CN106267230A - Preparation method of pH-sensitive drug self-gated mesoporous nano anti-tumor carrier - Google Patents
Preparation method of pH-sensitive drug self-gated mesoporous nano anti-tumor carrier Download PDFInfo
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- 239000003814 drug Substances 0.000 title claims abstract description 60
- 229940079593 drug Drugs 0.000 title claims abstract description 30
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 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 128
- 229960004679 doxorubicin Drugs 0.000 claims abstract description 63
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 52
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims abstract description 41
- GOUHYARYYWKXHS-UHFFFAOYSA-N 4-formylbenzoic acid Chemical compound OC(=O)C1=CC=C(C=O)C=C1 GOUHYARYYWKXHS-UHFFFAOYSA-N 0.000 claims abstract description 22
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims abstract description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 15
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 13
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 13
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 13
- YUYCVXFAYWRXLS-UHFFFAOYSA-N trimethoxysilane Chemical compound CO[SiH](OC)OC YUYCVXFAYWRXLS-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 6
- 239000002539 nanocarrier Substances 0.000 claims abstract description 6
- 238000007112 amidation reaction Methods 0.000 claims abstract description 5
- 230000007935 neutral effect Effects 0.000 claims abstract description 3
- 229910052814 silicon oxide Inorganic materials 0.000 claims description 26
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 12
- 230000004044 response Effects 0.000 claims description 10
- 238000007789 sealing Methods 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 9
- 229910052710 silicon Inorganic materials 0.000 claims description 8
- 239000010703 silicon Substances 0.000 claims description 8
- 235000012239 silicon dioxide Nutrition 0.000 claims description 8
- 229910003978 SiClx Inorganic materials 0.000 claims description 6
- 239000004408 titanium dioxide Substances 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 238000011068 loading method Methods 0.000 claims description 5
- XDLMVUHYZWKMMD-UHFFFAOYSA-N 3-trimethoxysilylpropyl 2-methylprop-2-enoate Chemical compound CO[Si](OC)(OC)CCCOC(=O)C(C)=C XDLMVUHYZWKMMD-UHFFFAOYSA-N 0.000 claims description 4
- 241000790917 Dioxys <bee> Species 0.000 claims description 4
- 230000009435 amidation Effects 0.000 claims description 4
- 238000011938 amidation process Methods 0.000 claims description 4
- 238000005576 amination reaction Methods 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 3
- 239000002086 nanomaterial Substances 0.000 claims description 3
- 229930012538 Paclitaxel Natural products 0.000 claims description 2
- 239000012670 alkaline solution Substances 0.000 claims description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 claims description 2
- 229960001467 bortezomib Drugs 0.000 claims description 2
- 238000007654 immersion Methods 0.000 claims description 2
- 229960001592 paclitaxel Drugs 0.000 claims description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims 2
- 238000009792 diffusion process Methods 0.000 claims 1
- 230000009881 electrostatic interaction Effects 0.000 claims 1
- 229910052697 platinum Inorganic materials 0.000 claims 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims 1
- 229960004528 vincristine Drugs 0.000 claims 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 14
- 239000000463 material Substances 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 6
- 239000002253 acid Substances 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 230000002349 favourable effect Effects 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 229910001868 water Inorganic materials 0.000 description 8
- 239000002105 nanoparticle Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 5
- 229910021641 deionized water Inorganic materials 0.000 description 5
- 238000012377 drug delivery Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- -1 benzaldehyde Imines Chemical class 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000013335 mesoporous material Substances 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- WYTZZXDRDKSJID-UHFFFAOYSA-N (3-aminopropyl)triethoxysilane Chemical compound CCO[Si](OCC)(OCC)CCCN WYTZZXDRDKSJID-UHFFFAOYSA-N 0.000 description 2
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 description 2
- 229930195573 Amycin Natural products 0.000 description 2
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 2
- 229940081974 saccharin Drugs 0.000 description 2
- 235000019204 saccharin Nutrition 0.000 description 2
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 2
- 150000003613 toluenes Chemical class 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- HAWSQZCWOQZXHI-UHFFFAOYSA-N CPT-OH Natural products C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000712 assembly Effects 0.000 description 1
- 238000000429 assembly Methods 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 231100000783 metal toxicity Toxicity 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001875 tumorinhibitory effect Effects 0.000 description 1
Classifications
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- 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
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a pH-sensitive, drug-self-gated and mesoporous nano anti-tumor carrier, which comprises the following steps: reacting the ordered mesoporous silica with amino-containing trimethoxy silane to obtain surface aminated mesoporous silica; carrying out amidation reaction on p-carboxybenzaldehyde and aminated mesoporous silica to obtain mesoporous silica with benzaldehyde surface; under the weak acid condition, broad-spectrum antitumor drug doxorubicin is loaded into benzaldehyde-typed mesoporous silica, and the neutral condition is recovered to obtain the pH-sensitive DOX-loaded DOX self-gated mesoporous nano-carrier. The pH-sensitive drug self-gated mesoporous nano anti-tumor carrier designed by the invention does not need complex auxiliary chemical molecules as gating materials, is favorable for reducing the toxic and side effects of external components in the actual tumor treatment process, and has high efficiency and tumor acid microenvironment sensitive drug release performance.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to that a kind of pH is sensitive, medicine oneself gate, meso-porous nano resists
Tumor carrier.
Background technology
Mesoporous silicon dioxide nano particle (MSNs) is that a class has high-specific surface area, big pore volume, physical dimension are controlled, carry
Dose is high and has the emerging inorganic nano material of good biocompatibility.MSNs material is at drug delivery system in recent years
Applied research cause widely studied, be expected to become the pharmaceutical carrier of a new generation.The most rationally, efficiently and delicately control
The release from mesopore orbit of the pharmacy thing is focus and the difficult point of current research.One effective medicine Based Intelligent Control release system
It is able to ensure that delivering drug molecule arrives target spot and can controllably discharge, therefore often requires that pharmaceutical carrier arrives focus
Medicine " zero release " is accomplished, to reduce the toxic and side effects of normal tissue before position.Only use blank MSNs material as medicine
Thing carrier also cannot realize Based Intelligent Control and discharge this target.Although with general inorganic nano-particle, organic molecule and supermolecule
The rate of release of medicine can be made preferably by assemblies etc. as the molecular switch of " gate ", the opening of the channel being used for blocking MSNs
Regulation.But the problem that this system is brought is obvious equally, first: these gate materials have the preparation technology of complexity and potential
Toxic and side effects.Such as inorganic nanoparticles can enter into internal after disconnecting, and introduces the brightest to normal structure and cell
Aobvious heavy metal toxicity.Second: the microenvironment for tumor locus cannot accomplish that the sensitive intelligence of medicine discharges.Such as, at present
Most of acid response systems of development all can only realize the response of relatively low (pH<4.0) or higher (pH>11.0) pH value,
Almost without response under nearly physiological condition.Therefore, design and not only there is hypotoxicity but also possess the door of tumor microenvironment pH sensitive property
Control switching material is significant for mesoporous material development in tumour medicine transmission system.
Summary of the invention
For above-mentioned problems faced, it is an object of the invention to design a kind of using anti-tumor medicine itself as gate
The mesoporous medicine-carried system of switching material.Specific as follows: to use the Metaporous silicon dioxide material of benzaldehyde functionalizing, medicine is divided
Sub-DOX, simultaneously as drug delivery and gate controlled switch material, forms benzoyl by the aldehyde radical of amino intrinsic for DOX with benzaldehyde
Imines covalent bond, reaches the effect (shown in Fig. 1) of DOX drug molecule " oneself's gate (Self-gatekeeper) ".And, by
Rupturing under tumor tissues and cell weak acid environment in saccharin key, the DOX blocking effect made eliminates, its internal load
Drug molecule therefore reach the controllable release of pH response, finally constructed medicine " oneself's door of pH sensitivity itself
Control " administration nano-drug administration system.Meanwhile, the mesoporous drug-supplying system of medicine " oneself's gate " can be applied to other tools neatly
There are pH response medicine and mesoporous material, there is popularity and the alternative advantage of mesoporous material that drug molecule uses,
Have a good application prospect.
In order to realize foregoing invention purpose, the technical scheme that the present invention takes is:
A kind of pH is sensitive, medicine oneself gate, the preparation method of meso-porous nano antitumor carrier, it is characterised in that: use
The mesoporous silicon oxide of benzaldehyde and broad-spectrum anti-cancer drug doxorubicin (DOX) are contained respectively as meso-porous nano carrier in surface
With gate drug molecule；The sensitive saccharin covalent bond of pH, energy is formed by the aldehyde radical of amino intrinsic for DOX with benzaldehyde
Realize the controllable release that the pH of drug molecule triggers.
Its preparation method comprises the steps:
(1) mesoporous silicon oxide and the trimethoxy silane containing amino are reacted obtain the meso-porous titanium dioxide of surface amination
Silicon；Trimethoxy silane containing amino is methacrylic acid-3-(trimethoxysilyl) propyl ester, relative to mesoporous dioxy
The component of SiClx, the trimethoxy silane consumption containing amino is 0.1 2 weight portions；
(2) p-carboxybenzaldehyde and amidized mesoporous silicon oxide are carried out amidation process and obtain surface benzaldehyde base
Mesoporous silicon oxide；The consumption of p-carboxybenzaldehyde is 0.1-4 weight portion；Amidation reagent is EDC and NHS, EDC and NHS
Mass ratio is 1:1-1:2；Solvent is H2O and DMF, H2O and DMF volume ratio is 4:1-1:4, and the response time is 12-48 hour；
(3) under mildly acidic conditions broad-spectrum anti-cancer drug doxorubicin (DOX) is loaded into the meso-porous titanium dioxide of benzaldehyde base
Silicon, recovers to realize DOX sealing of hole to neutrallty condition, i.e. can get Jie of the oneself's gate being loaded with antitumor drug DOX sensitive for pH
Hole nano-carrier.
The mesoporous silicon oxide of step (1) is based on ordered mesopore silicon dioxide nano material, mean diameter 50 300
Nm, aperture 2.4-3.5 nm, specific surface 400 1200 m2/g.Gate drug molecule is that the wide spectrum containing amino group resists
Tumour medicine doxorubicin (DOX).
The solutions of weak acidity loading gate drug molecule DOX in step (3) is pH 2-6.8；Gate drug molecule
(DOX) condition of sealing of hole is immersion 10min-12h in the neutrality or alkaline solution of pH 7.4 12.
A kind of pH is sensitive, medicine oneself gate, the preparation method of meso-porous nano antitumor carrier, it is characterised in that:
Surface is used to contain the mesoporous silicon oxide of benzaldehyde and broad-spectrum anti-cancer drug doxorubicin (DOX) respectively as meso-porous nano
Carrier and gate drug molecule；
Its preparation method comprises the steps:
(1) mesoporous silicon oxide and the trimethoxy silane containing amino are reacted obtain the meso-porous titanium dioxide of surface amination
Silicon；Trimethoxy silane containing amino is methacrylic acid-3-(trimethoxysilyl) propyl ester, relative to mesoporous dioxy
The component of SiClx, the trimethoxy silane consumption containing amino is 0.1 2 weight portions；
(2) p-carboxybenzaldehyde and amidized mesoporous silicon oxide are carried out amidation process and obtain surface benzaldehyde base
Mesoporous silicon oxide；The consumption of p-carboxybenzaldehyde is 0.1-4 weight portion；Amidation reagent is EDC and NHS, EDC and NHS
Mass ratio is 1:1-1:2；Solvent is H2O and DMF, H2O and DMF volume ratio is 4:1-1:4, and the response time is 12-48 hour；
(3) drug molecule will be loaded under mildly acidic conditions and be loaded into the mesoporous silicon oxide of benzaldehyde base, recover to neutral or
Alkalescence condition realizes DOX sealing of hole, and the meso-porous nano that i.e. can get the oneself's gate being loaded with antitumor drug DOX sensitive for pH carries
Body；The described molecular weight loading drug molecule is not higher than 1000Da, for camptothecine, paclitaxel, cisplatin, bortezomib, Changchun
New alkali, one or more of Xi Tabin.
In step (3), solutions of weak acidity is pH 2-6.8；The condition of DOX sealing of hole be pH 7.4 12 neutrality or
Alkalescence DOX solution soaks 10min-12h.
A kind of pH is sensitive, medicine oneself gate, meso-porous nano antitumor carrier, load for described one or more
Pharmaceutical carrier that is that drug molecule carries altogether and that be prepared by DOX molecule sealing of hole.
The present invention compared with prior art, has the advantages that
Mesoporous drug-supplying system involved in the present invention, is not required to use extra " gate " to go to block duct, but utilizes dexterously
Use medicine itself as " oneself's gate " switching material, advantageously reduce extraneous ingredients poison in actual tumor therapeutic procedure
Side effect, has simple high efficiency and the medicine-releasing performance of acidic cancer microenvironment sensitivity.And, this control releaser
Tie up to that there is under physiological environment the sensitiveest pH response, the medicine realizing controlled-release of tumor microenvironment and cell interior can be realized
Put.Having suggestive, the mesoporous drug delivery system of medicine " oneself's gate " can be applied to other neatly and have antitumor
The small-molecule drug of activity, controls aspect have potential using value equally in combining of cancer.
Accompanying drawing explanation
PH sensitivity Covalently attached interaction between Fig. 1 antitumor drug amycin (DOX) and benzaldehyde and DOX molecule oneself
Gating principles figure；
Mesoporous silicon oxide that Fig. 2 DOX molecule oneself gates, that be mounted with DOX molecule；
The medicine-releasing performance of mesoporous drug-supplying system that Fig. 3 DOX molecule oneself gates, that be mounted with DOX molecule；
In-vivo tumour inhibition (20 days) that Fig. 4 DOX molecule oneself gates, that be mounted with the mesoporous drug-supplying system of DOX molecule.
Medicine releasability that Fig. 5 DOX molecule oneself gates, that be mounted with the mesoporous drug-supplying system of 10-hydroxy-camptothecin molecule
Energy.
Detailed description of the invention
Below by embodiment, the present invention is further described.
(1) DOX molecule oneself gate, the mesoporous drug-supplying system that is mounted with DOX drug molecule
Weigh the mesoporous silicon oxide that 1 g is dried to be scattered in 20 ml dry toluenes, add (3-aminopropyl) triethoxysilicane
Alkane (APTES) 500 μ L, 120 DEG C are refluxed 16 hours under an argon, after reaction terminates, filter, and mix with ether and dichloromethane
Close solution (1:1) to wash 2 times, vacuum drying, obtain surface amino groups SiClx ball.20 ml water are added in the flask of 100 ml, 5
Ml DMF, p-carboxybenzaldehyde 45 mg, EDC 77 mg, NHS 46 mg, regulate pH value 5 ~ 6 with dilute hydrochloric acid, and activation is to carboxyl benzene
The carboxyl of formaldehyde, is subsequently adding 0.85 g silicon amide ball, and reaction is filtered the most afterwards, washes with water three times, then washs with DMF,
Soaked overnight, ethanol is resuspended, vacuum drying, obtains the mesoporous silicon oxide that benzaldehyde is modified.It is dispersed in the second of 200 ml
Alcohol and 1 g NH4NO3Mixed solution in, at 80 DEG C reflux 8 hours, remove template CTAB, final products filter and use
Washing with alcohol, is vacuum dried 24 h, obtains mesoporous silicon dioxide nano particle that benzaldehyde is modified.
Weigh 200 mg amycin (DOX) to be dissolved in the deionized water of 5 ml pH 5 ~ 6, add mesoporous silicon oxide
Nanoparticle 100 mg, after 24 hours, fully adsorbs DOX in centrifuge tube, filters, by deionized water quick wash and mistake
Filter.Washed once with the sodium hydroxide deionized water solution of pH=8.5, and regulation returns to neutrallty condition, lyophilizing, obtains DOX
Mesoporous drug-supplying system that molecule oneself gates, that be mounted with DOX drug molecule.
The projection Electronic Speculum result of nanometer system is as in figure 2 it is shown, load the mesoporous silicon oxide after DOX and DOX gates
Mesopore orbit structure thickens, and surface area is by 1200m2/ g drops to 600m2About/g.By testing it at condition of different pH
Under DOX molecule release performance it is found that this drug delivery system has obvious pH sensitive property (Fig. 3).Internal tumor is real
Testing result to also demonstrate that, mesoporous drug-supplying system that this DOX molecule oneself gates, that be mounted with DOX drug molecule is than simple employing
DOX medicine has obvious tumor inhibitory effect (Fig. 4).
(2) DOX molecule oneself gate, the mesoporous drug-supplying system that is mounted with 10-hydroxycamptothecine drug molecule
Weigh the mesoporous silicon oxide that 1 g is dried to be scattered in 20 ml dry toluenes, add (3-aminopropyl) triethoxysilicane
Alkane (APTES) 500 μ L, 120 DEG C are refluxed 16 hours under an argon, after reaction terminates, filter, and mix with ether and dichloromethane
Close solution (1:1) to wash 2 times, vacuum drying, obtain surface amino groups SiClx ball.20 ml water are added in the flask of 100 ml, 5
Ml DMF, p-carboxybenzaldehyde 45 mg, EDC 77 mg, NHS 46 mg, regulate pH value 5 ~ 6 with dilute hydrochloric acid, and activation is to carboxyl benzene
The carboxyl of formaldehyde, is subsequently adding 0.85 g silicon amide ball, and reaction is filtered the most afterwards, washes with water three times, then washs with DMF,
Soaked overnight, ethanol is resuspended, vacuum drying, obtains the mesoporous silicon oxide that benzaldehyde is modified.It is dispersed in the second of 200 ml
Alcohol and 1 g NH4NO3Mixed solution in, at 80 DEG C reflux 8 hours, remove template CTAB, final products filter and use
Washing with alcohol, is vacuum dried 24 h, obtains mesoporous silicon dioxide nano particle that benzaldehyde is modified.
Weigh 200 mg 10-hydroxycamptothecines to be dissolved in 5 ml DMSO, add mesoporous silicon dioxide nano particle 100
Mg, regulation pH value to 6.0, after 24 hours, fully adsorbs in centrifuge tube, filters, with deionized water quick wash and filtration.
With the DOX aqueous solution of pH=8.5, deionized water wash once, lyophilizing, obtain DOX molecule oneself gate, be mounted with 10-hydroxyl
The mesoporous drug-supplying system of base camptothecin molecule.By testing its 10-hydroxycamptothecine molecule release property under condition of different pH
Can be it is found that this drug delivery system has obvious pH sensitive property (Fig. 5).
The above is only the preferred embodiment of the present invention, it should be pointed out that: for the ordinary skill people of the art
For Yuan, under the premise without departing from the principles of the invention, it is also possible to make the replacement of some improvement and equivalents, these improve
The technical scheme obtained with equivalent also should belong to protection scope of the present invention.
Claims (7)
1. a pH is sensitive, medicine oneself gate, the preparation method of meso-porous nano antitumor carrier, it is characterised in that: adopt
The mesoporous silicon oxide and the broad-spectrum anti-cancer drug doxorubicin (DOX) that contain benzaldehyde with surface carry respectively as meso-porous nano
Body and gate drug molecule；
Its preparation method comprises the steps:
(1) mesoporous silicon oxide and the trimethoxy silane containing amino are reacted obtain the meso-porous titanium dioxide of surface amination
Silicon；Trimethoxy silane containing amino is methacrylic acid-3-(trimethoxysilyl) propyl ester, relative to mesoporous dioxy
The component of SiClx, the trimethoxy silane consumption containing amino is 0.1 2 weight portions；
(2) p-carboxybenzaldehyde and amidized mesoporous silicon oxide are carried out amidation process and obtain surface benzaldehyde base
Mesoporous silicon oxide；The consumption of p-carboxybenzaldehyde is 0.1-4 weight portion；Amidation reagent is EDC and NHS, EDC and NHS
Mass ratio is 1:1-1:2；Solvent is H2O and DMF, H2O and DMF volume ratio is 4:1-1:4, and the response time is 12-48 hour；
(3) under mildly acidic conditions broad-spectrum anti-cancer drug doxorubicin (DOX) is loaded into the meso-porous titanium dioxide of benzaldehyde base
Silicon, recovers to neutral or alkaline condition to realize DOX sealing of hole, i.e. can get the sensitive self-door being loaded with antitumor drug DOX of pH
The meso-porous nano carrier of control.
A kind of pH the most according to claim 1 is sensitive, medicine oneself gate, the preparation of meso-porous nano antitumor carrier
Method, it is characterised in that the mesoporous silicon oxide of step (1) is based on ordered mesopore silicon dioxide nano material, mean diameter
50 300 nm, aperture 2.4-3.5 nm, specific surface 400 1200 m2/g。
A kind of pH the most according to claim 1 is sensitive, medicine oneself gate, the preparation of meso-porous nano antitumor carrier
Method, it is characterised in that gate drug molecule is the broad-spectrum anti-cancer drug doxorubicin (DOX) containing amino group.
A kind of pH the most according to claim 1 is sensitive, medicine oneself gate, the preparation of meso-porous nano antitumor carrier
Method, it is characterised in that the solutions of weak acidity loading gate drug molecule DOX in step (3) is pH 2-6.8；Gate medicine
The condition of molecule (DOX) sealing of hole is immersion 10min-12h in the neutrality or alkaline solution of pH 7.4 12.
5. a pH is sensitive, medicine oneself gate, the preparation method of meso-porous nano antitumor carrier, it is characterised in that: adopt
The mesoporous silicon oxide and the broad-spectrum anti-cancer drug doxorubicin (DOX) that contain benzaldehyde with surface carry respectively as meso-porous nano
Body and gate drug molecule；
Its preparation method comprises the steps:
(1) mesoporous silicon oxide and the trimethoxy silane containing amino are reacted obtain the meso-porous titanium dioxide of surface amination
Silicon；Trimethoxy silane containing amino is methacrylic acid-3-(trimethoxysilyl) propyl ester, relative to mesoporous dioxy
The component of SiClx, the trimethoxy silane consumption containing amino is 0.1 2 weight portions；
(2) p-carboxybenzaldehyde and amidized mesoporous silicon oxide are carried out amidation process and obtain surface benzaldehyde base
Mesoporous silicon oxide；The consumption of p-carboxybenzaldehyde is 0.1-4 weight portion；Amidation reagent is EDC and NHS, EDC and NHS
Mass ratio is 1:1-1:2；Solvent is H2O and DMF, H2O and DMF volume ratio is 4:1-1:4, and the response time is 12-48 hour；
(3) drug molecule will be loaded under mildly acidic conditions, be loaded into Jie of benzaldehyde base by molecule diffusion and electrostatic interaction
Hole silicon dioxide, recovers to realize DOX sealing of hole to neutrallty condition, i.e. can get the sensitive oneself being loaded with antitumor drug DOX of pH
The meso-porous nano carrier of gate；The described molecular weight loading drug molecule is not higher than 1000Da, for camptothecine, paclitaxel, suitable
Platinum, bortezomib, vincristine, one or more of Xi Tabin.
A kind of pH the most according to claim 5 is sensitive, medicine oneself gate, the preparation of meso-porous nano antitumor carrier
Method, it is characterised in that in step (3), solutions of weak acidity is pH 2-6.8；The condition of DOX sealing of hole is at pH 7.4 12
Alkaline DOX solution in soak 10min-12h.
7. pH is sensitive, medicine oneself gate, a meso-porous nano antitumor carrier, for the one described in claim 5 or
Pharmaceutical carrier that is that multiple loading drug molecule carries altogether and that be prepared by DOX molecule sealing of hole.
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| CN111973752A (en) * | 2020-09-03 | 2020-11-24 | 中山大学·深圳 | Urotropine-loaded mesoporous nano silicon spheres and preparation method thereof |
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