CN110604816A - 一种纳米诊疗剂及其制备方法与应用 - Google Patents
一种纳米诊疗剂及其制备方法与应用 Download PDFInfo
- Publication number
- CN110604816A CN110604816A CN201910801568.6A CN201910801568A CN110604816A CN 110604816 A CN110604816 A CN 110604816A CN 201910801568 A CN201910801568 A CN 201910801568A CN 110604816 A CN110604816 A CN 110604816A
- Authority
- CN
- China
- Prior art keywords
- donor
- gold
- nano
- treatment agent
- vesicle
- 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
- 238000003745 diagnosis Methods 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical group [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims abstract description 53
- 239000010931 gold Substances 0.000 claims abstract description 50
- 229910052737 gold Inorganic materials 0.000 claims abstract description 50
- 229920000642 polymer Polymers 0.000 claims abstract description 33
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 32
- 239000002105 nanoparticle Substances 0.000 claims abstract description 32
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 239000002131 composite material Substances 0.000 claims abstract description 8
- 239000000463 material Substances 0.000 claims abstract description 5
- 239000000032 diagnostic agent Substances 0.000 claims description 28
- 229940039227 diagnostic agent Drugs 0.000 claims description 28
- 238000000502 dialysis Methods 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- 239000002245 particle Substances 0.000 claims description 13
- 239000011259 mixed solution Substances 0.000 claims description 12
- 238000001338 self-assembly Methods 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 229940124597 therapeutic agent Drugs 0.000 claims description 11
- UYJXRRSPUVSSMN-UHFFFAOYSA-P ammonium sulfide Chemical compound [NH4+].[NH4+].[S-2] UYJXRRSPUVSSMN-UHFFFAOYSA-P 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- 238000004132 cross linking Methods 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 8
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 6
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 6
- 239000012498 ultrapure water Substances 0.000 claims description 6
- 239000002077 nanosphere Substances 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- HIVLDXAAFGCOFU-UHFFFAOYSA-N ammonium hydrosulfide Chemical compound [NH4+].[SH-] HIVLDXAAFGCOFU-UHFFFAOYSA-N 0.000 claims description 4
- 238000004140 cleaning Methods 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 238000007789 sealing Methods 0.000 claims description 4
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 3
- 235000018417 cysteine Nutrition 0.000 claims description 3
- 150000002343 gold Chemical class 0.000 claims description 3
- 230000036571 hydration Effects 0.000 claims description 3
- 238000006703 hydration reaction Methods 0.000 claims description 3
- 229930182817 methionine Natural products 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000002091 nanocage Substances 0.000 claims description 3
- 239000002120 nanofilm Substances 0.000 claims description 3
- 239000002057 nanoflower Substances 0.000 claims description 3
- 239000002078 nanoshell Substances 0.000 claims description 3
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 3
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 3
- 239000012798 spherical particle Substances 0.000 claims description 3
- 239000010409 thin film Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002064 nanoplatelet Substances 0.000 claims description 2
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 9
- 238000007626 photothermal therapy Methods 0.000 abstract description 8
- 239000002253 acid Substances 0.000 abstract description 6
- 230000002195 synergetic effect Effects 0.000 abstract description 6
- 210000004027 cell Anatomy 0.000 description 13
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 10
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000007789 gas Substances 0.000 description 8
- 239000002609 medium Substances 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 239000001284 azanium sulfanide Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 230000001678 irradiating effect Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229920001442 polyethylene glycol-block-polycaprolactone Polymers 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 208000030224 brain astrocytoma Diseases 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001808 coupling effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000001967 indiganyl group Chemical group [H][In]([H])[*] 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- AGBQKNBQESQNJD-UHFFFAOYSA-M lipoate Chemical compound [O-]C(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-M 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000008155 medical solution Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- MCPLVIGCWWTHFH-UHFFFAOYSA-L methyl blue Chemical compound [Na+].[Na+].C1=CC(S(=O)(=O)[O-])=CC=C1NC1=CC=C(C(=C2C=CC(C=C2)=[NH+]C=2C=CC(=CC=2)S([O-])(=O)=O)C=2C=CC(NC=3C=CC(=CC=3)S([O-])(=O)=O)=CC=2)C=C1 MCPLVIGCWWTHFH-UHFFFAOYSA-L 0.000 description 1
- IHYNKGRWCDKNEG-UHFFFAOYSA-N n-(4-bromophenyl)-2,6-dihydroxybenzamide Chemical compound OC1=CC=CC(O)=C1C(=O)NC1=CC=C(Br)C=C1 IHYNKGRWCDKNEG-UHFFFAOYSA-N 0.000 description 1
- 239000002055 nanoplate Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229920000575 polymersome Polymers 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- YJGJRYWNNHUESM-UHFFFAOYSA-J triacetyloxystannyl acetate Chemical compound [Sn+4].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O YJGJRYWNNHUESM-UHFFFAOYSA-J 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000007332 vesicle formation Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
-
- 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
- A61K41/0042—Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
-
- 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
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/227—Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
-
- 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)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Physics & Mathematics (AREA)
- Acoustics & Sound (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Radiology & Medical Imaging (AREA)
- Engineering & Computer Science (AREA)
- Dispersion Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开一种纳米诊疗剂及其制备方法与应用,其中,所述纳米诊疗剂包括具有空腔的囊泡及装载在所述空腔内的H2S供体;所述囊泡的材料是由两亲性两嵌段聚合物修饰金纳米颗粒形成的复合物。本发明的聚合物囊泡层镶嵌有金纳米颗粒的复合物囊泡的结构稳定性强,光热转换效率高;其与其空腔中装载的H2S供体形成的纳米诊疗剂具有光控释放的特点,能够在肿瘤部位控制释放出装载的H2S供体;H2S供体在肿瘤酸环境下分解出内源性H2S可实现对肿瘤进行光热治疗与气体治疗的协同治疗,具有高效的肿瘤治疗效果。
Description
技术领域
本发明涉及生物医学材料技术领域,尤其涉及一种纳米诊疗剂及其制备方法与应用。
背景技术
硫化氢(H2S)是一种具有臭鸡蛋气味的无色气体。过去,人们主要偏重于其毒性方面的研究;然而,1989年Goodwin等在鼠、牛及人的大脑中发现有相对较高浓度的内源性H2S,提示了H2S可能有较重要的生理作用。内源性H2S与一氧化氮、一氧化碳类似,是人体内重要的生物信使分子。
近年来研究发现,内源性H2S可选择性地诱导肿瘤细胞调亡,同时又可以保护正常的细胞。但是,H2S供体(例如:硫化铵、硫氢化铵)稳定性差、释放速度较快,而当前常用的聚合物囊泡难以稳定地将H2S供体运输到肿瘤部位,导致H2S供体与聚合物囊泡形成的诊疗剂对肿瘤的治疗效果差。
因此,现有技术还有待于改进和发展。
发明内容
鉴于上述现有技术的不足,本发明的目的在于提供一种纳米诊疗剂及其制备方法与应用,旨在解决当前常用的聚合物囊泡难以稳定地将H2S供体运输到肿瘤部位,导致H2S供体与聚合物囊泡形成的诊疗剂对肿瘤的治疗效果差的问题。
本发明的技术方案如下:
一种纳米诊疗剂,其中,所述纳米诊疗剂包括具有空腔的囊泡及装载在所述空腔内的H2S供体;所述囊泡的材料是由两亲性两嵌段聚合物修饰金纳米颗粒形成的复合物。
所述的纳米诊疗剂,其中,所述两亲性两嵌段聚合物的结构式为其中,m=45,n=200-500。
所述的纳米诊疗剂,其中,所述金纳米颗粒选自金纳米球、金纳米杯、金纳米笼、金纳米棒、金纳米片、金纳米壳、金纳米膜和金纳米花中的一种或多种。
所述的纳米诊疗剂,其中,所述H2S供体选自硫化钠、硫氢化钠、硫代硫酸钠、硫脲、甲硫氨酸、半胱氨酸、硫化铵和硫氢化铵中的一种或多种。
所述的纳米诊疗剂,其中,所述纳米诊疗剂为球形颗粒,其粒径为100-500nm。
一种如上任一所述的纳米诊疗剂的制备方法,其中,包括步骤:
A、两亲性两嵌段聚合物、金纳米颗粒在N,N-二甲基甲酰胺与水的混合溶剂中进行交联反应,反应结束后,反应液经固液分离,清洗,得到复合物;
B、复合物与H2S供体进行自组装,得到纳米诊疗剂。
所述的制备方法,其中,步骤A中,所述两亲性两嵌段聚合物、金纳米颗粒的质量比为1:1-5;所述交联反应的时间6-24h。
所述的制备方法,其中,步骤B中,所述自组装的方法选自薄膜水化法、透析法、微流控法中的一种。
所述的制备方法,其中,步骤B中,所述自组装的方法为透析法,所述复合物与H2S供体进行自组装的具体步骤包括:H2S供体溶于有机溶剂形成H2S供体溶液,将复合物加到H2S供体溶液中形成混合液,然后将混合液转移至透析袋中、封口,将装有混合液的透析袋置于超纯水中进行透析。
一种如上任一所述的纳米诊疗剂在制备肿瘤治疗剂中的应用。
有益效果:本发明的聚合物囊泡层镶嵌有金纳米颗粒的复合物囊泡的结构稳定性强,光热转换效率高;其与其空腔中装载的H2S供体形成的纳米诊疗剂具有光控释放的特点,能够在肿瘤部位控制释放出装载的H2S供体;H2S供体在肿瘤酸环境下分解出内源性H2S可实现对肿瘤进行光热治疗与气体治疗的协同治疗,相对于单一的光热治疗或气体治疗,具有更高效的肿瘤治疗效果。
附图说明
图1为本发明实施例1制得的纳米诊疗剂(GV-AH)的SEM图。
图2为本发明实施例1制得的纳米诊疗剂(GV-AH)的水合粒径分布图。
图3为本发明实施例2中,pH=6.8时,不同浓度的纳米诊疗剂(GV-AH)溶液的产H2S量的变化图。
图4为本发明实施例3中,不同照射条件下,随着纳米诊疗剂(GV-AH)浓度的升高,U-87MG细胞的细胞存活率变化对比图。
具体实施方式
本发明提供一种纳米诊疗剂及其制备方法与应用,为使本发明的目的、技术方案及效果更加清楚、明确,以下对本发明进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
本发明实施例提供一种纳米诊疗剂,其中,所述纳米诊疗剂包括具有空腔的囊泡及装载在所述空腔内的H2S供体;所述囊泡的材料是由两亲性两嵌段聚合物修饰金纳米颗粒形成的复合物。
本实施例的聚合物囊泡层镶嵌有金纳米颗粒的复合物囊泡的结构稳定性强,光热转换效率高;其与其空腔中装载的H2S供体形成的纳米诊疗剂具有光控释放的特点,能够在肿瘤部位控制释放出装载的H2S供体;H2S供体在肿瘤酸环境下分解出内源性H2S可实现对肿瘤进行光热治疗与气体治疗的协同治疗,相对于单一的光热治疗或气体治疗,具有更高效的肿瘤治疗效果。
在一种实施方式中,所述两亲性两嵌段聚合物的结构式为其中,m=45,n=200-500。该两亲性两嵌段聚合物具有良好的生物相容性和可降解性。
在一种实施方式中,所述金纳米颗粒可选自但不限于金纳米球、金纳米杯、金纳米笼、金纳米棒、金纳米片、金纳米壳、金纳米膜和金纳米花中的一种或多种。在一种优选的实施方式中,所述金纳米颗粒为金纳米球;进一步在一种优选的实施方式中,所述金纳米球的粒径为26nm。
在一种实施方式中,所述H2S供体可选自但不限于硫化钠、硫氢化钠、硫代硫酸钠、硫脲、甲硫氨酸、半胱氨酸、硫化铵和硫氢化铵中的一种或多种。在一种优选的实施方式中,所述H2S供体为硫化铵。硫化铵遇热易分解,在肿瘤酸环境下可快速分解出内源性H2S。
在一种实施方式中,所述纳米诊疗剂为球形颗粒,其粒径为100-500nm。
本发明实施例提供一种如上任一所述的纳米诊疗剂的制备方法,其中,包括步骤:
A、两亲性两嵌段聚合物、金纳米颗粒在N,N-二甲基甲酰胺与水的混合溶剂中进行交联反应,反应结束后,反应液经固液分离,清洗,得到复合物;
B、复合物与H2S供体进行自组装,得到纳米诊疗剂。
本实施例的纳米诊疗剂的制备方法简单,有利于实现大量生产。本实施例的纳米诊疗剂包括具有空腔的囊泡及装载在所述空腔内的H2S供体;其中,囊泡中,两亲性两嵌段聚合物将金纳米颗粒之间的距离拉近,使得囊泡膜中相邻金纳米颗粒间存在表面等离子耦合效应而具有很强的光热作用,可以增强光声和超声成像,自组装形成的囊泡本身具有空腔,可原位装载H2S供体,形成纳米诊疗剂。
在一种实施方式中,步骤A中,所述两亲性两嵌段聚合物、金纳米颗粒的质量比为1:1-5;所述交联反应的时间6-24h。在一种优选的实施方式中,所述交联反应的时间为12h。上述反应条件下,两亲性两嵌段聚合物和金纳米颗粒可进行充分交联。
在一种实施方式中,步骤A中,反应液经固液分离时,所述固液分离的方式可为但不限于离心、过滤。在一种优选的实施方式中,所述固液分离的方式为离心。
在一种实施方式中,步骤A中,所述清洗次数可为但不限于6-12次。在一种优选的实施方式中,所述清洗次数为8次。进一步在一种实施方式中,所述清洗用的溶剂可为但不限于四氢呋喃。上述清洗条件下,可除去绝大部分过量的两亲性两嵌段聚合物,有利于下一步中囊泡的形成。
在一种实施方式中,步骤B中,所述自组装的方法选自薄膜水化法、透析法、微流控法中的一种。在一种优选的实施方式中,步骤B中,所述自组装的方法为透析法,所述复合物与H2S供体进行自组装的具体步骤包括:H2S供体溶于有机溶剂形成H2S供体溶液,将复合物加到H2S供体溶液中形成混合液,然后将混合液转移至透析袋中、封口,将装有混合液的透析袋置于超纯水中进行透析。进一步在一种实施方式中,所述有机溶剂选自四氢呋喃(THF)、N,N-二甲基甲酰胺(DMF)和二甲基亚砜(DMSO)中的一种或多种。进一步在一种优选的实施方式中,所述有机溶剂为二甲基亚砜。采用二甲基亚砜作为溶剂可大大缩短制备纳米诊疗剂时的透析时间,减少H2S供体与空气接触的时间。进一步在一种实施方式中,步骤B中,所述H2S供体溶液中,H2S供体的浓度为0.001-2mM;所述透析的时间0.5-6h。在上述浓度范围内,H2S供体(例如硫化铵)不会干扰囊泡的形成;上述限定的透析时间较短,可减少H2S供体(例如硫化铵)的变质。
本发明实施例还提供一种如上任一所述的纳米诊疗剂在制备肿瘤治疗剂中的应用。
本实施例的纳米诊疗剂具有光控释放的特点,能够在肿瘤部位控制释放出装载的H2S供体;H2S供体在肿瘤酸环境下分解出内源性H2S可实现对肿瘤进行光热治疗与气体治疗的协同治疗,相对于单一的光热治疗或气体治疗,具有更高效的肿瘤治疗效果。
下面通过实施例对本发明进行详细说明。
实施例1纳米诊疗剂(GV-AH)的制备
(1)金纳米颗粒的制备:将250mL的超纯水,500μL浓度为50mg/mL的HAuCl4·3H2O水溶液转入圆底烧瓶中,混合液加热至回流,在稳定的转速下加入10mL浓度为1wt%的柠檬酸钠水溶液进行还原,反应30min,反应液由淡黄色转变为红色,得到粒径为19nm的金纳米颗粒,其形貌为球形;接着将反应温度降至90℃,迅速加入500μL浓度为50mg/mL HAuCl4·3H2O水溶液和10mL的浓度为1wt%的柠檬酸钠水溶液,重复两次,得到粒径为26nm的金纳米颗粒的水溶液,该金纳米颗粒的形貌为球形。
(2)两亲性两嵌段聚合物的制备,制备反应式为如上式所示,具体制备步骤为:(2a)在圆底烧瓶中加入50mg聚合物1(PEO-PEG2000-OH),770mg己内酯,无水无氧的条件下加入1滴乙酸锡(SnOct)作为引发剂,135℃反应18h,向反应液中加入适量的无水乙醚,有固体析出,固液分离,干燥固体,得聚合物2(PEO-PEG-b-PCL)。
(2b)将干燥的400mg聚合物2(PEO-PEG-b-PCL),15mg N,N-二环己基碳酰亚胺(DCC),2mg 4-二甲氨基吡啶(DMAP),12mg硫辛酸共同放入三颈瓶中,加入2mL二氯甲烷,反应过夜,反应结束后向液反应液加入适量的正己烷,有固体析出,固液分离,干燥固体,得聚合物3(0PEO-PEG-b-PCL-TE),即两亲性两嵌段聚合物,其中,m=45,n=200-500。
(3)复合物的制备:取50mL步骤(1)制得的粒径为26nm的金纳米颗粒的水溶液,将其离心浓缩,去掉多余的水溶液,形成浓缩后的金纳米颗粒溶液;将5mg步骤(2)制得的两亲性两嵌段聚合物溶解到10mL N,N-二甲基甲酰胺中,形成两亲性两嵌段聚合物溶液;接着将浓缩后的金纳米颗粒溶液在超声的条件下缓慢的加入到两亲性两嵌段聚合物溶液中,超声1h,然后静置过夜,金纳米颗粒和两亲性两嵌段聚合物充分进行交联反应。反应结束后对反应液进行离心,用四氢呋喃进行清洗,重复清洗8次,得到复合物。
(4)纳米诊疗剂(GV-AH)的制备:将步骤(3)制得的10mg复合物溶于10mL浓度为1mM的硫化铵的二甲基亚砜溶液中,形成混合液。取2mL混合液转移至透析袋中,两端封住,将透析袋放入超纯水中透析1h,得到纳米诊疗剂(GV-AH)。
该纳米诊疗剂(GV-AH)的扫描电镜(SEM)测试结果如图1所示;可知其形貌为球形。将该纳米诊疗剂(GV-AH)分散到1mL超纯水中,使用马尔文纳米粒度电位仪(型号为MalvernNano-ZS)对其水合粒径进行测试,其水合粒径分布情况如图2所示,可知该纳米诊疗剂(GV-AH)的水合粒径平均值为219.9nm,粒径分布指数(PDI)小于0.2;表明该实施例制得的纳米诊疗剂(GV-AH)粒径分布窄,尺寸均匀。
实施例2纳米诊疗剂(GV-AH)产H2S的性能评价
配置不同浓度(12.5μg/mL、25μg/mL、50μg/mL、100μg/mL200μg/mL、400μg/mL)的pH=6.8的纳米诊疗剂溶液,使用808nm的激光器照射10min,功率为1W/cm2;用标准甲基蓝显色法测量溶液中的H2S的含量。
根据标准图谱对照,计算所产生H2S的含量;同种条件(pH=6.8)下,不同浓度的纳米诊疗剂溶液的产H2S量变化如图3所示,可知,随着纳米诊疗剂的浓度的升高,纳米诊疗剂溶液的产H2S量逐渐增大。
实施例3采用标准的MTT法评价光热与内源性H2S对U-87MG细胞的协同治疗
将U-87MG细胞(人脑星形胶质母细胞瘤细胞)以每孔5×103密度接种到的96孔板(孔中均含有DMEM培养基)中,并于37℃、体积浓度为5%的CO2条件下培育24h。接着吸出96孔板中的旧培养基,分为两组,向每组的孔中分别加入含有不同浓度的纳米诊疗剂(GV-AH)(0、18.75μg/mL、37.5μg/mL、75μg/mL、150μg/mL、300μg/mL)的DMEM培养基,继续培养24h后;吸出96孔板中的旧培养基,在每个孔加入100μL DMEM培养基;然后选择其中一组作为光照组,对光照组的每一个孔都使用808nm的激光器照射5min,功率为1W/cm2;另一组作为对照组,不进行光照,培养5min。之后对两组进行同样的操作:吸出96孔板中的旧培养基,在每个孔中加入100μL含10wt%MTT(3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐,3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide)的培养基溶液,继续培养1h。
然后在Bio-Tel EL×800型酶标仪上检测每孔的OD490值(检测波长为490nm时测试得的光密度(optical density)值),按照公式:细胞存活率(%)=(样品的OD490值/空白OD490值)×100%,计算U-87MG细胞的存活率。在不同照射条件下,随着纳米诊疗剂(GV-AH)浓度的升高,U-87MG细胞的细胞存活率变化变化对比如图4所示。可知随着纳米诊疗剂(GV-AH)浓度的升高,U-87MG细胞的存活率会逐渐降低,表明纳米诊疗剂(GV-AH)产生内源性H2S对U-87MG细胞有一定的杀伤作用;可知相对于未进行光照组的U-87MG细胞,进行808nm的激光器照射组的U-87MG细胞的存活率呈显著地降低,表明光照与纳米诊疗剂(GV-AH)对肿瘤(U-87MG细胞)的协同治疗效果更显著。
综上所述,本发明提供一种纳米诊疗剂及其制备方法与应用。本发明的聚合物囊泡层镶嵌有金纳米颗粒的复合物囊泡的结构稳定性强,光热转换效率高;其与其空腔中装载的H2S供体形成的纳米诊疗剂具有光控释放的特点,能够在肿瘤部位控制释放出装载的H2S供体;H2S供体在肿瘤酸环境下分解出内源性H2S可实现对肿瘤进行光热治疗与气体治疗的协同治疗,具有高效的肿瘤治疗效果。
应当理解的是,本发明的应用不限于上述的举例,对本领域普通技术人员来说,可以根据上述说明加以改进或变换,所有这些改进和变换都应属于本发明所附权利要求的保护范围。
Claims (10)
1.一种纳米诊疗剂,其特征在于,所述纳米诊疗剂包括具有空腔的囊泡及装载在所述空腔内的H2S供体;所述囊泡的材料是由两亲性两嵌段聚合物修饰金纳米颗粒形成的复合物。
2.根据权利要求1所述的纳米诊疗剂,其特征在于,所述两亲性两嵌段聚合物的结构式为其中,m=45,n=200-500。
3.根据权利要求1所述的纳米诊疗剂,其特征在于,所述金纳米颗粒选自金纳米球、金纳米杯、金纳米笼、金纳米棒、金纳米片、金纳米壳、金纳米膜和金纳米花中的一种或多种。
4.根据权利要求1所述的纳米诊疗剂,其特征在于,所述H2S供体选自硫化钠、硫氢化钠、硫代硫酸钠、硫脲、甲硫氨酸、半胱氨酸、硫化铵和硫氢化铵中的一种或多种。
5.根据权利要求1所述的纳米诊疗剂,其特征在于,所述纳米诊疗剂为球形颗粒,其粒径为100-500nm。
6.一种如权利要求1-5任一所述的纳米诊疗剂的制备方法,其特征在于,包括步骤:
A、两亲性两嵌段聚合物、金纳米颗粒在N,N-二甲基甲酰胺与水的混合溶剂中进行交联反应,反应结束后,反应液经固液分离,清洗,得到复合物;
B、复合物与H2S供体进行自组装,得到纳米诊疗剂。
7.根据权利要求6所述的制备方法,其特征在于,步骤A中,所述两亲性两嵌段聚合物、金纳米颗粒的质量比为1:1-5;所述交联反应的时间6-24h。
8.根据权利要求6所述的制备方法,其特征在于,步骤B中,所述自组装的方法选自薄膜水化法、透析法、微流控法中的一种。
9.根据权利要求6所述的制备方法,其特征在于,步骤B中,所述自组装的方法为透析法,所述复合物与H2S供体进行自组装的具体步骤包括:H2S供体溶于有机溶剂形成H2S供体溶液,将复合物加到H2S供体溶液中形成混合液,然后将混合液转移至透析袋中、封口,将装有混合液的透析袋置于超纯水中进行透析。
10.一种如权利要求1-5任一所述的纳米诊疗剂在制备肿瘤治疗剂中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910801568.6A CN110604816B (zh) | 2019-08-28 | 2019-08-28 | 一种纳米诊疗剂及其制备方法与应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910801568.6A CN110604816B (zh) | 2019-08-28 | 2019-08-28 | 一种纳米诊疗剂及其制备方法与应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110604816A true CN110604816A (zh) | 2019-12-24 |
CN110604816B CN110604816B (zh) | 2022-06-14 |
Family
ID=68890893
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910801568.6A Active CN110604816B (zh) | 2019-08-28 | 2019-08-28 | 一种纳米诊疗剂及其制备方法与应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110604816B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115351288A (zh) * | 2022-08-23 | 2022-11-18 | 西北工业大学 | 一种金纳米花及其制备方法和应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070212331A1 (en) * | 2006-03-07 | 2007-09-13 | Baldassare Joseph J | Methods and compositions for selectively killing cells |
CN108653733A (zh) * | 2018-05-21 | 2018-10-16 | 中国医学科学院生物医学工程研究所 | 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 |
-
2019
- 2019-08-28 CN CN201910801568.6A patent/CN110604816B/zh active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070212331A1 (en) * | 2006-03-07 | 2007-09-13 | Baldassare Joseph J | Methods and compositions for selectively killing cells |
CN108653733A (zh) * | 2018-05-21 | 2018-10-16 | 中国医学科学院生物医学工程研究所 | 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 |
Non-Patent Citations (2)
Title |
---|
LIN ZHOU等: ""codelivery of sh-aspirin and curcumin by mPeg-Plga nanoparticles enhanced antitumor activity by inducing mitochondrial apoptosis"", 《INTERNATIONAL JOURNAL OF NANOMEDICINE》 * |
王洁等: ""贵金属纳米颗粒杂化囊泡的制备及拉曼增强效果研究"", 《高分子学报》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115351288A (zh) * | 2022-08-23 | 2022-11-18 | 西北工业大学 | 一种金纳米花及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
CN110604816B (zh) | 2022-06-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Yadav et al. | 2D MoS2‐based nanomaterials for therapeutic, bioimaging, and biosensing applications | |
Shao et al. | Biodegradable titanium nitride MXene quantum dots for cancer phototheranostics in NIR-I/II biowindows | |
Lee et al. | Light‐responsive inorganic biomaterials for biomedical applications | |
Soleymaniha et al. | Promoting role of MXene nanosheets in biomedical sciences: therapeutic and biosensing innovations | |
Zhao et al. | Synthesis of graphene quantum dots and their applications in drug delivery | |
Wei et al. | Biomedical and bioactive engineered nanomaterials for targeted tumor photothermal therapy: A review | |
Lin et al. | Insights into 2D MXenes for versatile biomedical applications: current advances and challenges ahead | |
Sun et al. | One-pot solventless preparation of PEGylated black phosphorus nanoparticles for photoacoustic imaging and photothermal therapy of cancer | |
Kumar et al. | Advanced metal and carbon nanostructures for medical, drug delivery and bio-imaging applications | |
Goel et al. | Synthesis and biomedical applications of copper sulfide nanoparticles: from sensors to theranostics | |
Zhang et al. | Nanostructured manganese dioxide for anticancer applications: preparation, diagnosis, and therapy | |
Madni et al. | Graphene-based nanocomposites: synthesis and their theranostic applications | |
Lu et al. | Molybdenum disulfide nanosheets: From exfoliation preparation to biosensing and cancer therapy applications | |
Parameswaranpillai et al. | Nanocomposite materials: synthesis, properties and applications | |
Wang et al. | 2D nanostructures beyond graphene: preparation, biocompatibility and biodegradation behaviors | |
Liu et al. | Stable metallic 1T-WS 2 ultrathin nanosheets as a promising agent for near-infrared photothermal ablation cancer therapy | |
Pourmadadi et al. | A comprehensive review of synthesis, structure, properties, and functionalization of MoS2; emphasis on drug delivery, photothermal therapy, and tissue engineering applications | |
CN108324955B (zh) | 一种超小硫化铜负载的中空介孔硅靶向纳米载药复合物的制备方法 | |
Joshi et al. | Graphene quantum dots-from emergence to nanotheranostic applications | |
Zhou et al. | Molybdenum‐based nanomaterials for photothermal cancer therapy | |
CN106692970B (zh) | 一种硒化铋纳米复合材料及其制备方法和应用 | |
CN106729742A (zh) | 一种肿瘤靶向丝胶蛋白胶束及其制备方法和应用 | |
Xu et al. | NIR-II driven plasmon-enhanced cascade reaction for tumor microenvironment-regulated catalytic therapy based on bio-breakable Au–Ag nanozyme | |
ul Ain et al. | Copper sulfide nanostructures: Synthesis and biological applications | |
CN106902350B (zh) | 一种金属掺杂的光热碳纳米材料及其制备方法和应用 |
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 |