CN111588690A - 一种响应性透明质酸荧光纳米凝胶、制备方法和应用 - Google Patents
一种响应性透明质酸荧光纳米凝胶、制备方法和应用 Download PDFInfo
- Publication number
- CN111588690A CN111588690A CN202010398601.8A CN202010398601A CN111588690A CN 111588690 A CN111588690 A CN 111588690A CN 202010398601 A CN202010398601 A CN 202010398601A CN 111588690 A CN111588690 A CN 111588690A
- Authority
- CN
- China
- Prior art keywords
- hyaluronic acid
- nanogel
- solution
- fluorescence
- preparation
- 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
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 107
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 107
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 104
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 31
- 229940079593 drug Drugs 0.000 claims abstract description 27
- 229910000510 noble metal Inorganic materials 0.000 claims abstract description 19
- 238000011068 loading method Methods 0.000 claims abstract description 15
- 239000000243 solution Substances 0.000 claims description 51
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 239000011259 mixed solution Substances 0.000 claims description 32
- 239000000839 emulsion Substances 0.000 claims description 29
- 238000003756 stirring Methods 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 239000012279 sodium borohydride Substances 0.000 claims description 14
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 239000008367 deionised water Substances 0.000 claims description 12
- 229910021641 deionized water Inorganic materials 0.000 claims description 12
- 239000005457 ice water Substances 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 230000001376 precipitating effect Effects 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 claims description 8
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 claims description 8
- 229960003067 cystine Drugs 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- DJVKJGIZQFBFGS-UHFFFAOYSA-N n-[2-[2-(prop-2-enoylamino)ethyldisulfanyl]ethyl]prop-2-enamide Chemical compound C=CC(=O)NCCSSCCNC(=O)C=C DJVKJGIZQFBFGS-UHFFFAOYSA-N 0.000 claims description 8
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 8
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 8
- DCUFMVPCXCSVNP-UHFFFAOYSA-N methacrylic anhydride Chemical compound CC(=C)C(=O)OC(=O)C(C)=C DCUFMVPCXCSVNP-UHFFFAOYSA-N 0.000 claims description 7
- 239000003431 cross linking reagent Substances 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 abstract description 32
- 206010028980 Neoplasm Diseases 0.000 abstract description 14
- 229940009456 adriamycin Drugs 0.000 abstract description 8
- 238000011065 in-situ storage Methods 0.000 abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 5
- 230000002829 reductive effect Effects 0.000 abstract description 4
- 230000001960 triggered effect Effects 0.000 abstract description 4
- 239000000084 colloidal system Substances 0.000 abstract description 3
- 238000004132 cross linking Methods 0.000 abstract description 3
- 230000008685 targeting Effects 0.000 abstract description 3
- 238000013270 controlled release Methods 0.000 abstract description 2
- 150000001993 dienes Chemical class 0.000 abstract description 2
- 150000002500 ions Chemical class 0.000 abstract description 2
- 230000003287 optical effect Effects 0.000 abstract description 2
- 239000000499 gel Substances 0.000 description 29
- 239000002245 particle Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 238000000502 dialysis Methods 0.000 description 13
- 229960004679 doxorubicin Drugs 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000002189 fluorescence spectrum Methods 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 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 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 238000002296 dynamic light scattering Methods 0.000 description 6
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 6
- 229910052737 gold Inorganic materials 0.000 description 6
- 239000010931 gold Substances 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 230000005540 biological transmission Effects 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000001000 micrograph Methods 0.000 description 4
- 229910052709 silver Inorganic materials 0.000 description 4
- 239000004332 silver Substances 0.000 description 4
- 150000003384 small molecules Chemical class 0.000 description 4
- 108010024636 Glutathione Proteins 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229960003180 glutathione Drugs 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000002077 nanosphere Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- -1 Methacrylic acylated hyaluronic acid Chemical class 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000012984 biological imaging Methods 0.000 description 2
- OOTFVKOQINZBBF-UHFFFAOYSA-N cystamine Chemical compound CCSSCCN OOTFVKOQINZBBF-UHFFFAOYSA-N 0.000 description 2
- 229940099500 cystamine Drugs 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- 238000000703 high-speed centrifugation Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 231100000915 pathological change Toxicity 0.000 description 2
- 230000036285 pathological change Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 102100032912 CD44 antigen Human genes 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 1
- 102100027735 Hyaluronan mediated motility receptor Human genes 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 238000004224 UV/Vis absorption spectrophotometry Methods 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 210000001099 axilla Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000013267 controlled drug release Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 108010003425 hyaluronan-mediated motility receptor Proteins 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 239000002539 nanocarrier Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 238000012634 optical imaging Methods 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000002096 quantum dot Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Images
Classifications
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
本发明提供了一种响应性透明质酸荧光纳米凝胶、制备方法和应用,以携二硫键的双烯烃分子交联透明质酸制备出尺寸可控的纳米凝胶,进一步在该凝胶内原位还原贵金属离子产生荧光纳米团簇,赋予了透明质酸纳米凝胶由可见至近红外范围的荧光。本发明的透明质酸荧光纳米凝胶尺寸可控且生物相容性良好,具有较高的胶体和光学稳定性。该荧光纳米凝胶对药物阿霉素的负载率高,拥有优异的肿瘤主动靶向性,受还原微环境触发能加速释放所负载的药物。因此,本发明所涉纳米凝胶在抗肿瘤药物负载、靶向控制释放及荧光示踪等医学领域具有较大的应用潜能。
Description
技术领域
本发明属于高分子复合材料及生物成像、载药技术领域,具体涉及一种响应性透明质酸荧光纳米凝胶、制备方法和应用。
背景技术
透明质酸(Hyaluronic Acid,HA),是一种广泛分布于动物和人体细胞外基质中的天然线性粘多糖。独特的分子结构及理化性质令HA在机体内显示出多种重要的生理功能,如调节蛋白质与电解质扩散及运转,组织和稳定细胞外基质,调节细胞的粘附性,并介导细胞增殖与分化。因此,生物医药及日化等多个领域均可见到透明质酸及其衍生物的使用。HA携带有丰富的官能团可用于物理化学修饰,且多种癌细胞的表面被证实存在HA受体(CD44和RHAMM)过度表达,使得以透明质酸构筑抗肿瘤靶向药物递送系统成为一个有价值的课题。
因分子结构明确、电荷定量、拥有离散的电子跃迁及生物低毒性,贵金属(金和银等)的荧光纳米簇(Nanoclusters)作为功能材料的研究备受青睐。由十数个至上百个原子聚集形成的贵金属纳米簇,粒径小于2纳米,实现了单原子与纳米粒子特性间鸿沟的跨越。相比于其它形式纳米颗粒具有表面等离子共振激起的光散射及吸收,接近电子费米波长尺寸的金属簇表现出由可见至近红外波段的良好的荧光发射特性(400-900nm)。近红外荧光拥有较强的组织穿透性,且可明显区别于组织自发荧光,贵金属纳米簇因而被作为生物探针用于体内外成像。相比于传统荧光染料,纳米簇具有荧光波长可调性、显著的光稳定性、Stoke位移大及多指数荧光寿命等优势;而与无机的荧光量子点相比,这类纳米簇的低生物毒性与快速肾清除能力又更胜一筹。另外,基于提升荧光效率同时提供生理环境中胶体稳定性的需求,贵金属纳米簇在制备时即设计以各种活性大分子(BSA、DNA蛋白质、多糖等)进行表面修饰或者包裹。因此,所制得的各种纳米级荧光颗粒或凝胶具有进一步化学修饰潜能,奠定了探针类新产品开发的基础。
近年来,研究表明:纳米载体能够控制药物抵达病灶部位并快速释放药物从而提高抗肿瘤效果,降低化疗药物毒副作用的同时压制了癌细胞耐药概率。通过理化交联亲水性或两亲性聚合物形成具有空间网状结构的纳米凝胶,因高含水量、大比表面及高生物相容性等特性而成为常见的药物载体。通常,肿瘤组织内的生理微环境与正常组织相比有显著的差异,诸如pH值更低、乏氧、还原性谷胱甘肽浓度超高等。鉴于此,科技工作者巧妙设计并构造出大量刺激响应性或多重响应的纳米凝胶,用作抗肿瘤药物的递送载体。因此,响应性纳米凝胶不仅保证了药物递送系统进入体循环时的稳定性,同时能够实现药物富集于瘤内快速释放。
发明内容
本发明的目的在于提供一种响应性透明质酸荧光纳米凝胶,能够负载药物进行靶向肿瘤的递送,完成瘤内富集和药物触发释放,同时荧光赋予了成像示踪能力。
本发明另一目的在于提供一种响应性透明质酸荧光纳米凝胶的制备方法,利用含二硫键小分子交联水溶性透明质酸合成尺寸均匀且可控的还原响应纳米凝胶,进一步原位还原负载贵金属纳米簇制得荧光纳米凝胶。
本发明最后一个目的在于提供一种响应性透明质酸荧光纳米凝胶的应用,用于负载药物。
本发明具体技术方案如下:
一种响应性透明质酸荧光纳米凝胶的制备方法,包括以下步骤:
1)制备甲基丙烯酰化的透明质酸;
2)甲基丙烯酰化透明质酸与交联剂加热溶解于去离子水中,氮气保护下,加热条件下加入过硫酸钾,搅拌反应后,过滤、透析,制得纳米透明质酸纳米凝胶乳液;
3)将步骤2)制备的纳米透明质酸纳米凝胶乳液与贵金属溶液混合,调节至碱性后,加入还原性溶液,冰水浴搅拌反应,过滤、透析,得到响应性透明质酸荧光纳米凝胶。
步骤1)具体为:
将透明质酸溶解于干燥的二甲亚砜DMSO,再加缚酸剂后,得到混合溶液1,将DMSO与甲基丙烯酸酐的混合溶液2滴入混合溶液1中,室温搅拌后,用乙醇沉淀并洗涤产物,所得浅黄色粗产品溶于水后,以稀氢氧化钠溶液调节pH至中性,然后用乙醇沉淀洗涤三次,所得产物真空干燥后,得到甲基丙烯酰化的透明质酸。
步骤1)中:
所述缚酸剂为三乙胺;
透明质酸与干燥的二甲亚砜的用量比为5:80-150g/ml。
透明质酸与三乙胺的用量比为5:3-6g/ml。
透明质酸与甲基丙烯酸酐的用量比为5:4-8g/ml。
DMSO与甲基丙烯酸酐的混合溶液2中DMSO与甲基丙烯酸酐体积比为2-5:4-8;
所述室温搅拌,搅拌时间为6-12h;
所述稀氢氧化钠溶液浓度0.1-0.5mol/L。
优选的,步骤1)具体为:5克透明质酸溶解于80-150mL干燥的二甲亚砜(DMSO),再加3-6mL三乙胺后,得到混合溶液1,将DMSO与甲基丙烯酸酐的混合溶液2滴入得到混合溶液1中,室温搅拌反应6-12小时后,用乙醇沉淀并洗涤产物,所得浅黄色粗产品溶于50-90mL水后,以浓度0.1-0.5mol/L的氢氧化钠溶液调节pH至中性,再用乙醇沉淀洗涤三次,真空干燥后,用核磁共振氢谱确认得到甲基丙烯酰化的透明质酸。
步骤2)中所述交联剂为N,N-双(丙烯酰)胱胺或N,N-双(丙烯酰)胱胺酸;
步骤2)所述交联剂为N,N-双(丙烯酰)胱胺时,步骤2)具体为:等质量的甲基丙烯酰化透明质酸与N,N-双(丙烯酰)胱胺加热溶解于去离子水,配制成混合溶液,在氮气保护下,混合溶液升高温度至80℃加入过硫酸钾,在80℃搅拌下反应,所得白色乳液产品过滤,滤液用透析袋,在去离子水中透析以去除体系内的小分子。
进一步的,混合溶液中,甲基丙烯酰化透明质酸与N,N-双(丙烯酰)胱胺总浓度为2-5.2g/L;过硫酸钾与去离子水用量比为1-2:300g/ml;所述搅拌下反应10分钟,
或者,步骤2)中所述交联剂为N,N-双(丙烯酰)胱胺酸时,步骤2)具体为:等质量的甲基丙烯酰化透明质酸与N,N-双(丙烯酰)胱胺酸通过加热溶解于去离子水,配制成混合溶液,在氮气保护下,混合液升高温度至80℃加入过硫酸钾,在80℃搅拌下反应,所得白色乳液产品被过滤,滤液用透析袋在去离子水中透析48小时以去除体系内的小分子。
进一步的,混合溶液中,甲基丙烯酰化透明质酸与N,N-双(丙烯酰)胱胺酸总浓度为1-2g/L;过硫酸钾与去离子水用量比为2-3:300g/ml;所述搅拌下反应30分钟。
步骤3)中透明质酸纳米凝胶乳液与贵金属溶液的体积比为50:1-5;所述贵金属溶液浓度为10-15mg/mL;步骤3)中,所述贵金属溶液为氯金酸溶液或硝酸银溶液;
步骤3)中所述透明质酸纳米凝胶乳液与还原性溶液体积比为50:2;所述还原性溶液为硼氢化钠(NaBH4)冰水溶液。步骤3)中,所述贵金属溶液与还原性溶液中硼氢化钠(NaBH4)的用量比为1-5mL:2.5×10-4-4.2×10-5mol。
步骤3)中调节至8-10;
步骤3)中冰水浴反应8-48h;
优选的,步骤3)具体为:
取50mL上述制备的透明质酸纳米凝胶乳液,将5mL10 mg/mL氯金酸溶液在搅拌下缓慢滴入其中,以稀氢氧化钠溶液将混合液的pH值调到10后,滴入含4.2×10-5mol硼氢化钠(NaBH4)的2mL硼氢化钠冰水液,冰水浴中搅拌24-48小时后,乳液变成浅棕色,过滤所得乳液,滤液装入Cut-off分子量为14000的透析袋中透析24小时以除去小分子副产物,得到响应性透明质酸荧光纳米凝胶;既可用于负载,更可用作检测探针,且在pH值3-11的广泛范围介质中的稳定性,粒径变化不大。本步骤中,硼氢化钠与透明质酸协同原位还原所得金纳米簇分散于凝胶内二硫键上,荧光光谱研究表明:该凝胶拥有峰值位于655纳米处的宽荧光发射,此外,发射波长延伸到了700-800纳米的近红外光区。
或者,步骤3)具体为:取50mL上述制备的透明质酸纳米凝胶乳液,将1mL15 mg/mL硝酸银溶液在搅拌下缓慢滴入其中,以稀氢氧化钠溶液将混合液的pH值调到8后,滴入含2.5×10-4mol硼氢化钠(NaBH4)的2mL硼氢化钠冰水液,搅拌8-12小时后,硼氢化钠与透明质酸协同原位还原所得银纳米簇分散于凝胶内二硫键上,乳液变成橙红色,过滤所得乳液,滤液装入Cut-off分子量为14000的透析袋中透析24小时以除去小分子副产物,经动态光散射测定所得纳米凝胶平均粒径为254纳米,且在pH值3-11的广泛范围内粒径变化不大。荧光光谱研究表明:该凝胶拥有峰值位于630纳米处的宽荧光发射,此外,发射波长延伸到了700-800纳米的近红外光区。
本发明提供的一种响应性透明质酸荧光纳米凝胶,采用上述方法制备得到。所述响应性透明质酸荧光纳米凝胶为纳米球形。纳米球形有利于其在血管里的传递和组织渗透。
本发明提供的一种响应性透明质酸荧光纳米凝胶的应用,具体用于负载药物。
具体方法为:
将4mL 5mg/mL响应性透明质酸荧光纳米凝胶乳液于搅拌下以氢氧化钠液调节pH至8,而后滴加1mL 2-2.5mg/mL盐酸阿霉素水溶液,在黑暗环境中将混合液搅拌过夜,时间8-12小时,用高速离心40分钟除去未被负载的阿霉素,沉积物重新分散在10mM的磷酸缓冲液(pH=7.4,PBS)中,即得负载阿霉素的透明质酸荧光纳米凝胶。利用紫外可见吸收光谱和荧光光谱检测并计算得到纳米凝胶的载药量及载药效率分别为:16%和96%。
本发明利用含二硫键小分子交联水溶性透明质酸合成尺寸均匀且可控的还原响应纳米凝胶,二硫键赋予纳米凝胶还原环境敏感性、贵金属纳米簇拥有延伸至近红外区的荧光发射,近红外光将有利于其由活体内穿透组织发出外界能检测到的光,这对活体成像非常有用。
本发明以携二硫键的双烯烃分子交联透明质酸制备出尺寸可控的纳米凝胶,进一步在该凝胶内原位还原贵金属离子产生荧光纳米团簇,赋予了透明质酸纳米凝胶由可见至近红外范围的荧光。本发明的透明质酸荧光纳米凝胶尺寸可控且生物相容性良好,具有较高的胶体和光学稳定性。该荧光纳米凝胶对药物阿霉素的负载率高,拥有优异的肿瘤主动靶向性,受还原微环境触发能加速释放所负载的药物。因此,本发明所涉纳米凝胶在抗肿瘤药物负载、靶向控制释放及荧光示踪等医学领域具有较大的应用潜能。
本发明提供了生物相容、还原响应的荧光透明质酸纳米凝胶、制备方法及其药物控释、生物成像应用。与现有技术相比,本发明原位负载贵金属纳米团簇获取荧光的交联透明质酸凝胶,能够负载药物,而且,细胞存活率均大于90%即基本无毒性;纳米凝胶负载的阿霉素对癌细胞的杀伤作用比裸药有明显的增加。而且,透明质酸荧光纳米凝胶能够将抗肿瘤药物有效递送至病变部位,同时能够实现实时的追踪。
附图说明
图2为各种透明质酸与胱胺投料浓度所制纳米凝胶的水合粒径及表面电位;
图3为包覆金纳米簇的透明质酸荧光纳米凝胶的透射电子显微镜图;
图4为包覆金纳米簇的透明质酸荧光纳米凝胶的紫外可见吸收光谱和荧光发射光谱图(内插图为荧光纳米凝胶在可见光与紫外光照射下的);
图5为负载阿霉素的透明质酸荧光纳米凝胶在不同介质中的药物释放曲线;
图6为不同浓度的透明质酸荧光纳米凝胶与阿霉素裸药、负载阿霉素纳米凝胶对A549细胞孵育后,细胞相对存活率图(左图为各种浓度空纳米凝胶对细胞作用,右图为各种药物浓度的两种样品对细胞作用);
图7为透明质酸荧光纳米凝胶在荷瘤小鼠体内的近红外光学成像结果;
图8为包覆银纳米簇的透明质酸荧光纳米凝胶的透射电子显微镜图。
具体实施方式
实施例1
一种响应性透明质酸荧光纳米凝胶的制备方法,包括以下步骤:
1)将5克透明质酸溶解于120mL干燥的二甲亚砜(DMSO),在加6mL三乙胺后,得到混合溶液1,将甲基丙烯酸酐4ml与2ml DMSO混合得到的混合溶液2滴入溶液1中,室温搅拌12小时后,用乙醇沉淀并洗涤产物,所得浅黄色粗产品溶于80mL水后,以0.1mol/L的氢氧化钠溶液调节pH至中性,用乙醇沉淀洗涤三次,粉末真空干燥后,用核磁共振氢谱确认结果为部分甲基丙烯酰化的透明质酸,如图1所示;
图1为透明质酸与甲基丙烯酰化透明质酸的核磁共振氢谱;图中1为透明质酸H谱;2-为甲基丙烯酰化透明质酸氢谱,该氢谱中a为甲基丙烯酰化透明质酸烯烃基团H1特征峰,b为甲基丙烯酰化透明质酸烯烃基团H2特征峰,c为甲基丙烯酰化透明质酸烯烃基团CH3特征峰。
2)等质量的甲基丙烯酰化透明质酸与N,N-双(丙烯酰)胱胺通过加热溶解于300mL去离子水,配制成甲基丙烯酰化透明质酸与N,N-双(丙烯酰)胱胺总浓度为2g/L的混合溶液,在氮气保护下,混合液升高温度至80℃后加入2g过硫酸钾,搅拌下反应10分钟,所得白色乳液产品,过滤,滤液用透析袋(Cut-off分子量为14000)在去离子水中透析48小时以去除体系内的小分子。动态光散射检测显示所得纳米凝胶水合粒径为124纳米。
3)取50mL上述制备的124纳米透明质酸纳米凝胶乳液,将5mL 10mg/mL氯金酸溶液在搅拌下缓慢滴入其中,以0.1mol/L的氢氧化钠溶液将混合液的pH值调到10后,滴入含4.2×10-5mol硼氢化钠(NaBH4)的硼氢化钠冰水液,冰水浴中搅拌48小时后,乳液变成浅棕色,过滤所得乳液,滤液装入透析袋(Cut-off分子量为14000)中透析24小时以除去小分子副产物,经动态光散射测定所得纳米凝胶平均粒径为128纳米,且在3-11的广泛pH值范围内粒径变化不大。荧光光谱研究表明:该凝胶拥有峰值位于655纳米处的宽荧光发射,此外,发射波长延伸到了700-800纳米的近红外光区。
图3为包覆金纳米簇的透明质酸荧光纳米凝胶的透射电子显微镜图,为纳米球形。图4为包覆金纳米簇的透明质酸荧光纳米凝胶的紫外可见吸收光谱和荧光发射光谱图(内插图为荧光纳米凝胶在可见光与紫外光照射下的)。
重复实施例1,不同在于步骤2)中甲基丙烯酰化透明质酸与N,N-双(丙烯酰)胱胺总浓度分别2.6、4和5.2g/L的溶液,对应的,步骤2)最终得到的纳米凝胶水合粒径分别为125、138及206纳米。
图1为各种透明质酸与胱胺投料浓度所制纳米凝胶的水合粒径及表面电位。
实施例2
一种响应性透明质酸荧光纳米凝胶的应用,具体用于负载药物。
具体方法为负载阿霉素的透明质酸荧光纳米凝胶(HA-MC)的制备:
将4mL前述128纳米的5mg/mL透明质酸荧光纳米凝胶乳液于搅拌下以氢氧化钠液调节pH至8,而后滴加1mL 2.5mg/mL盐酸阿霉素水溶液。在黑暗环境中将混合液搅拌12小时,用高速离心40分钟除去未被负载的阿霉素,沉积物重新分散在10mM的磷酸缓冲液(pH=7.4,PBS)中,即得负载阿霉素的透明质酸荧光纳米凝胶。利用紫外可见吸收光谱和荧光光谱检测并计算得到纳米凝胶的载药量及载药效率分别为:16%和96%,动态光散射测定载药荧光纳米凝胶的平均粒径为143纳米。
负载阿霉素的透明质酸荧光纳米凝胶的体外释放和细胞毒性:
取上述所制得的0.5mL负载阿霉素的透明质酸荧光纳米凝胶的溶液置于透析袋(Cut-off分子量为14000)中,然后将透析袋浸入5mL浓度为10mM的PBS溶液中,在37℃搅拌下进行释放实验。PBS溶液分别为pH=7.4、pH=7.4且含10mM谷胱甘肽(glutathione,GSH)、pH=5.0且含10mM谷胱甘肽,每隔一段时间用等量新鲜的释放介质替换原来介质,用紫外可见吸收光谱通过标准曲线法检测介质中阿霉素的含量。根据介质中药物含量计算释放的百分率,结果如图5所示,可以看到负载于纳米凝胶的药物显示了持续释放特性,同时酸性及还原性环境将触发药物加速释放。
利用A549细胞株与阿霉素、透明质酸荧光纳米凝胶和载药荧光纳米凝胶进行孵育后,以MTT法检测活细胞相对数量计算确认其细胞毒性。以5×103个/孔的密度将A549细胞接种于96孔板,培养24小时后,加入5微升不同浓度的样品溶液,再24小时后除去培养基并用冷PBS洗涤两次,每孔补加200微升含10%MTT溶液(5mg/mL,pH=7.4PBS)的培养基,继续37℃孵育4小时。弃除上清液后,每孔加入150微升DMSO,室温振摇10分钟,以酶标仪测定570纳米处的吸光度。未处理的细胞作为参照,据此计算细胞存活率。结果如图6所示,结果表明,本发明所制备的透明质酸荧光纳米凝胶甚至在高浓度下,细胞存活率均大于90%即基本无毒性;纳米凝胶负载的阿霉素对癌细胞的杀伤作用比裸药有明显的增加。
透明质酸荧光纳米凝胶的体内荧光成像:
将106个H22肿癌细胞通过皮下注射接种于ICR小鼠的左腋下建立小鼠模型。待生长一周左右,选择固体瘤体积合适(约100mm3)的小鼠。取上述制备的128纳米的透明质酸荧光纳米凝胶液0.2mL静脉注射入小鼠体内,以近红外荧光成像的方法对荷瘤小鼠进行实时成像。结果如图7所示,表明纳米凝胶在主动及被动靶向作用下能在注射后1小时迅速进入肿瘤部位,并于48小时后达到富集峰值,直到96小时后瘤内仍有纳米凝胶的聚集。证明透明质酸荧光纳米凝胶能够将抗肿瘤药物有效递送至病变部位,同时能够实现实时的追踪。
实施例3
一种响应性透明质酸荧光纳米凝胶的制备方法,包括以下步骤:
1)将5克透明质酸溶解于120mL干燥的二甲亚砜(DMSO),在加6mL三乙胺后,得到混合溶液1,将甲基丙烯酸,6ml与5ml DMSO混合得到的混合溶液2滴入混合溶液1中。室温搅拌12小时后,用乙醇沉淀并洗涤产物,所得浅黄色粗产品溶于80mL水后,以稀氢氧化钠溶液调节pH至中性,用乙醇沉淀洗涤三次,粉末真空干燥后,用核磁共振氢谱确认结果为,甲基丙烯酰化的透明质酸。
2)等质量的甲基丙烯酰化透明质酸与N,N-双(丙烯酰)胱胺酸通过加热溶解于300mL去离子水,配制成甲基丙烯酰化透明质酸与N,N-双(丙烯酰)胱胺酸总浓度为1g/L的溶液,在氮气保护下,混合液升高温度至80℃后加入2g过硫酸钾,搅拌下反应30分钟,所得白色乳液产品,过滤,滤液用透析袋(Cut-off分子量为14000)在去离子水中透析48小时以去除体系内的小分子。动态光散射检测显示所得纳米凝胶水合粒径为236纳米。
3)取50mL上述制备的236纳米透明质酸纳米凝胶乳液,将1mL 15mg/mL硝酸银溶液在搅拌下缓慢滴入其中,以稀氢氧化钠溶液将混合液的pH值调到8后,滴入含2.5×10-4mol硼氢化钠(NaBH4)的硼氢化钠冰水液,搅拌8小时后,乳液变成橙红色,过滤所得乳液,滤液装入透析袋(Cut-off分子量为14000)中透析24小时以除去小分子副产物,经动态光散射测定所得纳米凝胶平均粒径为254纳米,且在3-11的广泛pH值范围内粒径变化不大。荧光光谱研究表明:该凝胶拥有峰值位于630纳米处的宽荧光发射,此外,发射波长延伸到了700-800纳米的近红外光区。
重复实施例3,不同在于步骤2)中甲基丙烯酰化透明质酸与N,N-双(丙烯酰)胱胺酸总浓度分别为1.2和1.7g/L,对应的步骤2)最终得到的纳米凝胶水合粒径分别为295及436纳米。图8为包覆银纳米簇的透明质酸荧光纳米凝胶的透射电子显微镜图。
Claims (10)
1.一种响应性透明质酸荧光纳米凝胶的制备方法,其特征在于,所述制备方法包括以下步骤:
1)制备甲基丙烯酰化的透明质酸;
2)甲基丙烯酰化透明质酸与交联剂加热溶解于去离子水中,氮气保护下,加热条件下加入过硫酸钾,搅拌反应后,过滤、透析,制得纳米透明质酸纳米凝胶乳液;
3)将步骤2)制备的纳米透明质酸纳米凝胶乳液与贵金属溶液混合,调节至碱性后,加入还原性溶液,冰水浴搅拌反应,过滤、透析,得到响应性透明质酸荧光纳米凝胶。
2.根据权利要求1所述的制备方法,其特征在于,步骤1)具体为:
将透明质酸溶解于干燥的二甲亚砜DMSO,再加缚酸剂后,得到混合溶液1,将DMSO与甲基丙烯酸酐的混合溶液2滴入混合溶液1中,室温搅拌后,用乙醇沉淀并洗涤产物,所得浅黄色粗产品溶于水后,以稀氢氧化钠溶液调节pH至中性,然后用乙醇沉淀洗涤三次,所得产物真空干燥后,得到甲基丙烯酰化的透明质酸。
3.根据权利要求1所述的制备方法,其特征在于,步骤2)中所述交联剂为N,N-双(丙烯酰)胱胺或N,N-双(丙烯酰)胱胺酸。
4.根据权利要求1所述的制备方法,其特征在于,步骤3)中透明质酸纳米凝胶乳液与贵金属溶液的体积比为50:1-5;所述贵金属溶液浓度为10-15mg/mL。
5.根据权利要求1或4所述的制备方法,步骤3)中所述贵金属溶液为氯金酸溶液或硝酸银溶液。
6.根据权利要求1或4所述的制备方法,其特征在于,步骤3)中调节至8-10。
7.根据权利要求1所述的制备方法,其特征在于,步骤3)中冰水浴反应8-48h。
8.根据权利要求1所述的制备方法,其特征在于,步骤3)中,所述还原性溶液为硼氢化钠(NaBH4)冰水溶液,所述贵金属溶液与还原性溶液中硼氢化钠(NaBH4)的用量比为1-5mL:2.5×10-4-4.2×10-5mol。
9.一种权利要求1-8任一项所述的制备方法制备的响应性透明质酸荧光纳米凝胶。
10.一种权利要求1-8任一项所述的制备方法制备的响应性透明质酸荧光纳米凝胶用于负载药物。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010398601.8A CN111588690B (zh) | 2020-05-12 | 2020-05-12 | 一种响应性透明质酸荧光纳米凝胶、制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010398601.8A CN111588690B (zh) | 2020-05-12 | 2020-05-12 | 一种响应性透明质酸荧光纳米凝胶、制备方法和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111588690A true CN111588690A (zh) | 2020-08-28 |
CN111588690B CN111588690B (zh) | 2022-12-02 |
Family
ID=72180514
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010398601.8A Active CN111588690B (zh) | 2020-05-12 | 2020-05-12 | 一种响应性透明质酸荧光纳米凝胶、制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111588690B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115368508A (zh) * | 2022-08-02 | 2022-11-22 | 安徽工程大学 | 一种酸化响应的透明质酸纳米凝胶及其制法与应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110105594A (zh) * | 2019-05-26 | 2019-08-09 | 杭州枫霖科技有限公司 | 一种具有快速固化功能的透明质酸钠水凝胶及其制备方法 |
CN111097070A (zh) * | 2020-01-09 | 2020-05-05 | 上海交通大学 | 一种用于抑制肿瘤和促进修复的可注射生物活性水凝胶 |
-
2020
- 2020-05-12 CN CN202010398601.8A patent/CN111588690B/zh active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110105594A (zh) * | 2019-05-26 | 2019-08-09 | 杭州枫霖科技有限公司 | 一种具有快速固化功能的透明质酸钠水凝胶及其制备方法 |
CN111097070A (zh) * | 2020-01-09 | 2020-05-05 | 上海交通大学 | 一种用于抑制肿瘤和促进修复的可注射生物活性水凝胶 |
Non-Patent Citations (2)
Title |
---|
CHENCHEN YANG等: "Redox Responsive Hyaluronic Acid Nanogels for Treating RHAMM (CD168) Over-expressive Cancer, both Primary and Metastatic Tumors", 《THERANOSTICS》 * |
YING CHEN等: "Near-Infrared Emitting Gold Cluster−Poly(acrylic acid) Hybrid Nanogels", 《ACS MACRO LETTERS》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115368508A (zh) * | 2022-08-02 | 2022-11-22 | 安徽工程大学 | 一种酸化响应的透明质酸纳米凝胶及其制法与应用 |
Also Published As
Publication number | Publication date |
---|---|
CN111588690B (zh) | 2022-12-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Wang et al. | Carbon-based hybrid nanogels: a synergistic nanoplatform for combined biosensing, bioimaging, and responsive drug delivery | |
Barman et al. | Dendrimer as a multifunctional capping agent for metal nanoparticles for use in bioimaging, drug delivery and sensor applications | |
Rajabzadeh-Khosroshahi et al. | Chitosan/agarose/graphitic carbon nitride nanocomposite as an efficient pH-sensitive drug delivery system for anticancer curcumin releasing | |
Wu et al. | Enzyme-responsive multifunctional peptide coating of gold nanorods improves tumor targeting and photothermal therapy efficacy | |
Muddineti et al. | Xanthan gum stabilized PEGylated gold nanoparticles for improved delivery of curcumin in cancer | |
Bao et al. | pH‐sensitive carbon quantum dots− doxorubicin nanoparticles for tumor cellular targeted drug delivery | |
Chen et al. | Dual activated NIR-II fluorescence and photoacoustic imaging-guided cancer chemo-radiotherapy using hybrid plasmonic-fluorescent assemblies | |
Asadishad et al. | In vitro release behavior and cytotoxicity of doxorubicin-loaded gold nanoparticles in cancerous cells | |
Wang et al. | Multifunctional Fe 3 O 4–CdTe@ SiO 2–carboxymethyl chitosan drug nanocarriers: synergistic effect towards magnetic targeted drug delivery and cell imaging | |
Najafi et al. | Effect of grafting ratio of poly (propylene imine) dendrimer onto gold nanoparticles on the properties of colloidal hybrids, their DOX loading and release behavior and cytotoxicity | |
Chen et al. | Drug loaded multilayered gold nanorods for combined photothermal and chemotherapy | |
Dash et al. | Hyaluronic acid-modified, IR780-conjugated and doxorubicin-loaded reduced graphene oxide for targeted cancer chemo/photothermal/photodynamic therapy | |
CN108210938B (zh) | 一种多功能靶向纳米荧光探针及其制备与应用 | |
Liu et al. | Impact of PEGylation on the biological effects and light heat conversion efficiency of gold nanoshells on silica nanorattles | |
Wang et al. | Phenylboronic acid-decorated gelatin nanoparticles for enhanced tumor targeting and penetration | |
Fang et al. | Sgc8 aptamer targeted glutathione-responsive nanoassemblies containing Ara-C prodrug for the treatment of acute lymphoblastic leukemia | |
Gao et al. | AuNRs@ MIL-101-based stimuli-responsive nanoplatform with supramolecular gates for image-guided chemo-photothermal therapy | |
CN108310397B (zh) | 一种具有sers/荧光双模态靶向肿瘤细胞成像的诊疗试剂及其制备方法 | |
Lin et al. | Responsive hyaluronic acid-gold cluster hybrid nanogel theranostic systems | |
Jiang et al. | Persistent luminescent multifunctional drug delivery nano-platform based on nanomaterial ZnGa 2 O 4: Cr 3+, Sn 4+ for imaging-guided cancer chemotherapy | |
Zhu et al. | Facile preparation of indocyanine green and tiny gold nanoclusters co-loaded nanocapsules for targeted synergistic sono-/photo-therapy | |
Liu et al. | Recent Advances and Future Prospects of Aggregation‐induced Emission Carbohydrate Polymers | |
Xiao et al. | Colloidal hydroxyethyl starch for tumor-targeted platinum delivery | |
Maddahfar et al. | Stable and highly efficient antibody–nanoparticles conjugation | |
Huang et al. | Self-assembled nanoparticles based on a cationic conjugated polymer/hyaluronan–cisplatin complex as a multifunctional platform for simultaneous tumor-targeting cell imaging and drug delivery |
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 |