CC=CC=C1 XUMALORDVCFWKV-IBGZPJMESA-N 0.000 claims abstract description 13
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 12
- 238000000502 dialysis Methods 0.000 claims abstract description 11
- 230000000694 effects Effects 0.000 claims abstract description 10
- 231100000331 toxic Toxicity 0.000 claims abstract description 9
- 230000002588 toxic effect Effects 0.000 claims abstract description 9
- 230000007246 mechanism Effects 0.000 claims abstract description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 72
- 239000000243 solution Substances 0.000 claims description 39
- 239000000843 powder Substances 0.000 claims description 11
- 239000011259 mixed solution Substances 0.000 claims description 10
- 238000011068 loading method Methods 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 8
- 230000008685 targeting Effects 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 238000005538 encapsulation Methods 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 239000000523 sample Substances 0.000 claims description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 3
- 238000003760 magnetic stirring Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 230000037429 base substitution Effects 0.000 claims 1
- 238000010298 pulverizing process Methods 0.000 claims 1
- 238000009169 immunotherapy Methods 0.000 abstract description 9
- 210000004881 tumor cell Anatomy 0.000 abstract description 9
- 238000001126 phototherapy Methods 0.000 abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 abstract description 7
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 7
- SURLGNKAQXKNSP-DBLYXWCISA-N chlorin Chemical compound C\1=C/2\N/C(=C\C3=N/C(=C\C=4NC(/C=C\5/C=CC/1=N/5)=CC=4)/C=C3)/CC\2 SURLGNKAQXKNSP-DBLYXWCISA-N 0.000 abstract description 6
- 238000005286 illumination Methods 0.000 abstract description 4
- 238000001338 self-assembly Methods 0.000 abstract description 3
- 206010067484 Adverse reaction Diseases 0.000 abstract description 2
- 230000006838 adverse reaction Effects 0.000 abstract description 2
- 239000012141 concentrate Substances 0.000 abstract description 2
- 230000002209 hydrophobic effect Effects 0.000 abstract description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- 210000001519 tissue Anatomy 0.000 description 11
- 239000003642 reactive oxygen metabolite Substances 0.000 description 9
- 238000004108 freeze drying Methods 0.000 description 7
- 229960003180 glutathione Drugs 0.000 description 7
- 230000006872 improvement Effects 0.000 description 7
- 230000008901 benefit Effects 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 238000002296 dynamic light scattering Methods 0.000 description 3
- 230000000149 penetrating effect Effects 0.000 description 3
- 238000002428 photodynamic therapy Methods 0.000 description 3
- 238000009210 therapy by ultrasound Methods 0.000 description 3
- ZKSVYBRJSMBDMV-UHFFFAOYSA-N 1,3-diphenyl-2-benzofuran Chemical compound C1=CC=CC=C1C1=C2C=CC=CC2=C(C=2C=CC=CC=2)O1 ZKSVYBRJSMBDMV-UHFFFAOYSA-N 0.000 description 2
- YCLSOMLVSHPPFV-UHFFFAOYSA-N 3-(2-carboxyethyldisulfanyl)propanoic acid Chemical compound OC(=O)CCSSCCC(O)=O YCLSOMLVSHPPFV-UHFFFAOYSA-N 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000011258 core-shell material Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000005008 immunosuppressive cell Anatomy 0.000 description 2
- 239000008176 lyophilized powder Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000005375 photometry Methods 0.000 description 2
- 238000007626 photothermal therapy Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000004043 responsiveness Effects 0.000 description 2
- OYINILBBZAQBEV-UWJYYQICSA-N (17s,18s)-18-(2-carboxyethyl)-20-(carboxymethyl)-12-ethenyl-7-ethyl-3,8,13,17-tetramethyl-17,18,22,23-tetrahydroporphyrin-2-carboxylic acid Chemical compound N1C2=C(C)C(C=C)=C1C=C(N1)C(C)=C(CC)C1=CC(C(C)=C1C(O)=O)=NC1=C(CC(O)=O)C([C@@H](CCC(O)=O)[C@@H]1C)=NC1=C2 OYINILBBZAQBEV-UWJYYQICSA-N 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 206010020843 Hyperthermia Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000012828 PI3K inhibitor Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 208000037844 advanced solid tumor Diseases 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical class C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000036031 hyperthermia Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004880 lymph fluid Anatomy 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
- A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
- A61K47/6939—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being a polysaccharide, e.g. starch, chitosan, chitin, cellulose or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y20/00—Nanooptics, e.g. quantum optics or photonic crystals
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nanotechnology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Immunology (AREA)
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Optics & Photonics (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medical Informatics (AREA)
- General Engineering & Computer Science (AREA)
- Manufacturing & Machinery (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- Composite Materials (AREA)
- Materials Engineering (AREA)
- Biochemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开了一种Ce6@CMCS‑DSP‑IPI549抗肿瘤纳米传递系统及其制备方法,可调节作用靶点、控制时间并且能在肿瘤细胞处浓集、有效降低光敏剂的毒副作用、提高溶解性、减少机体不良反应。将键合了免疫疗法的抗肿瘤药物IPI‑549和二硫键集团的两亲性前药CMCS‑DSP‑IPI549溶解于去离子水中，通过滴加法加入含疏水性光敏剂二氢卟吩(Ce6)的有机溶液，经过超声破碎和透析自组装得到一种Ce6@CMCS‑DSP‑IPI549抗肿瘤纳米传递系统。该纳米传递系统将两种不同作用机制的药物合成并包封在一个纳米粒中，采用免疫治疗与光治疗双通路联合治疗肿瘤，在肿瘤微环境及特定近红外光照中可以释放出两种药物，为临床上肿瘤治疗提供新的方法学和理论依据。
Description
技术领域
本发明涉及医药技术领域，尤其涉及一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备方法。
背景技术
肿瘤是一种具有高度特异性的疾病，其中每个肿瘤是由具有不同遗传背景的癌细胞组成，因此每个肿瘤的表现不同对药物的反应也不同。癌细胞在体内一旦脱落器官组织，游离的癌细胞可以随血液或淋巴液播散全身，形成转移，危及生命。
治疗肿瘤的传统方式是化疗，即通过口服或者静脉注射抗肿瘤药物，经体循环将药物传输到达病灶部位，杀死肿瘤细胞。但大部分抗肿瘤药对肿瘤细胞组织与正常细胞组织没有选择性，对正常细胞会造成无法避免的伤害，对人体造成较大的伤害，病人承受较大痛苦。其次，由于人体内存在着生物屏障(如血脑屏障)，只有少量的药物能达到病灶区域，导致生物利用度低；另外，长期给药会造成机体产生耐药性，造成肿瘤治疗更困难。为了解决上述问题，利用新剂型或新技术的药物传递系统正在蓬勃发展。
发明内容
基于以上现有技术的不足，本发明所解决的技术问题在于提供一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统及其制备方法。该方法制备的核壳型纳米粒，不仅具有较好的稳定性和肿瘤靶向性，而且具有较好的免疫治疗性和近红外光响应性，可以改善肿瘤微环境中的免疫抑制细胞并且可以调节近红外光的作用靶点、作用时间来调控光敏剂的释放。
为了解决上述技术问题，本发明提供一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备方法，其特征在于，包含如下步骤：
(1)DSP-IPI549中间体的合成：
取一定的DSP溶解于DMSO中，搅拌至完全溶解；另取IPI-549溶解于DMSO中，再缓缓滴入上述DSP溶液中，室温下避光磁力搅拌反应24h，用DMSO和去离子水的混合溶液和水透析，冷冻干燥后得DSP-IPI549中间体冻干粉末；
(2)CMCS-DSP-IPI549前药的合成：
将DSP-IPI549冻干粉末溶解于DMSO中，得到DSP-IPI549溶液；取CMCS，溶解于去离子水中，调节pH值为7.4，超声5min，得到CMCS溶液；将DSP-IPI549溶液缓慢滴入CMCS溶液中，室温下避光磁力搅拌反应24h，以DMSO和去离子水7:3-3:7的混合溶液和去离子水透析，冷冻干燥后得CMCS-DSP-IPI549前药冻干粉末；
(3)Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备
将Ce6溶于DMSO配制成溶液A，CMCS-DSP-IPI549前药溶于去离子水中配制成溶液B，在磁力搅拌器上将溶液A逐滴加入到溶液B中，在室温避光下搅拌4小时，低温超声粉碎，即得Ce6@CMCS-DSP-IPI549纳米粒溶液，去离子水中透析4h，冷冻干燥，即得Ce6@CMCS-DSP-IPI549纳米粒冻干粉末，即为所述Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统。
作为上述技术方案的优选，本发明提供的Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备方法进一步包括下列技术特征的部分或全部：
作为上述技术方案的改进，所述步骤(1)中，DSP和IPI549的摩尔比为1:1；所述DMSO和去离子水的混合溶液是DMSO与水的体积比为1:9的混合溶液。
作为上述技术方案的改进，所述步骤(2)中，CMCS的摩尔质量为1×104，并且羧甲基取代度为85％；所述步骤(2)中CMCS与DSP-IPI549的质量比为1:1.3～3.3；所得到的CMCS-DSP-IPI549前药的载药率为10.17％～13.63％。其中，使用紫外光度法测定的载药率
作为上述技术方案的改进，所述步骤(3)中，CMCS-DSP-IPI549前药与光敏剂Ce6的质量比为5:1-15:1。
作为上述技术方案的改进，所述步骤(1)中，透析袋的截留分子量为500Da，步骤(2)-(3)，透析袋的截留分子量为3 500Da。
作为上述技术方案的改进，所述步骤(3)中，低温超声粉碎是使用超声波细胞粉碎机，探头在低温下超声3.0s，间歇2.0s，功率为90w的脉冲方式工作10min。
作为上述技术方案的改进，所述步骤(3)得到的Ce6@CMCS-DSP-IPI549纳米粒粒径大小范围为141-396nm，载药率为6.49％-10.92％，包封率为55.68％-72.65％。其中，所述纳米粒是用动态光散射仪(DLS)测得，使用紫外光度法测定的载药率和包封率。
一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统，所述Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统是由如上述任意方法制备而成。
一种上任一所述的Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的应用，其特征在于：将两种不同作用机制的药物合成及包封在同个纳米粒中，采用免疫治疗与光治疗双通路联合治疗肿瘤，在肿瘤微环境及特定近红外光照中释放出两种药物，提高药物的溶解性、降低毒副作用、增加靶向性，为临床上肿瘤治疗提供新的方法学和理论依据
作为上述技术方案的优选，本发明提供的Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的应用进一步包括下列技术特征的部分或全部：
作为上述技术方案的改进，所述近红外光波长为606nm。
作为免疫学临床候选肿瘤药物的IPI-549是在对异喹诺酮类PI3K抑制剂的优化过程中发现的，其选择性是其他脂类和蛋白激酶的100倍以上，IC50为16nM。IPI-549显示出良好的药代动力学特性，并且对PI3K-γ介导的中性粒细胞迁移有抑制作用，该药物目前正处于Ⅰ期临床试验(受试者为晚期实体瘤患者)。在动物实验(小鼠，大鼠，狗和猴子)中发现，IPI-549具有优异的口服生物利用度，清除率低，半衰期较短(小鼠、大鼠、狗和猴子的t1/2分别为3.2、4.4、6.7、4.3小时)并且容易分布到各个组织中(平均分布容积为1.2L/kg)。作为一种小分子激酶抑制剂，IPI-549是一种联合治疗肿瘤的理想首选药物。
纳米载药系统，是指采用物理包埋或化学共价偶合的方法将药物与天然或合成的高分子载体连接在一起后，制备成纳米尺寸的药物传递系统。该系统提高了药物的生物利用度，降低药物对机体的毒副作用，可特异性识别病灶区域，并控制药物释放。该系统具有靶向性，减少药物对正常细胞和组织的伤害，定向将药物运送到肿瘤区域，降低药物毒性。
羧甲基壳聚糖(CMCS)是一种应用比较广泛的高分子药物载体，因其具有良好的生物安全性和生物相容性、有多个活性集团且容易被生物降解等特点，已被广泛应用于医药生物领域。CMCS的活性集团可以与药物发生反应形成共价键，在血液循环中可以稳定存在，因此CMCS已被开发作为小分子抗肿瘤药物递送系统中的载体，该系统可以改善小分子药物水溶性、延长半衰期、降低毒副作用、提高靶向性。
谷胱甘肽(GSH)是在人体内存在的含巯基的多肽蛋白，在体液中或细胞外，GSH浓度仅仅为微摩尔级(2-20μM)，而细胞内的GSH浓度一般到达毫摩尔级(2-10mM)，由于癌细胞内高度缺氧，导致GSH浓度为正常细胞的4倍，二硫键在此环境下易断裂。含二硫键的3,3’-二硫代二丙酸双(N-羟基琥珀酰亚胺酯)(DSP)可以应用于抗肿瘤药物纳米传递系统，既可降低抗肿瘤药物和载体的空间位阻，又可利用二硫键易被高浓度GSH裂解的特性，在肿瘤细胞或组织中靶向释放药物。
光治疗是一种新兴的肿瘤治疗法，可以在特定靶点进行局部治疗，是通过紫外或近红外光源照射并激发肿瘤细胞或组织中蓄积的光敏药物，产生局部高热或者活性氧(ROS)，从而杀伤肿瘤细胞。紫外光的组织穿透能力弱且对机体容易产生损伤，而近红外光的组织穿透能力强可达到肿瘤深处、对机体几乎无损伤，所以一般使用650-950nm的近红外光源。光治疗具有创口小、患者身体不适度低且接受度高、可控制作用位点和时间、毒副作用低等优点。光治疗分为光动力疗法(PDT)和光热疗法(PTT)。二氢卟吩e6(Ce6)是应用于PDT治疗中的第二代光敏剂，属于叶绿素衍生物，已被FDA批准应用。Ce6激发后具有较强的穿透力、较高的ROS产率以及荧光成像能力等优点。
将光敏剂Ce6通过滴加法加入到含CMCS-DSP-IPI549前药的水溶液中，搅拌混合均匀后，通过超声破碎和透析自组装获得一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统，可以改善肿瘤微环境中的免疫抑制细胞、提高ROS产率、控制作用位点和时间，通过两种不同作用机理的免疫治疗和光治疗联合来发挥更好的抗肿瘤治疗作用。
与现有技术相比，本发明的技术方案具有如下有益效果：
1.将两种不同作用机制的药物合成及包封在同个纳米粒中，采用免疫治疗与光动力治疗双通路联合治疗肿瘤，在肿瘤微环境及特定近红外光照中释放出两种药物，提高药物的溶解性、降低毒副作用、增加靶向性，为临床上免疫治疗及光治疗提供新的方法学和理论依据。
2.近红外光对机体无损伤，且可通过外界调整近红外光的作用部位和作用时间来控制光敏剂Ce6的释放，产生ROS杀伤肿瘤细胞或组织。
3.利用二硫键的还原敏感性，Ce6@CMCS-DSP-IPI549纳米粒增加了光敏剂Ce6的靶向性、提高了药物的生物利用度、降低其对正常细胞或组织的毒副作用。
上述说明仅是本发明技术方案的概述，为了能够更清楚了解本发明的技术手段，而可依照说明书的内容予以实施，并且为了让本发明的上述和其他目的、特征和优点能够更明显易懂，以下结合优选实施例，详细说明如下。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对实施例的附图作简单地介绍。
图1为本发明实施例1制备的Ce6@CMCS-DSP-IPI549纳米粒的透射电镜图；
图2为本发明实施例1制备的Ce6@CMCS-DSP-IPI549纳米粒在不同浓度GSH下的释放曲线，其中IPI-549(A),Ce6(B)；
图3为本发明实施例1制备的Ce6@CMCS-DSP-IPI549纳米粒与单线态氧探针(DPBF)在426nm处的吸光度。
具体实施方式
下面详细说明本发明的具体实施方式，其作为本说明书的一部分，通过实施例来说明本发明的原理，本发明的其他方面、特征及其优点通过该详细说明将会变得一目了然。
实施例1：
(1)DSP-IPI549中间体的合成：
精密称取DSP 20mg溶解于4.2mL DMSO中，搅拌至完全溶解。另精密称取IPI-54927mg溶解于5.6mL的DMSO中，再缓缓滴入上述DSP溶液中，室温下避光磁力搅拌反应24h，转移至透析袋(截留分子量为500Da)，以1:9的DMSO和去离子水的混合溶液透析48h，再用去离子水透析24h。冷冻干燥后得DSP-IPI549中间体冻干粉末。
(2)CMCS-DSP-IPI549前药的合成：
精密称取DSP-IPI549冻干粉末20mg溶解于7mL DMSO中，精密称取CMCS 6mg，溶解于70mL去离子水中，调节pH值为7.4，超声5min，得CMCS溶液。将DSP-IPI549溶液缓慢滴入CMCS溶液中，室温下避光磁力搅拌反应24h，转移至透析袋中(截留分子量为3500Da)，以7:3/5:5/3:7的DMSO和去离子水的混合溶液分别透析12h，再用去离子水透析24h。冷冻干燥后得冻干粉末，将此冻干粉末溶解于40mL的DMSO中，并进行超声10min，再过滤，以除去溶于DMSO的反应物，重复操作3次。滤饼溶解于去离子水中，于透析袋中用纯水透析24h，冷冻干燥，得CMCS-DSP-IPI549前药冻干粉末。
(3)一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备
称取1mg Ce6溶于1mL DMSO配制成1mg/mL的溶液，10mg CMCS-DSP-IPI549溶于1mL去离子水中配制成10mg/mL的溶液，在磁力搅拌器上将Ce6溶液逐滴加入到水溶液中，在室温避光下搅拌4小时，将其转移到超声波细胞粉碎机，探头在低温下超声3.0s，间歇2.0s，功率为90w的脉冲方式工作10min，即得Ce6@CMCS-DSP-IPI549纳米粒溶液，转移至透析袋(截留分子量为3500Da)于去离子水中透析4h，冷冻干燥，即得Ce6@CMCS-DSP-IPI549纳米粒冻干粉末。
本实施例中制得的Ce6@CMCS-DSP-IPI549纳米粒的载药量为8.05％，包封率为64.42％。
实施例2：
本实施例与实施例1的区别在于：本实施例在(3)中称取2mg Ce6溶于1mL DMSO配制成2mg/mL的溶液，其他制备原料组成以及一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备过程同实施例1。
本实施例中制得的Ce6@CMCS-DSP-IPI549纳米粒的载药量为10.92％，包封率为55.68％。
实施例3：
本实施例与实施例1的区别在于：本实施例在(3)中称取15mg CMCS-DSP-IPI549溶于1mL去离子水中配制成15mg/mL的溶液，其他制备原料组成以及一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备过程同实施例1。
本实施例中制得的Ce6@CMCS-DSP-IPI549纳米粒的载药量为6.49％，包封率为72.65％。
纳米粒的表征实验：
为了证明实施例1中制备的Ce6@CMCS-DSP-IPI549能在水溶液中自组装形成核壳纳米粒，我们采用透射电镜进行了表征(见图1)，结果显示Ce6@CMCS-DSP-IPI549纳米粒呈圆球状，形态规整，分布较均匀；采用动态光散射仪表征这个纳米粒的平均粒径为218.8±4.59nm。
为了证明实施例1中制备的Ce6@CMCS-DSP-IPI549纳米传递系统具有GSH响应性，我们根据正常细胞及肿瘤细胞中GSH的浓度设立了4个浓度梯度，制作了的Ce6@CMCS-DSP-IPI549纳米传递系统在267nm(IPI-549)和402nm(Ce6)处的释放曲线(见图2)。
在近红外光606nm下照射后，Ce6可激发产生的ROS与单线态氧探针(DPBF)发生化学反应，导致其在426nm处的吸光度降低，从而反应ROS的产率。为了证明实施例1中制备的Ce6@CMCS-DSP-IPI549纳米传递系统在近红外光的照射下产生ROS，在606nm的近红外光下照射不同时间后测定426nm处的吸光度(见图3)。
本发明公开了一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统及其制备方法,可调节作用靶点、控制时间并且能在肿瘤细胞处浓集、有效降低光敏剂的毒副作用、提高溶解性、减少机体不良反应，为临床抗肿瘤药物的开发提供新的思路和理论依据。将键合了免疫疗法的抗肿瘤药物IPI-549和二硫键集团的两亲性前药CMCS-DSP-IPI549溶解于去离子水中，通过滴加法加入含疏水性光敏剂二氢卟吩(Ce6)的有机溶液，经过超声破碎和透析自组装得到一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统。该纳米传递系统将两种不同作用机制的药物合成并包封在一个纳米粒中，采用免疫治疗与光治疗双通路联合治疗肿瘤，在肿瘤微环境及特定近红外光照中可以释放出两种药物，为临床上肿瘤治疗提供新的方法学和理论依据。
本发明所列举的各原料，以及本发明各原料的上下限、区间取值，以及工艺参数(如温度、时间等)的上下限、区间取值都能实现本发明，在此不一一列举实施例。
以上所述是本发明的优选实施方式而已，当然不能以此来限定本发明之权利范围，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和变动，这些改进和变动也视为本发明的保护范围。
Claims (10)
1.一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备方法，其特征在于，包含如下步骤：
(1)DSP-IPI549中间体的合成：
取一定的DSP溶解于DMSO中，搅拌至完全溶解；另取IPI-549溶解于DMSO中，再缓缓滴入上述DSP溶液中，室温下避光磁力搅拌反应24h，用DMSO和去离子水的混合溶液和水透析，冷冻干燥后得DSP-IPI549中间体冻干粉末；
(2)CMCS-DSP-IPI549前药的合成：
将DSP-IPI549冻干粉末溶解于DMSO中，得到DSP-IPI549溶液；取CMCS，溶解于去离子水中，调节pH值为7.4，超声5min，得到CMCS溶液；将DSP-IPI549溶液缓慢滴入CMCS溶液中，室温下避光磁力搅拌反应24h，以DMSO和去离子水7:3-3:7的混合溶液和去离子水透析，冷冻干燥后得CMCS-DSP-IPI549前药冻干粉末；
(3)Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备
将Ce6溶于DMSO配制成溶液A，CMCS-DSP-IPI549前药溶于去离子水中配制成溶液B，在磁力搅拌器上将溶液A逐滴加入到溶液B中，在室温避光下搅拌4小时，低温超声粉碎，即得Ce6@CMCS-DSP-IPI549纳米粒溶液，去离子水中透析4h，冷冻干燥，即得Ce6@CMCS-DSP-IPI549纳米粒冻干粉末，即为所述Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统。
2.如权利要求1所述的Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备方法，其特征在于：所述步骤(1)中，DSP和IPI549的摩尔比为1:1；所述DMSO和去离子水的混合溶液是DMSO与水的体积比为1:9的混合溶液。
3.如权利要求1所述的Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备方法，其特征在于：所述步骤(2)中，CMCS的摩尔质量为1×104，并且羧甲基取代度为85％；所述步骤(2)中CMCS与DSP-IPI549的质量比为1:1.3～3.3；所得到的CMCS-DSP-IPI549前药的载药率为10.17％～13.63％。
4.如权利要求1所述的Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备方法，其特征在于：所述步骤(3)中，CMCS-DSP-IPI549前药与光敏剂Ce6的质量比为5:1-15:1。
5.如权利要求1所述的Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备方法，其特征在于：所述步骤(1)中，透析袋的截留分子量为500Da，步骤(2)-(3)，透析袋的截留分子量为3 500Da。
6.如权利要求1所述的Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备方法，其特征在于：所述步骤(3)中，低温超声粉碎是使用超声波细胞粉碎机，探头在低温下超声3.0s，间歇2.0s，功率为90w的脉冲方式工作10min。
7.如权利要求1所述的Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备方法，其特征在于：所述步骤(3)得到的Ce6@CMCS-DSP-IPI549纳米粒粒径大小范围为141-396nm，载药率为6.49％-10.92％，包封率为55.68％-72.65％。
8.一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统，其特征在于：所述Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统是由如权利要求1-7任意方法制备而成。
9.一种如权利要求1-8任一所述的Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的应用，其特征在于：将两种不同作用机制的药物合成及包封在同个纳米粒中，采用免疫治疗与光治疗双通路联合治疗肿瘤，在肿瘤微环境及特定近红外光照中释放出两种药物，提高药物的溶解性、降低毒副作用、增加靶向性，为临床上肿瘤治疗提供新的方法学和理论依据。
10.如权利要求9所述的Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的应用，其特征在于：所述近红外光波长为606nm。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011448169.5A CN112546025B (zh) | 2020-12-09 | 2020-12-09 | 一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011448169.5A CN112546025B (zh) | 2020-12-09 | 2020-12-09 | 一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112546025A true CN112546025A (zh) | 2021-03-26 |
| CN112546025B CN112546025B (zh) | 2023-06-06 |
Family
ID=75061014
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011448169.5A Active CN112546025B (zh) | 2020-12-09 | 2020-12-09 | 一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112546025B (zh) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114259476A (zh) * | 2021-12-29 | 2022-04-01 | 中南大学湘雅三医院 | 一种调控巨噬细胞的纳米制剂及其制备方法与应用 |
| CN116327706A (zh) * | 2023-02-01 | 2023-06-27 | 中山大学附属第八医院（深圳福田） | 一种纳米药物递送系统及其制备方法与应用 |
| US11939333B2 (en) | 2015-09-14 | 2024-03-26 | Infinity Pharmaceuticals, Inc. | Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same |
| US12152032B2 (en) | 2013-10-04 | 2024-11-26 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105708848A (zh) * | 2016-02-04 | 2016-06-29 | 武汉艾美博特医疗用品有限公司 | 一种环境响应性肿瘤靶向联合给药传递系统 |
| CN105749280A (zh) * | 2016-04-07 | 2016-07-13 | 沈阳大学 | 一种协同化疗与光动力治疗的肿瘤靶向纳米给药系统的制备及应用 |
| WO2017045192A1 (zh) * | 2015-09-18 | 2017-03-23 | 天津医科大学 | 靶向肿瘤的声、光动力载药纳米胶束及其制备方法和用途 |
| CN110179982A (zh) * | 2019-06-20 | 2019-08-30 | 武汉理工大学 | 一种具有化疗光疗联合作用的多功能靶向给药系统及其制备方法 |
| CN110859825A (zh) * | 2019-11-26 | 2020-03-06 | 武汉理工大学 | 一种靶向给药纳米传递系统的制备方法 |
-
2020
- 2020-12-09 CN CN202011448169.5A patent/CN112546025B/zh active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017045192A1 (zh) * | 2015-09-18 | 2017-03-23 | 天津医科大学 | 靶向肿瘤的声、光动力载药纳米胶束及其制备方法和用途 |
| CN105708848A (zh) * | 2016-02-04 | 2016-06-29 | 武汉艾美博特医疗用品有限公司 | 一种环境响应性肿瘤靶向联合给药传递系统 |
| CN105749280A (zh) * | 2016-04-07 | 2016-07-13 | 沈阳大学 | 一种协同化疗与光动力治疗的肿瘤靶向纳米给药系统的制备及应用 |
| CN110179982A (zh) * | 2019-06-20 | 2019-08-30 | 武汉理工大学 | 一种具有化疗光疗联合作用的多功能靶向给药系统及其制备方法 |
| CN110859825A (zh) * | 2019-11-26 | 2020-03-06 | 武汉理工大学 | 一种靶向给药纳米传递系统的制备方法 |
Non-Patent Citations (5)
| Title |
|---|
| CATHERINE A. EVANS等: "Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate", 《MEDICINAL CHEMISTRY LETTERS》 * |
| CATHERINE A. EVANS等: "Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate", 《MEDICINAL CHEMISTRY LETTERS》, vol. 7, no. 9, 22 July 2016 (2016-07-22) * |
| ZHANG XUEQIONG等: "Glutathione-dependent micelles based", 《JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION》 * |
| ZHANG XUEQIONG等: "Glutathione-dependent micelles based", 《JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION》, vol. 27, no. 18, 5 October 2016 (2016-10-05), pages 6 * |
| 许斌等: "恶性肿瘤免疫检查点抑制剂耐药机制及临床应用", 中国肿瘤, vol. 26, no. 9, pages 707 - 713 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12152032B2 (en) | 2013-10-04 | 2024-11-26 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| US11939333B2 (en) | 2015-09-14 | 2024-03-26 | Infinity Pharmaceuticals, Inc. | Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same |
| CN114259476A (zh) * | 2021-12-29 | 2022-04-01 | 中南大学湘雅三医院 | 一种调控巨噬细胞的纳米制剂及其制备方法与应用 |
| CN116327706A (zh) * | 2023-02-01 | 2023-06-27 | 中山大学附属第八医院（深圳福田） | 一种纳米药物递送系统及其制备方法与应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112546025B (zh) | 2023-06-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112546025B (zh) | 一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备方法 | |
| CN106139144B (zh) | 一种具有协同抗肿瘤特性的透明质酸修饰的金-碳纳米球及其制备方法与应用 | |
| US20100262115A1 (en) | Nanoparticles for cancer sonodynamic and photodynamic therapy | |
| CN108452303A (zh) | 一种载双药纳米制剂及其制备方法 | |
| CN110302395B (zh) | 一种可促肿瘤凝血和酶/pH双重响应性释药的纳米粒子及其制备方法与应用 | |
| CN102740875A (zh) | 基于人血清白蛋白的用于光动力疗法的纳米粒子载体系统 | |
| CN108295046A (zh) | 一种白蛋白纳米颗粒的制备方法及制得的白蛋白纳米颗粒与应用 | |
| CN114344482B (zh) | 一种基于金属有机骨架的多功能纳米粒及其制备方法与应用 | |
| CN108354913A (zh) | 一种纳米载药纳米系统在制备治疗难治性甲状腺癌的药物中的应用 | |
| Huang et al. | Multicomponent carrier-free nanodrugs for cancer treatment | |
| CN105194679A (zh) | 有抗肿瘤药物纳米层的透明质酸修饰的二氧化钛-氧化石墨烯复合材料制备方法及应用 | |
| CN113559064A (zh) | 一种新型自供氧脂质体纳米粒及其制备方法与应用 | |
| Chen et al. | Advances in photo-responsive hydrogel integrated with biomedical materials for antitumor applications | |
| CN113633784B (zh) | 一种热休克蛋白抑制增敏光热治疗的杂化纳米组装体及其制备与应用 | |
| CN103768598A (zh) | 一种可植入的富勒烯聚乳酸自团聚载药缓释微球的制备方法及应用 | |
| CN112933229A (zh) | 一种ir820与阿托伐醌无载体自组装纳米粒及其制备方法和应用 | |
| Yu et al. | Application of nanoscale metal-organic coordination polymers in cancer therapy | |
| CN110251672B (zh) | 一种纳米诊疗剂及其制备方法与应用 | |
| CN109953974B (zh) | 一种酶-还原双响应性透明质酸-聚硫化丙烯共聚物纳米胶囊的制备方法 | |
| CN109550050B (zh) | 一种负载黑色素的二氧化钼载药复合物及其制备和应用 | |
| CN109806394B (zh) | 一种介孔二氧化硅药物递送系统及其应用 | |
| Gu et al. | Mesoporous polydopamine (MPDA)-based drug delivery system for oral chemo-photothermal combinational therapy of orthotopic colon cancer | |
| CN107812189B (zh) | 一种主动靶向特定肿瘤细胞的竹红菌素纳米制剂及其制备方法和应用 | |
| CN110200945A (zh) | 一种光敏性多巴胺基纳米药物载体的制备方法 | |
| CN113827553B (zh) | 用于肿瘤光动力学治疗的瘤内注射给药的酞菁锌在位凝胶及其制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |