CN108404141B - A bone-targeted drug delivery system based on near-infrared region II quantum dots and its preparation method and application - Google Patents
A bone-targeted drug delivery system based on near-infrared region II quantum dots and its preparation method and application Download PDFInfo
- Publication number
- CN108404141B CN108404141B CN201810297951.8A CN201810297951A CN108404141B CN 108404141 B CN108404141 B CN 108404141B CN 201810297951 A CN201810297951 A CN 201810297951A CN 108404141 B CN108404141 B CN 108404141B
- Authority
- CN
- China
- Prior art keywords
- quantum dots
- infrared
- bone
- region
- drug delivery
- 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.)
- Active
Links
- 239000002096 quantum dot Substances 0.000 title claims abstract description 68
- 238000012377 drug delivery Methods 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 57
- 230000008685 targeting Effects 0.000 claims abstract description 39
- 239000003814 drug Substances 0.000 claims abstract description 35
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 20
- 229940079593 drug Drugs 0.000 claims abstract description 19
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 18
- 239000002245 particle Substances 0.000 claims abstract description 15
- 238000011282 treatment Methods 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 7
- 208000001132 Osteoporosis Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 201000008482 osteoarthritis Diseases 0.000 claims description 4
- FSJWWSXPIWGYKC-UHFFFAOYSA-M silver;silver;sulfanide Chemical class [SH-].[Ag].[Ag+] FSJWWSXPIWGYKC-UHFFFAOYSA-M 0.000 claims description 4
- 206010005949 Bone cancer Diseases 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 23
- 238000011160 research Methods 0.000 abstract description 8
- 230000000144 pharmacologic effect Effects 0.000 abstract description 7
- 230000008569 process Effects 0.000 abstract description 7
- 230000009286 beneficial effect Effects 0.000 abstract description 5
- 229910052588 hydroxylapatite Inorganic materials 0.000 abstract description 5
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 abstract description 5
- 230000004888 barrier function Effects 0.000 abstract description 4
- 230000002452 interceptive effect Effects 0.000 abstract 1
- 230000000704 physical effect Effects 0.000 abstract 1
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 239000000969 carrier Substances 0.000 description 12
- 241000699666 Mus <mouse, genus> Species 0.000 description 11
- 206010028980 Neoplasm Diseases 0.000 description 11
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 10
- 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 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 210000000689 upper leg Anatomy 0.000 description 6
- 230000000007 visual effect Effects 0.000 description 6
- 208000020084 Bone disease Diseases 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 238000010863 targeted diagnosis Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229910052946 acanthite Inorganic materials 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000000799 fluorescence microscopy Methods 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- 229940009456 adriamycin Drugs 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 238000011580 nude mouse model Methods 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 208000018084 Bone neoplasm Diseases 0.000 description 2
- 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
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- WNAHIZMDSQCWRP-UHFFFAOYSA-N dodecane-1-thiol Chemical compound CCCCCCCCCCCCS WNAHIZMDSQCWRP-UHFFFAOYSA-N 0.000 description 2
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 2
- 230000005611 electricity Effects 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- XCAUINMIESBTBL-UHFFFAOYSA-N lead(ii) sulfide Chemical compound [Pb]=S XCAUINMIESBTBL-UHFFFAOYSA-N 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- NSVHDIYWJVLAGH-UHFFFAOYSA-M silver;n,n-diethylcarbamodithioate Chemical compound [Ag+].CCN(CC)C([S-])=S NSVHDIYWJVLAGH-UHFFFAOYSA-M 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 210000001694 thigh bone Anatomy 0.000 description 2
- 210000005167 vascular cell Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- AGBQKNBQESQNJD-UHFFFAOYSA-N alpha-Lipoic acid Natural products OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000002449 bone cell Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000010382 chemical cross-linking Methods 0.000 description 1
- -1 china) Substances 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 230000002792 vascular Effects 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
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0065—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle
- A61K49/0067—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle quantum dots, fluorescent nanocrystals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Organic Chemistry (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Biomedical Technology (AREA)
- Immunology (AREA)
- Materials Engineering (AREA)
- Nanotechnology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明提供了一种基于近红外II区量子点的骨靶向给药系统及其制备方法和应用，所述给药系统包括近红外II区量子点，所述近红外II区量子点表面修饰有氨基聚乙二醇。本发明的近红外II区量子点的粒径小于20nm，可以通过血髓屏障到达骨组织，近红外II区量子点表面修饰有氨基聚乙二醇，呈正电性，可以通过静电力作用与骨骼中呈负电性的羟基磷灰石高效结合，量子点仅依靠物理作用，通过动力学和静电力吸附于骨组织上，实现了骨靶向效果，不会干扰药物的治疗效果，副作用小，由于载体中具有近红外II区荧光量子点，本发明可以通过近红外II区荧光信号全程追踪骨靶向过程，有利于药物的药理学研究。
The present invention provides a bone-targeted drug delivery system based on near-infrared region II quantum dots, a preparation method and application thereof, wherein the drug delivery system comprises near-infrared region II quantum dots, and the surface of the near-infrared region II quantum dots is modified There are amino polyethylene glycols. The particle size of the quantum dots in the near-infrared II region of the present invention is less than 20 nm, and can reach the bone tissue through the blood-medullary barrier. The surface of the quantum dots in the near-infrared II region is modified with amino polyethylene glycol, which is positively charged and can interact with bones through electrostatic force. The negatively charged hydroxyapatite is efficiently combined, and the quantum dots only rely on physical action, and are adsorbed on the bone tissue through kinetic and electrostatic forces to achieve the bone targeting effect without interfering with the therapeutic effect of the drug, and the side effects are small. The carrier has near-infrared II region fluorescent quantum dots, and the present invention can track the bone targeting process throughout the whole process through the near-infrared II region fluorescent signal, which is beneficial to the pharmacological research of drugs.
Description
Technical Field
The invention belongs to the technical field of biomedicine, and relates to a bone targeting drug delivery system based on near-infrared II-region quantum dots, and a preparation method and application thereof.
Background
Bones are the scaffolds of the body, and the health of bones directly affects the living and life quality of the body. In recent years, the incidence of bone diseases such as osteoporosis, osteoarthritis, and bone tumors has increased year by year, and the quality of life of patients has been seriously affected. The bone tissue system is huge and widely distributed in the body, and in the treatment process of bone diseases, if a conventional administration mode is adopted, the medicine can reach the tissue and exert the medicine effect only by keeping a certain systemic concentration, but systemic side effects can be caused, and the medicine poisoning treatment scheme has certain limitation in the treatment of the bone diseases. Currently, the above problems are mainly solved by bone-targeted drug delivery solutions.
One of the key factors affecting bone-targeted drug delivery systems is the carrier. The carrier should be designed to be of a moderate size to pass the dense "bone marrow-blood barrier" and to be able to bind to the hydroxyapatite, the main component of bone tissue, to achieve a bone targeting effect. Currently known bone-targeted drug delivery carriers include tetracycline carriers, gem-bisphosphonate carriers, polypropionic acid carriers, small-molecule heterocyclic carriers and oligo-skin carriers, which can be combined with hydroxyapatite, but the bone-targeted drug delivery systems really applied to clinic are few.
On one hand, most substances with bone targeting effects often have certain pharmacological effects, possibly generate interference or even unknown side effects on treatment, and are not beneficial to evaluating the treatment effect of a target drug; on the other hand, the research on the distribution, metabolism and drug targeting of bone targeting drugs in bones is difficult, the conventional pharmacological detection method is destructive to bone tissues, and the existing nondestructive detection method mainly depends on radioactive element labeling, has strong side effect and poor popularization, and seriously limits the research on the bone targeting drug delivery.
CN 104288786A discloses a tumor targeted diagnosis and treatment system based on near-infrared quantum dots and a preparation method thereof, wherein the tumor targeted diagnosis and treatment system comprises: an inner core composed of near-infrared quantum dots; modified PEG molecules coated on the surface of the inner core; a tumor vascular targeting molecule coupled to the modified PEG molecule by chemical cross-linking; an anti-tumor angiogenesis drug assembled in the tumor targeted diagnosis and treatment system. The tumor targeted diagnosis and treatment system can realize in-situ, real-time, visual and quantitative diagnosis, treatment and evaluation of tumors, but in order to improve the specificity of targeted tumors, tumor blood vessel targeted molecules need to be coupled, the preparation method is more complicated and the cost is higher, and the tumor targeted diagnosis and treatment system can not realize bone targeting.
Therefore, the development of a visual carrier which has weak side effects and can effectively realize bone-targeted drug delivery and simultaneously realize real-time tracking is of great significance in the pharmacological research of bone disease treatment drugs.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a bone targeting drug delivery system based on near-infrared II region quantum dots, a preparation method and application thereof, wherein the quantum dots with the size smaller than 20nm can break the blood marrow barrier to reach bone tissues, and the visualized bone targeting delivery of drugs is realized on the premise of not depending on biological targeting molecules by combining amino polyethylene glycol with positive electricity modified on the surface of the quantum dots with hydroxyapatite with negative electricity in bones.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides an application of near-infrared II region quantum dots in the preparation of a bone targeting drug delivery system;
wherein, the surface of the near-infrared II region quantum dot is modified with amino polyethylene glycol.
According to the invention, the surface of the quantum dot in the near-infrared II region is modified with amino polyethylene glycol and is electropositive, and the quantum dot is efficiently combined with a main component of a skeleton, namely electronegative hydroxyapatite under the action of electrostatic force to realize the targeting of the quantum dot to a bone tissue.
In the invention, the amino polyethylene glycol is a polyethylene glycol of which the tail end comprises at least one amino group, the method for modifying the quantum dot by the polyethylene glycol is not particularly limited, and a person skilled in the art can select different methods and reaction conditions to modify the quantum dot according to actual conditions.
According to the invention, the surface of the quantum dot in the near-infrared II region is modified with the modified polyethylene glycol, so that the biological stability and biocompatibility of the quantum dot are improved, and the internal circulation of the quantum dot is facilitated.
In the invention, excessive amino polyethylene glycol is adopted to modify the near-infrared II region quantum dots, the obtained drug carrier has weaker electropositivity and is not easy to combine with negatively charged tissues under the condition of high blood flow rate, but after reaching the bone tissues, the compact structure of the bone tissues enables the blood flow rate and the quantum dot flow rate to be reduced, and meanwhile, as the positive charge amount carried by the quantum dots is matched with the negative charge amount of the bone tissues, the quantum dots are prevented from being adsorbed on other tissues, and the specific targeting of the quantum dots to the bone tissues is realized.
Because the tumor vascular cells and the bone cells are different in cell environment, cell properties and the like, the near-infrared II region quantum dot-based drug delivery system can not cause specific targeting on the tumor vascular cells.
Preferably, the near-infrared region II quantum dots comprise Ag2S quantum dot, Ag2Any one of Se quantum dots or PbS quantum dots or a combination of at least two of Se quantum dots or PbS quantum dots.
Preferably, the particle size of the near-infrared region II quantum dots is 2-20nm, for example, 2nm, 3nm, 4nm, 5nm, 6nm, 7nm, 8nm, 9nm, 10nm, 11nm, 12nm, 13nm, 14nm, 15nm, 16nm, 17nm, 18nm, 19nm or 20nm, preferably 3-10 nm.
In the invention, quantum dots with the particle size of less than 20nm are used as drug delivery carriers, which are beneficial to the carriers to reach bone tissues through the dense marrow-blood barrier by blood circulation.
In a second aspect, the present invention provides a drug delivery system comprising near-infrared region II quantum dots modified with aminopolyethylene glycol on the surface.
Preferably, the delivery system further comprises a drug.
In the present invention, the drug includes a drug for treating osteoporosis, osteoarthritis or bone tumors, for example, doxorubicin may be mentioned.
In a third aspect, the present invention provides a method of preparing a delivery system according to the second aspect, the method comprising:
adding the medicine into a solution containing the near-infrared II region quantum dots with the surfaces modified with the aminopolyethylene glycol, and stirring to obtain the drug delivery system.
In the present invention, the loading method of the drug is not particularly limited, and those skilled in the art can select different loading methods according to the drug characteristics.
Preferably, the mass ratio of the drug to the quantum dots is (1-5):1, for example, 1:1, 1:2, 1:3, 1:4 or 1:5, preferably (2-3): 1.
Preferably, the stirring time is 12-18h, for example 12h, 13h, 14h, 15h, 16h, 17h or 18h, preferably 15-16 h.
In a fourth aspect, the present invention provides the use of a delivery system according to the second aspect for the manufacture of a medicament for the treatment of an orthopaedic disorder.
Preferably, the orthopaedic disease comprises any one or a combination of at least two of osteoporosis, osteoarthritis or a bone tumour.
In a fifth aspect, the present invention provides a method of visual drug delivery, the method comprising:
the drug delivery system of the second aspect is delivered to the animal and visualized under a live imager for drug delivery.
Preferably, the input of the delivery system is 5-15mg/kg, for example 5mg/kg, 8mg/kg, 10mg/kg, 13mg/kg or 15mg/kg, preferably 10-13 mg/kg.
Preferably, the animal includes any one of mouse, rat, rabbit, dog, monkey, or pig or a combination of at least two thereof.
Preferably, the detection signal of the living body imager is a near infrared II-region signal.
According to the invention, the near-infrared II-region quantum dots are used as carriers, so that the tissue penetration and the spatial resolution are very high in living body fluorescence imaging, biological autofluorescence interference is hardly generated, the bone targeting process of the medicine can be tracked in a full range through near-infrared II-region fluorescence signals, the tracing effect is good, the method is simple and convenient, the cost is low, convenience is provided for pharmacological research, and a brand-new way is provided for treatment research of bone diseases.
The invention provides a visual bone-targeted drug delivery device, comprising:
a drug delivery element comprising a delivery system according to the second aspect for delivering near infrared region II quantum dots loaded with a drug into an animal;
and/or the fluorescence imaging element comprises a living body imager, and the detection signal of the living body imager is a near infrared II-zone fluorescence signal and is used for detecting the living body drug delivery condition in real time.
In a sixth aspect, the present invention provides a use of the drug delivery system according to the second aspect or the method according to the fifth aspect for visual bone-targeted drug delivery.
Compared with the prior art, the invention has the following beneficial effects:
(1) the near-infrared II region quantum dots which are modified with the amino polyethylene glycol and are less than 20nm are adsorbed on bone tissues by virtue of the action of dynamics and electrostatic force, do not have physiological action with the bone tissues, realize the bone targeting effect, do not interfere the treatment effect of the medicament, have small side effect and are beneficial to the pharmacological research of the medicament;
(2) the drug delivery system based on the near-infrared II-region quantum dots fully tracks the bone targeting process of the drug through the near-infrared II-region fluorescence signals in the living body fluorescence imaging, has very high tissue penetration and spatial resolution, almost has no biological autofluorescence interference, and has good tracing effect;
(3) the invention does not adopt complex and expensive bone targeting reagents, and has simple method and low cost.
Drawings
FIG. 1A shows the results of in vitro bone targeting experiments, which respectively use Ag with 10nm particle size modified with carboxyl polyethylene glycol and amino polyethylene glycol on the surface2Marking mouse thighbone for 3 hours by using quantum dots in near-infrared II region S, and imaging fluorescent small animals in near-infrared II region SImaging effect under the instrument, fig. 1(B) is a real object enlarged view of mouse femur;
FIG. 2 shows the results of in vivo bone targeting experiments, in which Ag with 10nm particle size, which is modified with aminopolyethylene glycol and loaded with adriamycin2And S, injecting the quantum dots in the near-infrared region II into a nude mouse intravenously, and performing imaging effect under a near-infrared region II fluorescence small animal imager.
Detailed Description
To further illustrate the technical means adopted by the present invention and the effects thereof, the present invention is further described below with reference to the embodiments and the accompanying drawings. It is to be understood that the specific embodiments described herein are merely illustrative of the invention and are not limiting of the invention.
The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or apparatus used are conventional products commercially available from normal sources, not indicated by the manufacturer.
Reagents and instrumentation:
(1)4-8 weeks female nude mice;
(2) primary reagent
Doxorubicin hydrochloride (sigma, usa), triethylamine (sigma, usa), silver diethyldithiocarbamate (sigma, usa), dodecanethiol (sigma, usa), cyclohexane (national medicine, china), ethanol (national medicine, china), dimethyl sulfoxide (national medicine, china), aminopolyethylene glycol (sigma, china), 1 × PBS buffer;
(3) main instrument
Near-infrared II zone fluorescent small animal in vivo imager (Yirui, China).
Example 1
0.1mmol of silver diethyldithiocarbamate, 10g of dodecanethiol were mixed and placed in a flask under N2Heating to 200 deg.C in atmosphere, maintaining for 1h, naturally cooling to room temperature, adding 50mL anhydrous ethanol, centrifuging, washing, dispersing in cyclohexane, adding 0.15g thioctic acid into cyclohexane, adding anhydrous ethanol of the same volume, and performing ultrasonic cleaningUltrasonic treating for 4 hr, centrifuging, washing with deionized water to obtain water soluble Ag with particle size of about 5nm2S quantum dots; 0.25mg of the above Ag2Dispersing S quantum dots in 100 mu L of dimethyl sulfoxide (DMSO), and mixing a 50 mu L DMSO solution containing 0.01mmol of NHS with the solution; adding 50 μ L DMSO solution containing 0.01mmol EDC into the above mixed solution, wrapping with aluminum foil, stirring for 1h, centrifuging, and dispersing in 100 μ L DMSO; a mixed solution of 0.5mg of aminopolyethylene glycol and 185. mu.L of 1 XPBS was added to 100. mu.L of Ag2Reacting in S/DMSO mixed solution at 4 deg.C in dark for 12h, washing, and centrifuging to obtain amino polyethylene glycol Ag2S(NH2-PEG-Ag2S) quantum dots.
Example 2 in vitro bone targeting experiments
Modifying the surface of Ag with amino polyethylene glycol and having a particle size of 10nm2And marking the mouse thighbone by the quantum dots in the near infrared II region for 3 hours, washing by PBS to remove the free quantum dots, and imaging under a fluorescent small animal imager in the near infrared II region.
Comparative example 1
Compared with example 2, Ag with 10nm particle size and surface modified carboxyl PEG is adopted2S near infrared II region quantum dot (COOH-PEG-Ag)2S) mark mouse femurs, otherwise the conditions were the same as in example 2.
As shown in FIG. 1(A), the results of in vitro bone targeting experiments were obtained by using NH under the same labeling conditions2-PEG-Ag2S binds to mouse femur with COOH-PEG-Ag2S was not bound to the mouse femur, and fig. 1(B) is a real enlarged view of the mouse femur.
Example 3 in vivo bone targeting experiments
(1) Preparation of adriamycin bone targeting drug delivery system
Dissolving 10mg doxorubicin hydrochloride in 1mL DMSO, adding 6. mu.L triethylamine, stirring for 2 hr, adding 5mg Ag with surface modified amino PEG and particle size of 10nm2S near-infrared II region quantum dots, adding 9mL of PBS buffer solution, stirring at room temperature in the dark for 15 hours, transferring the reaction solution into a 100K ultrafiltration centrifuge tube, centrifuging at 4000rpm for 30 minutes to remove free adriamycin, and washing with PBS for 3 times to obtain the adriamycinBone-targeted delivery system (NH) for mycin2-PEG-Ag2S-DOX)。
(2) Visual drug delivery
Injecting chloral hydrate solution into abdominal cavity of mouse for anesthesia, and adding NH2-PEG-Ag2200 μ g of Ag in terms of S-DOX2The input amount of S/mouse is input into the nude mouse body through tail vein, and is observed in the near infrared II area living body imaging instrument to track the bone targeting process of the adriamycin bone targeting drug delivery system.
As shown in FIG. 2, the results of the bone targeting experiment in vivo, NH injected into mice2-PEG-Ag2S is targeted to bone tissues, and the bone tissues of the vertebra, the sternum, the femur and the like of the mouse emit obvious near infrared II-region fluorescent signals.
Example 4
Compared with example 3, Ag with the surface modified with amino PEG and the particle size of 3nm is adopted2Se near infrared II region quantum dots and other conditions are the same as in example 3.
Example 5
Compared with the example 3, the PbS near infrared II region quantum dot with the particle size of 3nm is adopted, the surface of which is modified by amino PEG, and other conditions are the same as the example 3.
Example 6
Compared with example 3, Ag with 2nm particle diameter and surface modified amino PEG is adopted2And S near infrared II region quantum dots, and the other conditions are the same as those of the example 3.
Example 7
Compared with example 3, Ag with the surface modified with amino PEG and the particle size of 20nm is adopted2And S near infrared II region quantum dots, and the other conditions are the same as those of the example 3.
The results show that the delivery systems of examples 4 to 7 also have bone targeting effects.
In conclusion, the near-infrared II region quantum dots which are modified with amino polyethylene glycol and are smaller than 20nm are used as carriers, the carriers are adsorbed on bone tissues under the action of dynamics and electrostatic force and do not have physiological action with the bone tissues, the bone targeting effect is realized, the treatment effect of the medicine is not interfered, the side effect is small, and the pharmacological research of the medicine is facilitated; the near-infrared II-region quantum dots are used as carriers, the bone targeting process of the medicine is tracked in a full range through near-infrared II-region fluorescent signals in vivo fluorescence imaging, the tissue penetration degree and the spatial resolution are very high, biological autofluorescence interference hardly exists, and the tracing effect is good; the invention does not adopt complex and expensive bone targeting reagents, and has simple method and low cost.
The applicant states that the present invention is illustrated in detail by the above examples, but the present invention is not limited to the above detailed methods, i.e. it is not meant that the present invention must rely on the above detailed methods for its implementation. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (9)
1. An application of near-infrared II region quantum dots in preparing a bone targeting drug delivery system;
wherein, the surface of the near-infrared II region quantum dot is modified with amino polyethylene glycol;
the near-infrared II region quantum dots are Ag2S quantum dots;
the particle size of the near-infrared II region quantum dots is 3-10 nm.
2. The bone targeting drug delivery system is characterized in that the bone targeting drug delivery system is a near-infrared II region quantum dot modified with amino polyethylene glycol on the surface;
the near-infrared II region quantum dots are Ag2S quantum dots;
the particle size of the near-infrared II region quantum dots is 3-10 nm.
3. The bone-targeted drug delivery system of claim 2, wherein the drug delivery system further comprises a drug.
4. A method of preparing a bone-targeted drug delivery system according to claim 2 or 3, the method comprising:
adding the medicine into a solution containing the near-infrared II region quantum dots with the surfaces modified with amino polyethylene glycol, and stirring to obtain the bone targeting drug delivery system.
5. The method of claim 4, wherein the mass ratio of the drug to the quantum dot is (1-5): 1.
6. The method of claim 5, wherein the mass ratio of the drug to the quantum dots is (2-3): 1.
7. The method according to claim 6, wherein the stirring time is 12-18 h.
8. Use of a bone-targeted drug delivery system according to claim 2 or 3 for the preparation of a medicament for the treatment of an orthopaedic disorder.
9. Use according to claim 8, wherein the orthopaedic disease comprises any one or a combination of at least two of osteoporosis, osteoarthritis or a bone tumour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810297951.8A CN108404141B (en) | 2018-03-30 | 2018-03-30 | A bone-targeted drug delivery system based on near-infrared region II quantum dots and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810297951.8A CN108404141B (en) | 2018-03-30 | 2018-03-30 | A bone-targeted drug delivery system based on near-infrared region II quantum dots and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108404141A CN108404141A (en) | 2018-08-17 |
| CN108404141B true CN108404141B (en) | 2021-04-02 |
Family
ID=63134554
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810297951.8A Active CN108404141B (en) | 2018-03-30 | 2018-03-30 | A bone-targeted drug delivery system based on near-infrared region II quantum dots and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108404141B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109602945A (en) * | 2018-12-25 | 2019-04-12 | 上海纳米技术及应用国家工程研究中心有限公司 | The area NIR II fluorescence can monitor preparation method of degradation-type bone cement and products thereof and application |
| CN109705861B (en) * | 2019-01-11 | 2021-10-22 | 苏州大学 | Preparation method and imaging method of quantum dots for clinical skeletal in vivo imaging |
| CN110564404A (en) * | 2019-08-30 | 2019-12-13 | 苏州星烁纳米科技有限公司 | Preparation method of quantum dot, quantum dot composition and color film |
| CN116474122B (en) * | 2023-04-07 | 2025-07-22 | 武汉大学 | Quantum dot nano probe Ag2S@PEG-ABS and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102824647A (en) * | 2011-06-13 | 2012-12-19 | 香港中文大学 | Bone targeting delivery system based on small nucleic acid drug osteogenesis treatment and preparation method thereof |
| CN104288786A (en) * | 2013-07-17 | 2015-01-21 | 中国科学院苏州纳米技术与纳米仿生研究所 | Tumor targeted diagnosing and treating system based on near-infrared quantum dot and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9872881B2 (en) * | 2013-11-01 | 2018-01-23 | The Brigham And Women's Hospital, Inc. | Bone and metal targeted polymeric nanoparticles |
| CN107412164B (en) * | 2017-04-26 | 2020-10-20 | 温州医科大学附属口腔医院 | Preparation method of double-targeting drug-loaded nanoparticle lipid-polymer for osteoporosis |
-
2018
- 2018-03-30 CN CN201810297951.8A patent/CN108404141B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102824647A (en) * | 2011-06-13 | 2012-12-19 | 香港中文大学 | Bone targeting delivery system based on small nucleic acid drug osteogenesis treatment and preparation method thereof |
| CN104288786A (en) * | 2013-07-17 | 2015-01-21 | 中国科学院苏州纳米技术与纳米仿生研究所 | Tumor targeted diagnosing and treating system based on near-infrared quantum dot and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| "Heterobifunctional Poly(ethylene glycol) Derivatives for the Surface Modification of Gold Nanoparticles Toward Bone Mineral Targeting";Gamal M. S. Zayed et al.;《Macromol. Biosci.》;20120716;第12卷;摘要，fig3，table1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108404141A (en) | 2018-08-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108404141B (en) | A bone-targeted drug delivery system based on near-infrared region II quantum dots and its preparation method and application | |
| US10954348B2 (en) | Biocompatible nanoparticle and use thereof | |
| Patrick et al. | Radio-metal cross-linking of alginate hydrogels for non-invasive in vivo imaging | |
| Hao et al. | Stem cell-mediated delivery of nanogels loaded with ultrasmall iron oxide nanoparticles for enhanced tumor MR imaging | |
| Fahrenholtz et al. | Targeting breast cancer with sugar-coated carbon nanotubes | |
| Song et al. | Graphene oxide coating core–shell silver sulfide@ mesoporous silica for active targeted dual-mode imaging and chemo-photothermal synergistic therapy against tumors | |
| BR112014009753B1 (en) | BIOCOMPATIBLE NANOPARTICLE FUNCTIONED AND RESPECTIVE USE | |
| US20150231077A1 (en) | Amine passivated nanoparticles for cancer treatment and imaging | |
| CN109157662B (en) | A kind of human serum albumin-doxorubicin cross-linked nanoparticle and its application | |
| US20060014938A1 (en) | Stable aqueous colloidal lanthanide oxides | |
| Laranjeira et al. | Enhanced biosafety of silica coated gadolinium based nanoparticles | |
| CN103041407A (en) | Core-shell type nano-contrast agent, preparation method and application thereof | |
| Inagaki et al. | Near-infrared photoimmunotherapy (NIR-PIT) of bone metastases | |
| RU2611715C1 (en) | Method of increasing essential elements in body of broiler chickens in single muscular injection of highly dispersed nanoparticles of copper | |
| Alnasraui et al. | Investigation of dextran-coated magnetic nanoparticles encapsulated by medication and modified with folate for targeted drug delivery: Invitro and docking studies | |
| Vedakumari et al. | Radiopaque fibrin nanocomplex as a promising tool for X-ray imaging applications | |
| CN109395106B (en) | A kind of nanometer bismuth ball cluster with stable structure and its preparation method and application | |
| JP6851987B2 (en) | Gelatin particles, methods for producing gelatin particles, gelatin particle-encapsulating cells, and gelatin particle-encapsulating cells. | |
| EP3258922A1 (en) | Compositions and methods for nanoparticle-based drug delivery and imaging | |
| JP2008266214A (en) | Composite particles using gold iron oxide particles and MRI contrast agent | |
| CN102462847A (en) | Novel tumor targeting contrast agent | |
| JP7328654B2 (en) | METHOD FOR EVALUATING EFFECT OF CANDIDATE SUBSTANCE ON BIOLOGICAL ACTIVITY, BIODEGRADABLE PARTICLES, KIT, AND SYSTEM FOR EVALUATING EFFECT OF CANDIDATE SUBSTANCE ON BIO ACTIVITY | |
| WO2023031387A1 (en) | Use of nanoparticles for the treatment of fistulizing anoperineal lesions | |
| Hernandez Pichardo et al. | Multispectral optoacoustic tomography is more sensitive than micro‐computed tomography for tracking gold nanorod labelled mesenchymal stromal cells | |
| Liu et al. | Preparation and In Vitro and In Vivo Evaluation of Lung Cancer-Targeted Carbon Nanotube Ultrasound Contrast Agents |
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 |