CN113274398B - 一种抑制肿瘤细胞糖代谢的纳米自组装材料及其制备方法和应用 - Google Patents
一种抑制肿瘤细胞糖代谢的纳米自组装材料及其制备方法和应用 Download PDFInfo
- Publication number
- CN113274398B CN113274398B CN202110442089.7A CN202110442089A CN113274398B CN 113274398 B CN113274398 B CN 113274398B CN 202110442089 A CN202110442089 A CN 202110442089A CN 113274398 B CN113274398 B CN 113274398B
- Authority
- CN
- China
- Prior art keywords
- nano self
- pei
- dspe
- mpeg
- assembly material
- 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.)
- Expired - Fee Related
Links
- 239000000463 material Substances 0.000 title claims abstract description 40
- 210000004881 tumor cell Anatomy 0.000 title claims abstract description 37
- 238000001338 self-assembly Methods 0.000 title claims abstract description 36
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 230000023852 carbohydrate metabolic process Effects 0.000 title claims abstract description 12
- 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 claims abstract description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 13
- BKLJDIJJOOQUFG-UHFFFAOYSA-N 4-N-[1-[(4-cyanophenyl)methyl]-5-methyl-3-(trifluoromethyl)pyrazol-4-yl]-7-fluoroquinoline-2,4-dicarboxamide Chemical compound C(#N)C1=CC=C(CN2N=C(C(=C2C)NC(=O)C2=CC(=NC3=CC(=CC=C23)F)C(=O)N)C(F)(F)F)C=C1 BKLJDIJJOOQUFG-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003446 ligand Substances 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000007864 aqueous solution Substances 0.000 claims abstract description 10
- 229940009456 adriamycin Drugs 0.000 claims abstract description 8
- 238000009210 therapy by ultrasound Methods 0.000 claims abstract description 6
- 102000018711 Facilitative Glucose Transport Proteins Human genes 0.000 claims abstract description 5
- 238000004108 freeze drying Methods 0.000 claims abstract description 5
- 239000003112 inhibitor Substances 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims abstract description 5
- 108091052347 Glucose transporter family Proteins 0.000 claims abstract description 4
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 21
- 239000008367 deionised water Substances 0.000 claims description 12
- 229910021641 deionized water Inorganic materials 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 8
- 230000004060 metabolic process Effects 0.000 claims description 7
- 101000926206 Homo sapiens Putative glutathione hydrolase 3 proenzyme Proteins 0.000 claims description 6
- 102100034060 Putative glutathione hydrolase 3 proenzyme Human genes 0.000 claims description 6
- 229920002873 Polyethylenimine Polymers 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 230000002407 ATP formation Effects 0.000 claims description 4
- 239000004698 Polyethylene Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- -1 polyethylene Polymers 0.000 claims description 4
- 229920000573 polyethylene Polymers 0.000 claims description 4
- 230000035755 proliferation Effects 0.000 claims description 4
- 230000004153 glucose metabolism Effects 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- LVNGJLRDBYCPGB-UHFFFAOYSA-N 1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-UHFFFAOYSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 230000009881 electrostatic interaction Effects 0.000 claims description 2
- 230000037149 energy metabolism Effects 0.000 abstract description 4
- 239000002086 nanomaterial Substances 0.000 abstract description 3
- 108010027279 Facilitative Glucose Transport Proteins Proteins 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 229960001701 chloroform Drugs 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 4
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 108091006296 SLC2A1 Proteins 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 2
- 229960001259 diclofenac Drugs 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000004190 glucose uptake Effects 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- TTWYZDPBDWHJOR-IDIVVRGQSA-L adenosine triphosphate disodium Chemical compound [Na+].[Na+].C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O TTWYZDPBDWHJOR-IDIVVRGQSA-L 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000000081 effect on glucose Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 238000007626 photothermal therapy Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000007669 thermal treatment Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000005303 weighing 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
- A61K31/70—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
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/51—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 non-active ingredient being a modifying agent
- A61K47/54—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 non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
- A61K47/544—Phospholipids
-
- 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
- A61K47/51—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 non-active ingredient being a modifying agent
- A61K47/56—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
-
- 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)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种抑制肿瘤细胞糖代谢的纳米自组装材料及其制备方法和应用。所述纳米自组装材料是在室温下将mPEG‑SS‑PEI‑DSPE长链与阿霉素和DNA配体的混合物在水溶液中搅拌，随后将糖葡萄糖转运蛋白抑制剂BAY‑876溶解在三氯甲烷中，上述体系中，边超声边加热，冻干得到结构为BAY‑876@(mPEG‑SS‑PEI‑DSPE‑Dox‑Duplex)纳米自组装材料，可以很好的抑制肿瘤细胞的糖代谢。本发明采用一步法合成，该纳米材料可以很好的释放Dox和BAY‑876，分别作用于肿瘤细胞的DNA和葡萄糖转运蛋白，抑制肿瘤细胞的能量代谢，限制肿瘤细胞生长、繁殖。
Description
技术领域
本发明是涉及一种抑制肿瘤细胞糖代谢的纳米自组装材料及其制备方法和应用，属于生物材料研究领域。
背景技术
根据全球癌症统计数据分析，截至到2018年，全球新增癌症确诊病例已经远超1800 万，其中死亡人数更是高达960万，而且亚洲的死亡人数更是占了其中的70％，令人触目惊心。目前临床上针对肿瘤的治疗手段主要包括外科手术，放射性治疗(放疗)以及药物治疗(化疗)三大传统肿瘤治疗手段。虽然这些治疗方式已经广泛应用于临床肿瘤治疗，但是手术治疗切除不干净，导致肿瘤复发转移，化疗引起的肿瘤耐药性，放疗对周边正常组织无差别的伤害性，已经无法满足现代肿瘤治疗的需求。与传统肿瘤治疗方式相比，新兴的纳米医学表现出了更强的特异性强和更丰富的功能性以及更小的副作用。但是面对种类繁多，微环境复杂多变的实体肿瘤(包括弱酸性，氧气匮乏，高活性氧浓度，多种过表达酶以及还原性微环境等等)，纳米药物呈现出的治疗效果也往往不尽人意。如肿瘤乏氧导致的氧依赖型治疗效率低下，光穿透力较弱导致的光敏型治疗效率低下，光热治疗引起的炎症因子升高导致的肿瘤复发等等，以上种种的原因导致肿瘤治疗不彻底，易复发、易转移。
葡萄糖作为自然界分布最广且最为重要的一种单糖，是活细胞的能量来源和新陈代谢中间产物，即生物的主要供能物质，也是人体热能最主要的来源。普通食物在被人体内消化后，主要以葡萄糖的形式被吸收利用。葡萄糖能够在细胞中参与细胞的呼吸作用，迅速被氧化并释放ATP，供给细胞的各项生理活动。此外，葡萄糖与脂类形成的糖脂是组成细胞膜与神经组织的成分，与蛋白质结合成糖蛋白可构成抗体、某些酶和激素等具有重要生物活性的物质。因此，合理的控制肿瘤细胞内的葡萄糖就可以限制肿瘤细胞的生长和增殖。
Zhang等(ACS Nano 2017,11,1419-1431)将葡萄糖转运蛋白1的抑制剂双氯芬酸包覆在金棒外面，运送到肿瘤细胞内，用于抑制葡萄糖转运蛋白1的活性，限制肿瘤细胞的能量代谢，同时利用金棒的光热作用，对肿瘤实施光热治疗。在多种治疗方式下，可以很好的杀死肿瘤细胞。Wei等(J.Mater.Chem.B,2018,6,2078--2088)将Cu2+和一种Zn2+的光敏剂组成有机金属骨架化合物，递送到肿瘤细胞内，利用Cu2+和ATP的亲和作用，减少肿瘤细胞内ATP的含量，限制其能量代谢，使肿瘤细胞的耐受性降低，从而增强光动力治疗效果，成功杀灭了肿瘤细胞。
发明内容
本发明目的是，提供一种抑制肿瘤细胞糖代谢的纳米自组装材料及其制备方法和应用。
本发明采用的技术方案是：
一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法，包括以下步骤：
S1、在室温下将阿霉素和DNA配体混合，得到混合物Dox-Duplex，再将 mPEG-SS-PEI-DSPE长链与混合物Dox-Duplex加入到去离子水中，在水溶液体系中搅拌均匀，超声10-30分钟，得到mPEG-SS-PEI-DSPE-Dox-Duplex的水溶液；
S2、随后将葡萄糖转运蛋白抑制剂BAY-876溶解在三氯甲烷中，缓慢滴入到步骤(1)所得mPEG-SS-PEI-DSPE-Dox-Duplex的水溶液体系中，边超声边加热，保持温度不超过50摄氏度，直到液体变得澄清透明，再离心冻干，最终得到结构为 BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)的纳米自组装材料。
进一步的，步骤S1所述阿霉素和DNA配体混合摩尔比为1：2。
进一步的，步骤S1所述DNA配体的碱基序列为5'-ACC TGG GGG AGT ATT GCG GAGGAA GGT-3'和5'-ACC TTC CTC CGC AAT ACT CCC CCA GGT-3'。
进一步的，所述加入的mPEG-SS-PEI-DSPE，Dox-Duplex和BAY-876质量比为 1～5:1:1。
进一步的，步骤S1所述mPEG-SS-PEI-DSPE结构为聚乙二醇-双硫键-聚乙烯亚胺-二硬脂酰基磷脂酰乙醇胺，其中聚乙二醇分子量是2000，聚乙烯亚胺分子量是1800。
进一步的，步骤S1所述加入到去离子水中的mPEG-SS-PEI-DSPE长链与混合物Dox-Duplex的摩尔比为1：1。
进一步的，步骤S2所述三氯甲烷和步骤S1所述去离子水体积比为1:10～20。
进一步的，步骤S1所述mPEG-SS-PEI-DSPE和去离子水的投料比为1mg：1～5mL。
根据上述方法制备的结构为BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)的纳米自组装材料中，阿霉素和DNA配体的混合物通过静电作用与mPEG-SS-PEI-DSPE长链中的聚乙烯亚胺吸附在一起，BAY-876与二硬脂酰基磷脂酰乙醇胺结合，存储在纳米自组装材料中心。
所述的一种抑制肿瘤细胞糖代谢的纳米自组装材料纳米自组装材料在肿瘤治疗中应用，所述纳米自组装材料用于抑制肿瘤的葡萄糖代谢和ATP产生，以限制肿瘤细胞生长和增殖
有益效果：本发明提供的一种抑制肿瘤细胞糖代谢的纳米自组装材料纳米自组装材料及其制备方法和应用具有如下优点：
(1)本发明所述的纳米自组装材料制备方法简单，制备工艺简单高效，反应可以一步进行到底，减少了很多繁琐的合成步骤，合成方法简单明了。
(2)本发明所制备纳米自组装材料可以较好的响应肿瘤的微环境，释放出Dox和BAY-876，对正常组织细胞无伤害。
(3)本发明所制备纳米自组装材料可以很好的抑制肿瘤的葡萄糖代谢和ATP产生，限制肿瘤细胞生长和增殖。
附图说明
图1为本发明的纳米自组装材料制备方法流程图。
图2为本发明的纳米自组装材料的透射电镜(TEM)图。
图3为本发明的纳米自组装材料的粒径分布图。
图4为本发明的纳米自组装材料对肿瘤细胞葡萄糖摄取和ATP合成的抑制作用示意图。
具体实施方式
下面结合附图和实施例对本发明作进一步详细描述。总体上一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法包括有以下步骤：
S1、mPEG-SS-PEI-DSPE-Dox-Duplex纳米体系构建：在室温下将阿霉素和DNA配体混合，DNA配体的碱基序列为5'-ACC TGG GGG AGT ATT GCG GAG GAA GGT-3' 和5'-ACCTTC CTC CGC AAT ACT CCC CCA GGT-3'，混合摩尔比为1：2，得到混合物 Dox-Duplex，再将mPEG-SS-PEI-DSPE长链与混合物Dox-Duplex加入到去离子水中； mPEG-SS-PEI-DSPE结构为聚乙二醇-双硫键-聚乙烯亚胺-二硬脂酰基磷脂酰乙醇胺， PEG分子量是2000，PEI分子量是1800，摩尔比为1：1，在水溶液体系中搅拌均匀，超声10-30分钟，得到mPEG-SS-PEI-DSPE-Dox-Duplex的水溶液；其中，加入的 mPEG-SS-PEI-DSPE和Dox-Duplex质量比为1～5:1；所述mPEG-SS-PEI-DSPE和去离子水的投料比为1mg：1～5mL。
S2、随后将葡萄糖转运蛋白抑制剂BAY-876溶解在三氯甲烷中，缓慢滴入到步骤S1所得mPEG-SS-PEI-DSPE-Dox-Duplex的水溶液中，边超声边加热，直到液体变得澄清透明，再离心冻干最终得到BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)纳米自组装材料；其中，加入的BAY-876和步骤S1中Dox-Duplex的质量比为1:1；所述三氯甲烷和步骤S1所述去离子水体积比为1:10～20。
实施例：
BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)纳米自组装材料制备方法(具体过程如图1所示)：
S1、在室温下将阿霉素和DNA配体混合，得到混合物Dox-Duplex，称取50mg mPEG-SS-PEI-DSPE分散在50mL去离子水中，随后加入10mgDox-Duplex继续超声20 分钟。
S2、然后将5mgBAY-876溶解在5mL三氯甲烷中，缓慢滴入上述溶液中，边搅拌边超声，直到液体变得澄清透明为止，再离心冻干得到 BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)纳米自组装材料。
上述实施例中制备的BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)纳米自组装材料的透射电镜透如图2所示，可以很明显的观察到纳米材料形状规则，均一，最粒径在20nm 左右。
上述实施例中制备的BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)纳米自组装材料的粒径分布图如图3所示，可以明显地观察到纳米材料呈单分散，水合粒径在50-60纳米左右。
上述实施例中制备的BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)纳米自组装材料对肿瘤细胞(4T1细胞，小鼠乳腺癌细胞)葡萄糖摄取和ATP合成的抑制作用如图4所示，在72小时内，肿瘤细胞的葡萄糖摄取含量和ATP合成含量持续下降，表明纳米粒子对肿瘤的能量代谢有着优异的抑制作用。
Claims (9)
1.一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法，其特征在于，包括以下步骤：
S1、在室温下将阿霉素和DNA配体混合，得到混合物Dox-Duplex，再将mPEG-SS-PEI-DSPE长链与混合物Dox-Duplex加入到去离子水中，在水溶液体系中搅拌均匀，超声10-30分钟，得到聚乙二醇-双硫键-聚乙烯亚胺-二硬脂酰基磷脂酰乙醇胺mPEG-SS-PEI-DSPE-Dox-Duplex的水溶液；
所述DNA配体的碱基序列为5'-ACC TGG GGG AGT ATT GCG GAG GAA GGT-3'和5'-ACCTTC CTC CGC AAT ACT CCC CCA GGT-3'；
S2、随后将葡萄糖转运蛋白抑制剂BAY-876溶解在三氯甲烷中，缓慢滴入到步骤S1所得mPEG-SS-PEI-DSPE-Dox-Duplex的水溶液体系中，边超声边加热，保持温度不超过50摄氏度，直到液体变得澄清透明，再离心冻干，最终得到结构为BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)的纳米自组装材料。
2.根据权利要求1所述的一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法，其特征在于，步骤S1所述阿霉素和DNA配体混合的摩尔比为1：2。
3.根据权利要求1所述的一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法，其特征在于，所述加入的mPEG-SS-PEI-DSPE，Dox-Duplex和BAY-876质量比为1~5:1:1。
4.根据权利要求1所述的一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法，其特征在于，步骤S1所述mPEG-SS-PEI-DSPE结构为聚乙二醇-双硫键-聚乙烯亚胺-二硬脂酰基磷脂酰乙醇胺，其中聚乙二醇分子量是2000，聚乙烯亚胺分子量是1800。
5.根据权利要求1所述的一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法，其特征在于，步骤S1所述加入到去离子水中的mPEG-SS-PEI-DSPE长链与混合物Dox-Duplex的摩尔比为1：1。
6.根据权利要求1所述的一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法，其特征在于，步骤S2所述三氯甲烷和步骤S1所述去离子水体积比为1:10~20。
7.根据权利要求1所述的一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法，其特征在于，步骤S1所述mPEG-SS-PEI-DSPE和去离子水的投料比为1mg：1~5mL。
8.根据权利要求1~7任一所述方法制备的抑制肿瘤细胞糖代谢的纳米自组装材料，其特征在于，所述纳米自组装材料结构为BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)，其中阿霉素和DNA配体的混合物通过静电作用与mPEG-SS-PEI-DSPE长链中的聚乙烯亚胺吸附在一起，BAY-876与二硬脂酰基磷脂酰乙醇胺结合，存储在纳米自组装材料中心。
9.根据权利要求8所述的一种抑制肿瘤细胞糖代谢的纳米自组装材料在制备治疗肿瘤的药物中应用，其特征在于，所述纳米自组装材料用于抑制肿瘤的葡萄糖代谢和ATP产生，以限制肿瘤细胞生长和增殖。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110442089.7A CN113274398B (zh) | 2021-04-23 | 2021-04-23 | 一种抑制肿瘤细胞糖代谢的纳米自组装材料及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110442089.7A CN113274398B (zh) | 2021-04-23 | 2021-04-23 | 一种抑制肿瘤细胞糖代谢的纳米自组装材料及其制备方法和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113274398A CN113274398A (zh) | 2021-08-20 |
| CN113274398B true CN113274398B (zh) | 2022-05-03 |
Family
ID=77277243
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110442089.7A Expired - Fee Related CN113274398B (zh) | 2021-04-23 | 2021-04-23 | 一种抑制肿瘤细胞糖代谢的纳米自组装材料及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113274398B (zh) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106798923B (zh) * | 2015-11-26 | 2020-06-09 | 北京大学 | 功能靶向性载体材料二硬脂酰磷脂酰乙醇胺-聚乙二醇-聚乙烯亚胺化合物及其修饰的脂质体 |
-
2021
- 2021-04-23 CN CN202110442089.7A patent/CN113274398B/zh not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN113274398A (zh) | 2021-08-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108653754B (zh) | 一种透明质酸靶向聚多巴胺包覆相变型液态氟碳纳米超声造影剂 | |
| CN107007835B (zh) | 载普鲁士蓝靶向纳米复合物及其制备方法 | |
| CN108653733A (zh) | 具有气泡生成功能的双载蒽环类药物及光敏剂的聚合物囊泡与制备 | |
| CN102675655A (zh) | 一种水溶性富勒烯及其制备应用方法 | |
| CN114432265B (zh) | 负载日蟾蜍他灵的仿生纳米递送系统及其制备方法和应用 | |
| CN114848854B (zh) | 一种131i-hsa-icg纳米颗粒及其制备方法和应用 | |
| Yang et al. | Advanced nanomedicines for the regulation of cancer metabolism | |
| Han et al. | The development of live microorganism-based oxygen shuttles for enhanced hypoxic tumor therapy | |
| Wang et al. | Progress and perspectives of platinum nanozyme in cancer therapy | |
| Wu et al. | Size-transformable nanohybrids with pH/redox/enzymatic sensitivity for anticancer therapy | |
| Qiao et al. | Emerging platinum (0) nanotherapeutics for efficient cancer therapy | |
| Wu et al. | Manganese-based nanomaterials in diagnostics and chemodynamic therapy of cancers: new development | |
| Xu et al. | Anti-osteosarcoma trimodal synergistic therapy using NiFe-LDH and MXene nanocomposite for enhanced biocompatibility and efficacy | |
| CN113274398B (zh) | 一种抑制肿瘤细胞糖代谢的纳米自组装材料及其制备方法和应用 | |
| CN104587466A (zh) | 蛋白-聚吡咯复合物及蛋白-聚吡咯复合物衍生物的制备方法与应用 | |
| CN110251672B (zh) | 一种纳米诊疗剂及其制备方法与应用 | |
| WO2022016555A1 (zh) | 载铂类药物/光敏剂的蛋白纳米粒及其制备方法和应用 | |
| CN106606783B (zh) | 一种靶向共递释光敏剂与化疗药物的药物递释系统 | |
| CN114939165B (zh) | 可逆转多药耐药性的双金属纳米粒及其制备方法和应用 | |
| Li et al. | Neutrophil membrane camouflaged hybrid nanozymes for enhanced starvation/photothermal tumor therapy | |
| CN109806404B (zh) | 一种能够双级递氧的白蛋白纳米粒及其制备方法与应用 | |
| Cheng et al. | Folic acid mediated cisplatin magnetic nanodrug targeting in the treatment of oral squamous cell carcinoma | |
| Yan et al. | Photodynamic therapy strategy based on nanoscale metal-organic frameworks | |
| Liu et al. | Functionalized Organic–Inorganic Liposome Nanocomposites for the Effective Photo-Thermal Therapy of Breast Cancer | |
| Yang et al. | Ingenious designed a HER2-Specific macrophage biomimetic multifunctional nanoplatform for enhanced bio-photothermal synergistic therapy in HER2 positive breast cancer |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20220503 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |