CN107648612A - A kind of hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport the preparation and application of system - Google Patents

A kind of hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport the preparation and application of system Download PDF

Info

Publication number
CN107648612A
CN107648612A CN201710962097.8A CN201710962097A CN107648612A CN 107648612 A CN107648612 A CN 107648612A CN 201710962097 A CN201710962097 A CN 201710962097A CN 107648612 A CN107648612 A CN 107648612A
Authority
CN
China
Prior art keywords
hmn
qinghaosu
preparation
donor
cotransport
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
Application number
CN201710962097.8A
Other languages
Chinese (zh)
Other versions
CN107648612B (en
Inventor
张慧娟
张振中
祝杏
陈俭娇
张红岭
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhengzhou University
Original Assignee
Zhengzhou University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Zhengzhou University filed Critical Zhengzhou University
Priority to CN201710962097.8A priority Critical patent/CN107648612B/en
Publication of CN107648612A publication Critical patent/CN107648612A/en
Application granted granted Critical
Publication of CN107648612B publication Critical patent/CN107648612B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a kind of hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport the preparation and application of system, can effectively solve the problem of solubility of the qinghaosu in antineoplastic is prepared is low, and oral administration biaavailability is low, and metabolism is fast, unstable, the technical scheme of solution is to comprise the following steps：First sucrose is added in deionized water, centrifuged after reaction, washing precipitation drying, then Mn (NO are added dropwise3)2Solution, ultrasonic disperse, centrifuge washing drying, synthesize HMn2O3's；Add deionized water, Probe Ultrasonic Searching dissolving, qinghaosu is dissolved in ethanol, then with HMn2O3Solution mix, ice-bath ultrasonic process, dialysis freeze-drying, produce, preparation method of the present invention is simple, is greatly improved solubility and bioavilability of the qinghaosu in antineoplastic is prepared, significantly increases toxicity of the qinghaosu to tumour cell, there is provided high concentration Mn2+Magnetic resonance imaging can be significantly increased, realizes the diagnosis and treatment integration of tumour.

Description

A kind of hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport system preparation and Using
Technical field
The present invention relates to field of medicaments, particularly a kind of hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport system Preparation and application.
Background technology
Qinghaosu（ART）It is a kind of containing peroxy-radical, the Sesquiterpene lactones compound that there is anti-malarial to act on, it is anti- Malaria activity obtained it is universally acknowledged, have it is rapid-action, drug effect is high, less toxic side effect and other advantages.The research to deepen continuously discloses Such compound has good antitumor action, such as inducing cell cycle arrest, promotes Apoptosis, suppresses tumor vessel life Into, block tumour cell invasion and attack transfer etc..But ART has indissoluble, and oral administration biaavailability is low, metabolism is fast, and unstable lacks Point, therefore, how to strengthen ART antitumor action, it is that this area is badly in need of solving to realize its application in antineoplastic Problem.
Hollow mesoporous manganese sesquioxide managnic oxide（Hollow Mn2O3, HMn2O3）Nanoparticle has double-decker, and inside has larger Pore volume, its hollow and pore passage structure can load medicine, specific surface area is big, has very high Drug loadings ability.In human body Under neutral environment, HMn2O3It is capable of the integrality of holding structure, and in tumor locus slant acidity and strong reducing property microenvironment, HMn2O3Structure can progressively ablation, generate Mn2+, the medicine of one side load discharges into tumour cell, realizes tumor target therewith Position Mn2+The purpose discharged with same one-step site, reduce the toxic side effect of medicine；Another aspect Mn2+Generation cause tumour cell Lysosome osmotic pressure raises, and lysosome escape phenomenon is produced, in addition, Mn2+ART peroxide bridge can be destroyed by, which being incubated altogether with ART, makes it Free radical is produced, destruction of the free radical to tumour cell lysosome membrane can accelerate lysosome escape and cell nucleus targeting, show Write toxicity of the enhancing ART to tumour cell.Pass through hollow mesoporous manganese sesquioxide managnic oxide nanoparticle HMn2O3Load qinghaosu（ART）, system The hollow mesoporous door-control type Mn of standby tumour response2+Donor and ART cooperate with the system that cotransports, and can effectively strengthen ART antitumor work With, but at present it is not yet found that related research.
The content of the invention
For the above situation, to overcome the defect of prior art, the purpose of the present invention is just to provide a kind of hollow mesoporous door Control type Mn2+Donor and qinghaosu cotransport the preparation and application of system, can effectively solve qinghaosu in antineoplastic is prepared Solubility it is low, oral administration biaavailability is low, and metabolism is fast, it is unstable the problem of.
The technical scheme of solution is a kind of hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport system preparation and Using comprising the following steps：
（1）HMn2O3Synthesis：10-45g sucrose is added in 15-180mL deionized waters, reacts 3-7h at 145-295 DEG C, 12500-14000rpm centrifuges 9-11min, abandons supernatant, and precipitation is respectively washed 2-3 times with deionized water and absolute ethyl alcohol successively, 55- Dried at 59 DEG C, obtain black carbon powder；0.5-4.5g carbon dusts are weighed, 15- is added dropwise in 10-45mL deionized waters in ultrasonic disperse Mn (the NO of 45mL mass concentration 50%3)2Solution, ultrasonic disperse 13-16min, impregnate 30-70h, stirring, 12500- 13500rpm centrifuges 28-33min, abandons supernatant, precipitation is respectively washed 2-3 times with deionized water and absolute ethyl alcohol successively, at 55-65 DEG C Dry, be calcined 3-9h at 350-650 DEG C, produce HMn2O3；
（2）HMn2O3Load the preparation of qinghaosu：Weigh 5-20mg steps（1）The HMn of preparation2O3It is added to 2-40ml deionizations In water, Probe Ultrasonic Searching dissolving, HMn is obtained2O3Solution, weigh 20-40mg qinghaosus and be dissolved in 2-5ml ethanol, then with HMn2O3 Solution mixes, and ice-bath ultrasonic process 0.5-1h, the 2- that dialyses is put into molecular cut off MW=3500Da bag filter after being stirred at room temperature 3 days, freeze-drying, obtain hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport system.
Hollow mesoporous door-control type Mn prepared by methods described2+The cotransport particle diameter of system of donor and qinghaosu is 50-300 nm。
Hollow mesoporous door-control type Mn prepared by methods described2+What donor and qinghaosu cotransported system is preparing antineoplastic Application in thing.
Preparation method of the present invention is simple, is greatly improved solubility and biology profit of the qinghaosu in antineoplastic is prepared Expenditure, significantly increases toxicity of the qinghaosu to tumour cell, and hollow mesoporous manganese sesquioxide managnic oxide nanoparticulate carriers carry in tumor locus The high concentration Mn of confession2+Magnetic resonance imaging can be significantly increased, realizes the diagnosis and treatment integration of tumour.
Embodiment
The specific embodiment of the invention is described in further detail with reference to embodiments.
Embodiment 1
Hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport the preparation and application of system, comprise the following steps：
（1）HMn2O3Synthesis：10g sucrose is added in 15mL deionized waters, 7h, 12500rpm centrifugations are reacted at 145 DEG C 11min, supernatant is abandoned, precipitation is dried with deionized water and absolute ethyl alcohol respectively washing 2 times, 55 DEG C successively, obtains black carbon powder；Weigh Mn (the NO of 15mL mass concentration 50% are added dropwise in 10mL deionized waters in 0.5g carbon dusts, ultrasonic disperse3)2Solution, ultrasonic disperse 13min, 70h is impregnated, stirring, 12500rpm centrifugation 33min, abandons supernatant, precipitation is respectively washed with deionized water and absolute ethyl alcohol successively Wash 2 times, dried at 55 DEG C, be calcined 9h at 350 DEG C, produce HMn2O3；
（2）HMn2O3Load the preparation of qinghaosu：Weigh 5mg steps（1）The HMn of preparation2O3It is added in 2ml deionized waters, Probe Ultrasonic Searching dissolves, and obtains HMn2O3Solution, weigh 20mg qinghaosus and be dissolved in 2ml ethanol, then with HMn2O3Solution mixes, ice Bath is ultrasonically treated 0.5h, is put into after being stirred at room temperature in molecular cut off MW=3500Da bag filter, dialyses 2 days, freeze-drying, Obtain hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport system.
Embodiment 2
Hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport the preparation and application of system, comprise the following steps：
（1）HMn2O3Synthesis：30g sucrose is added in 100mL deionized waters, 4h, 13000rpm centrifugations are reacted at 200 DEG C 10min, supernatant is abandoned, precipitation is dried with deionized water and absolute ethyl alcohol respectively washing 3 times, 57 DEG C successively, obtains black carbon powder；Weigh Mn (the NO of 30mL mass concentration 50% are added dropwise in 30mL deionized waters in 2.0g carbon dusts, ultrasonic disperse3)2Solution, ultrasonic disperse 15min, 48h is impregnated, stirring, 13000rpm centrifugation 30min, abandons supernatant, precipitation is respectively washed with deionized water and absolute ethyl alcohol successively Wash 3 times, dried at 60 DEG C, be calcined 5h at 500 DEG C, produce HMn2O3；
（2）HMn2O3Load the preparation of qinghaosu：Weigh 10mg steps（1）The HMn of preparation2O3It is added in 20ml deionized waters, Probe Ultrasonic Searching dissolves, and obtains HMn2O3Solution, weigh 25mg qinghaosus and be dissolved in 3ml ethanol, then with HMn2O3Solution mixes, ice Bath is ultrasonically treated 0.5h, is put into molecular cut off MW=3500Da bag filter and dialyses 2 days after being stirred at room temperature, and is freeze-dried, obtains Hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport system.
Embodiment 3
Hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport the preparation and application of system, comprise the following steps：
（1）HMn2O3Synthesis：45g sucrose is added in 180mL deionized waters, 3h, 14000rpm centrifugations are reacted at 295 DEG C 9min, supernatant is abandoned, precipitation is dried with deionized water and absolute ethyl alcohol respectively washing 3 times, 59 DEG C successively, obtains black carbon powder；Weigh Mn (the NO of 45ml mass concentration 50% are added dropwise in 45mL deionized waters in 4.5g carbon dusts, ultrasonic disperse3)2Solution, ultrasonic disperse 16min, 70h is impregnated, stirring, 13500rpm centrifugation 28min, abandons supernatant, precipitation is respectively washed with deionized water and absolute ethyl alcohol successively Wash 3 times, dried at 65 DEG C, be calcined 3h at 650 DEG C, produce HMn2O3；
（2）HMn2O3Load the preparation of qinghaosu：Weigh 20mg steps（1）The HMn of preparation2O3It is added to 40ml deionized waters In, Probe Ultrasonic Searching dissolving, obtain HMn2O3Solution, weigh 40mg qinghaosus and be dissolved in 5ml ethanol, then with HMn2O3Solution mixes Close, ice-bath ultrasonic process 1h, be put into molecular cut off MW=3500Da bag filter and dialyse 3 days after being stirred at room temperature, freezing is dry It is dry, obtain hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport system.
The invention provides the hollow mesoporous door-control type Mn of escaped with lysosome function and cell nucleus targeting2+Donor and green grass or young crops Artemisin（ART）Antineoplastic cotransports system；Present invention selection is hollow with higher drug capacity value and biocompatibility Mesoporous manganese sesquioxide managnic oxide nanoparticle（Hollow Mn2O3, HMn2O3）As matrix material, antineoplastic ART, structure one are loaded Kind is with NMR imaging function, mesoporous door-control type drug transport system；The particle diameter of the nanometer system is 50-300nm, and size is equal First, good dispersion；The system mainly has the characteristics that：1) ART and HMn2O3The system that cotransports can be by two after entering target cell Kind of mechanism realizes lysosome escape and cell nucleus targeting, effectively strengthens ART antitumor action；2）The carrier is in tumour weak acid Mn can be used as under the specific environment of property and reproducibility2+Donor, there is gate effect, while realize ART and Mn2+Donor collaboration is altogether Transhipment, free radical is produced, strengthen ART antitumor actions；3）The Mn of tumor locus generation2+Magnetic resonance imaging can be significantly increased, it is real The diagnosis and treatment integration of existing tumour；4）Dosage needed for ART is antitumor is big, HMn2O3The high drug capacity of double layer hollow loose structure, can Effectively solve the problems, such as that ART dissolubilities are poor, dosage is big.
The present invention relates to a kind of hollow mesoporous door-control type Mn with lysosome escape function and cell nucleus targeting2+Donor with Qinghaosu（ART）Antineoplastic cotransports system.The hollow meso-porous nano grain of multifunction double-layer is prepared first（Hollow Mn2O3, HMn2O3）, using the material as matrix（Specific surface area is big, and capacity is big, and density is small, Mn2+Donor）, interior load ART.In tumour ring In border, the carrier structure is destroyed, and is fissioned to produce substantial amounts of Mn while small particles2+, cause and oozed in tumour cell lysosome Pressure sharply increases thoroughly, causes lysosome escape and cell nucleus targeting.Afterwards, ART and Mn2+Reaction produces a large amount of free radicals.One side Face, it is more obvious by destroying lysosome membrane structure lysosome escape phenomenon；On the other hand, the anti-of ART can be significantly increased Function of tumor.Meanwhile the Mn that the system generates under tomour specific microenvironment2+, tumor locus can be significantly increased as contrast agent Magnetic resonance imaging ability.In summary, the delivery system has Mn2+Donor cooperateed with ART cotransport, tumour response is synchronously released Put, the more mechanism in same site treatment tumour the characteristics of, tumour diagnosis and treatment integration can be achieved.
The mesoporous HMn of double layer hollow prepared by the present invention2O3There is larger pore volume, its hollow and duct inside nanoparticle Structure can load medicine, specific surface area is big, has very high Drug loadings ability.Found in experiment in human body neutral environment Under, HMn2O3It is capable of the integrality of holding structure, and in tumor locus slant acidity and strong reducing property microenvironment, HMn2O3Structure Meeting progressively ablation, generates Mn2+, the medicine of one side load discharges into tumour cell, realizes tumour target site Mn therewith2+With The purpose discharged with one-step site, reduce the toxic side effect of medicine；Another aspect Mn2+Generation cause tumour cell lysosome permeate Pressure rise, produces lysosome escape phenomenon, in addition, Mn2+Be incubated altogether with ART can destroy ART peroxide bridge make its produce free radical, Destruction of the free radical to tumour cell lysosome membrane can accelerate lysosome escape and cell nucleus targeting, significantly increase ART pairs The toxicity of tumour cell.Thus prepare Mn2+It is most important to the antitumor action for strengthening ART with ART symport systems.Strengthening Have tumour response release pharmic function while antitumous effect concurrently.
Due to the protective effect of hollow ball shell, medicine can avoid and plasma protein or other biological point in course of conveying Son interaction, therefore, can protect medicine to avoid being digested.In addition, the high concentration Mn that the carrier provides in tumor locus2+It can show Enhancing magnetic resonance imaging is write, realizes the diagnosis and treatment integration of tumour.
Mn of the present invention2+Donor and ART cooperate with the medicine-carried system that cotransports, by Mn2+Donor（HMn2O3Carrier）And ART compositions； Load ART HMn2O3Tumour cell is entered by endocytosis, is further distributed among the acidic organelles such as endosome and lysosome In, HMn2O3Decomposed under acid and reproducibility environment, generate and discharge Mn2+, Mn2+Association is produced by non-enzymatic reaction and ART Same-action, so as to effectively kill cancer cell, significantly enhance ART antitumous effect.
The present invention utilizes HMn2O3Structure, which is destroyed, in tumor environment produces Mn2+Instead of conventional Fe2+With the peroxide in ART Bridge reacts, and is found that this is passed medicine body system and passes through two kinds of mechanism in therapy mechanism（On the one hand：Mn2+Generation along with molten The rise of osmotic pressure, causes lysosome to rise brokenly in enzyme body, lysosome escape occurs, hence into nucleus；On the other hand：Mn2+ Reaction with ART produces free radical, so as to change the stability of lysosome membrane, causes medicine out to enter cell from lysosome Core.）Lysosome escape and cell nucleus targeting are realized, damages of the enhancing ART to DNA, significantly improves antitumous effect.Meanwhile The Mn of tumor locus aggregation2+NMR imaging function can be significantly increased, realizes the diagnosis and treatment integration of tumour.
The present invention uses Mn2+Cotransported with ART, produce lysosome escape and cell nucleus targeting phenomenon, it is anti-swollen to play collaboration Knurl acts on and Mn2+NMR imaging function, realize to tumour diagnosis and treatment integration.
Hollow mesoporous door-control type Mn2+Donor and ART collaborations cotransport and can significantly increase antitumor action
Described Mn2+Donor and ART collaborations cotransport medicine-carried system, available for inject, oral or drug delivery implant.Wherein inject Optimizing injection, freeze-dried powder is administered, oral administration preferably is selected from tablet, capsule, pill, syrup, granule, drug delivery implant It preferably is selected from gel, solution.
Described mesoporous door-control type Mn2+Donor and ART cotransport medicine-carried system, available for tumour medicine delivery system, lead to Cross appropriate modification and target administration, internal long circulating etc. can be achieved.
The present invention achieves consistent result by repeatedly testing repeatedly, and relevant experimental data is as follows
Experiment 1：Hollow mesoporous manganese sesquioxide managnic oxide（Hollow Mn2O3, HMn2O3）Mn of the nanoparticle under sour environment2+Generation is surveyed It is fixed
Prepare 100 μ g/ml HMn2O3The aqueous solution, solvent are respectively that the phosphate PBS of different pH=7.4 (is simulated normal Body fluid) and pH=4.0, GSH 5mM/L（Simulate tumour cell lysosome）, 100r/min, shake under the conditions of 37 DEG C, Mei Geyi Fix time and take out part, using Mn2+Kit measurement Mn2+Concentration.As a result HMn is shown2O3It is easier to decompose under sour environment Produce Mn2+, this shows HMn2O3In acidic cancer and the release Mn of strong reducing property position meeting environmental sensitivity2+, with qinghaosu （ART）Produce synergy.
Experiment 2：HMn2O3Load ART preparation
Weigh 10mg HMn2O3, add in 10ml ultra-pure waters, it is standby that 400W ultrasounds 20min makes it be uniformly dispersed in water.So After weigh 30mg ART and be dissolved in 3ml ethanol, ART mother liquors are obtained, in the presence of 400W ultrasounds, ice-water bath, by ART mother liquors Slowly it is added drop-wise to HMn2O3In solution, after being added dropwise, continue ultrasonic 0.5h, ART is fully diffused under strenuous exercise HMn2O3Mesopore orbit and hollow structure in, then by above-mentioned solution Probe Ultrasonic Searching（300W, 10 times, each 6s）, centrifugation （4000r/min, 5min）, it is then placed in bag filter（Molecular cut off MW=3500Da) in dialysis remove organic solvents and trip within 2 days From medicine, freeze-drying 48h obtains load ART HMn2O3（HMn2O3/ART）, saved backup at 4 DEG C.
Experiment 3：HMn2O3Medicine controlled releasings of/the ART under sour environment
By HMn2O3/ ART is placed in bag filter（The Da of molecular cut off MW=3500）In, immerse the phosphate PBS of different pH value Buffer solution（7.4：Simulate normal body fluid, 6.5：Simulate tumor tissues and pH=4.0, CGSH=5mM/L：Simulate lysosome）In, 100r/min, shake under the conditions of 37 DEG C, take out part at regular intervals, ART, measure are determined using ultraviolet ultraviolet spectrometer Its concentration simultaneously calculates rate of release.As a result show that said preparation drug release has obvious acidity sensitiveness, drug release rate is：pH4.0> pH6.5> pH7.4。
Experiment 4：HMn2O3The intracellular behavior of/ART medicine-carried systems
Cytologic experiment designs 1. FITC；②HMn2O3 ；③HMn2O3Tri- groups of/ART/FITC, passes through 1h, 2h, 4h, 6h administration The dyeing of lysosome red fluorescence, the dyeing of nucleus blue-fluorescence dyeing are carried out behind interval, it is carried out using laser co-focusing Take pictures, investigate the escape of its lysosome and cell nucleus targeting behavior.As a result show 1. FITC groups only have lysosome red fluorescence and Nucleus blue-fluorescence；②HMn2O3The lysosome escape of group and cell nucleus targeting have time dependence, and portion is begun with 4h Divide and escaped from from lysosome into nucleus, no matter 6h enters the quantity of nucleus or lysosome escape and cell nucleus targeting occurs Cell number all increase significantly；③HMn2O3The lysosome escape phenomenon of/FITC groups becomes apparent, the nearly all cells of 6h Interior carrier is all distributed in nucleus from lysosome escape.Destructions of the ART to nucleus is greatly enhanced by this mechanism, Nucleus is set to produce cavity, antitumous effect also significantly improves.
Experiment 5：HMn2O3The antitumor cytolytic activity of/ART medicine-carried systems
Anti tumor activity in vitro（Using Mouse mammary cells strain MCF-7 as research object）：Time effect：Use HMn2O3/ ART pairs Cell carries out single treatment, and its inhibitory action to growth of tumour cell is investigated in different time points（Srb assay）；Dosage effect： With various dose HMn2O3/ ART handles cell, and its inhibitory action to growth of tumour cell is investigated by srb assay.
Experiment is all provided with different experiments group above：HMn2O3、ART、HMn2O3/ART.As a result HMn is shown2O3/ ART is to cell Inhibitory action has obvious time dependence and concentration dependent, and ART and HMn2O3With significant collaboration tumor-inhibiting action；
Internal antitumor activity：MCF-7 cells are inoculated into the subcutaneous of nude mice flank, monitor the growing state of tumour every other day, and Record the general status of nude mice.When gross tumor volume reaches 100-300 mm3When, animal is grouped to simultaneously start to process at random（Vein Injection）：①ART；②HMn2O3；③HMn2O3/ART.Set saline control group and positive controls simultaneously.Continuous monitoring swells Knurl volume is untill animal is put to death.During by the 7th week, all mouse are put to death, tumour is taken out, weighs.Increase according to Relative tumor Grow rate T/C evaluation effects.
Test result indicates that compared to other groups, HMn2O3/ ART achieves significant Suppressive effect, Relative tumor in vivo Appreciation rate is minimum.
The present invention has the following advantages and advantages relative to prior art：
（1）The present invention uses HMn2O3 As ART carrier, Mn is 1. realized2+Donor cotransports with cooperateing with for ART, plays tumour Synergistic therapeutic action, the dosage and toxic side effect of medicine are significantly reduced, improve the therapeutic efficiency of medicine；2. effectively solves it Solubility problem, realize the controlled release of drug payload and medicine in tumour target site；
（2）HMn2O3Mn can be provided in tumor locus2+, Mn2+Can be with Magnetic resonance imaging, can obtain other imaging techniques can not It is close or be difficult to image close to position, it is integrated with diagnosis and treatment of the medicine cooperative achievement of institute load to tumour.With safety, soon The features such as fast, accurate clinical diagnosis；
（3）HMn2O3Under conditions of acidic cancer and strong reducing property, structure destroys release Mn2+, realize that osmotic pressure raises, lyase Body is escaped；Mn2+Reacted with ART and destroy peroxide bridge, discharge free radical, infringement, enhancing lysosome escape are produced to organelle film.Medicine After thing realizes lysosome escape in vivo, the characteristic of cell nucleus targeting is shown, ART antitumor action can be significantly increased.

Claims (6)

  1. A kind of 1. hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport the preparation method of system, it is characterised in that including with Lower step：
    （1）HMn2O3Synthesis：10-45g sucrose is added in 15-180mL deionized waters, reacts 3-7h at 145-295 DEG C, 12500-14000rpm centrifuges 9-11min, abandons supernatant, and precipitation is respectively washed 2-3 times with deionized water and absolute ethyl alcohol successively, 55- Dried at 59 DEG C, obtain black carbon powder；0.5-4.5g carbon dusts are weighed, 15- is added dropwise in 10-45mL deionized waters in ultrasonic disperse Mn (the NO of 45mL mass concentration 50%3)2Solution, ultrasonic disperse 13-16min, impregnate 30-70h, stirring, 12500- 13500rpm centrifuges 28-33min, abandons supernatant, precipitation is respectively washed 2-3 times with deionized water and absolute ethyl alcohol successively, at 55-65 DEG C Dry, be calcined 3-9h at 350-650 DEG C, produce HMn2O3；
    （2）HMn2O3Load the preparation of qinghaosu：Weigh 5-20mg steps（1）The HMn of preparation2O3It is added to 2-40ml deionizations In water, Probe Ultrasonic Searching dissolving, HMn is obtained2O3Solution, weigh 20-40mg qinghaosus and be dissolved in 2-5ml ethanol, then with HMn2O3 Solution mixes, and ice-bath ultrasonic process 0.5-1h, the 2- that dialyses is put into molecular cut off MW=3500Da bag filter after being stirred at room temperature 3 days, freeze-drying, obtain hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport system.
  2. 2. hollow mesoporous door-control type Mn according to claim 12+Donor and qinghaosu cotransport the preparation and application of system, It is characterised in that it includes following steps：
    （1）HMn2O3Synthesis：10g sucrose is added in 15mL deionized waters, 7h, 12500rpm centrifugations are reacted at 145 DEG C 11min, supernatant is abandoned, precipitation is dried with deionized water and absolute ethyl alcohol respectively washing 2 times, 55 DEG C successively, obtains black carbon powder；Weigh Mn (the NO of 15mL mass concentration 50% are added dropwise in 10mL deionized waters in 0.5g carbon dusts, ultrasonic disperse3)2Solution, ultrasonic disperse 13min, 70h is impregnated, stirring, 12500rpm centrifugation 33min, abandons supernatant, precipitation is respectively washed with deionized water and absolute ethyl alcohol successively Wash 2 times, dried at 55 DEG C, be calcined 9h at 350 DEG C, produce HMn2O3；
    （2）HMn2O3Load the preparation of qinghaosu：Weigh 5mg steps（1）The HMn of preparation2O3It is added in 2ml deionized waters, visits Head ultrasonic dissolution, obtains HMn2O3Solution, weigh 20mg qinghaosus and be dissolved in 2ml ethanol, then with HMn2O3Solution mixes, ice bath 0.5h is ultrasonically treated, is put into after being stirred at room temperature in molecular cut off MW=3500Da bag filter, is dialysed 2 days, freeze-drying, is obtained Hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport system.
  3. 3. hollow mesoporous door-control type Mn according to claim 12+Donor and qinghaosu cotransport the preparation and application of system, It is characterised in that it includes following steps：
    （1）HMn2O3Synthesis：30g sucrose is added in 100mL deionized waters, 4h, 13000rpm centrifugations are reacted at 200 DEG C 10min, supernatant is abandoned, precipitation is dried with deionized water and absolute ethyl alcohol respectively washing 3 times, 57 DEG C successively, obtains black carbon powder；Weigh Mn (the NO of 30mL mass concentration 50% are added dropwise in 30mL deionized waters in 2.0g carbon dusts, ultrasonic disperse3)2Solution, ultrasonic disperse 15min, 48h is impregnated, stirring, 13000rpm centrifugation 30min, abandons supernatant, precipitation is respectively washed with deionized water and absolute ethyl alcohol successively Wash 3 times, dried at 60 DEG C, be calcined 5h at 500 DEG C, produce HMn2O3；
    （2）HMn2O3Load the preparation of qinghaosu：Weigh 10mg steps（1）The HMn of preparation2O3It is added in 20ml deionized waters, Probe Ultrasonic Searching dissolves, and obtains HMn2O3Solution, weigh 25mg qinghaosus and be dissolved in 3ml ethanol, then with HMn2O3Solution mixes, ice Bath is ultrasonically treated 0.5h, is put into molecular cut off MW=3500Da bag filter and dialyses 2 days after being stirred at room temperature, and is freeze-dried, obtains Hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport system.
  4. The preparation of system and should 4. hollow mesoporous door-control type Mn2+ donors according to claim 1 and qinghaosu cotransport With, it is characterised in that comprise the following steps：
    （1）HMn2O3Synthesis：45g sucrose is added in 180mL deionized waters, 3h, 14000rpm centrifugations are reacted at 295 DEG C 9min, supernatant is abandoned, precipitation is dried with deionized water and absolute ethyl alcohol respectively washing 3 times, 59 DEG C successively, obtains black carbon powder；Weigh Mn (the NO of 45ml mass concentration 50% are added dropwise in 45mL deionized waters in 4.5g carbon dusts, ultrasonic disperse3)2Solution, ultrasonic disperse 16min, 70h is impregnated, stirring, 13500rpm centrifugation 28min, abandons supernatant, precipitation is respectively washed with deionized water and absolute ethyl alcohol successively Wash 3 times, dried at 65 DEG C, be calcined 3h at 650 DEG C, produce HMn2O3；
    （2）HMn2O3Load the preparation of qinghaosu：Weigh 20mg steps（1）The HMn of preparation2O3It is added in 40ml deionized waters, Probe Ultrasonic Searching dissolves, and obtains HMn2O3Solution, weigh 40mg qinghaosus and be dissolved in 5ml ethanol, then with HMn2O3Solution mixes, ice Bath is ultrasonically treated 1h, is put into molecular cut off MW=3500Da bag filter and dialyses 3 days after being stirred at room temperature, and is freeze-dried, in obtaining Empty mesoporous door-control type Mn2+Donor and qinghaosu cotransport system.
  5. 5. hollow mesoporous door-control type Mn prepared by any one of claim 1 or 2-4 methods described2+Donor and qinghaosu cotransport body The particle diameter of system is 50-300 nm.
  6. 6. hollow mesoporous door-control type Mn prepared by any one of claim 1 or 2-4 methods described2+Donor and qinghaosu cotransport body The application in antineoplastic is prepared of system.
CN201710962097.8A 2017-10-16 2017-10-16 Hollow mesoporous gated Mn2+Preparation and application of donor and artemisinin co-transport system Active CN107648612B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710962097.8A CN107648612B (en) 2017-10-16 2017-10-16 Hollow mesoporous gated Mn2+Preparation and application of donor and artemisinin co-transport system

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710962097.8A CN107648612B (en) 2017-10-16 2017-10-16 Hollow mesoporous gated Mn2+Preparation and application of donor and artemisinin co-transport system

Publications (2)

Publication Number Publication Date
CN107648612A true CN107648612A (en) 2018-02-02
CN107648612B CN107648612B (en) 2020-01-10

Family

ID=61118742

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710962097.8A Active CN107648612B (en) 2017-10-16 2017-10-16 Hollow mesoporous gated Mn2+Preparation and application of donor and artemisinin co-transport system

Country Status (1)

Country Link
CN (1) CN107648612B (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105056244A (en) * 2015-08-01 2015-11-18 郑州大学 Mesoporous gating Fe<2+> donor and Fe<2+>-dependence anti-tumor medicine cotransport system, and preparation method and application thereof
CN106344925A (en) * 2016-08-25 2017-01-25 郑州大学 Preparation and application of cotransport system of Mn<2+> donor and chloroquine drugs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105056244A (en) * 2015-08-01 2015-11-18 郑州大学 Mesoporous gating Fe<2+> donor and Fe<2+>-dependence anti-tumor medicine cotransport system, and preparation method and application thereof
CN106344925A (en) * 2016-08-25 2017-01-25 郑州大学 Preparation and application of cotransport system of Mn<2+> donor and chloroquine drugs

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHENGCHENG QI ET AL.: "Novel nonenzymatic hydrogen peroxide sensor based on Fe3O4/PPy/Ag nanocomposites", 《JOURNAL OF ELECTROANALYTICAL CHEMISTRY》 *
JINJIN SHI ET AL.: "A tumoral acidic pH-responsive drug delivery system based on a novel photosensitizer (fullerene) for in vitro and in vivo chemo-photodynamic therapy", 《ACTA BIOMATERIALIA》 *
ZHAOWEI CHEN ET AL.: "Bioresponsive Hyaluronic Acid-Capped Mesoporous Silica Nanoparticles for Targeted Drug Delivery", 《 CHEMISTRY A EUROPEAN JOURNAL》 *

Also Published As

Publication number Publication date
CN107648612B (en) 2020-01-10

Similar Documents

Publication Publication Date Title
CN106177986B (en) A kind of lipid-polymer medicine-carried nano particles and its preparation method and application
Stowe et al. Mitochondrial reactive oxygen species production in excitable cells: modulators of mitochondrial and cell function
Sun et al. Ultrasound-mediated destruction of oxygen and paclitaxel loaded lipid microbubbles for combination therapy in hypoxic ovarian cancer cells
Liu et al. Ultrasound-mediated destruction of paclitaxel and oxygen loaded lipid microbubbles for combination therapy in ovarian cancer xenografts
Jin et al. The combined administration of parthenolide and ginsenoside CK in long circulation liposomes with targeted tLyp-1 ligand induce mitochondria-mediated lung cancer apoptosis
CN105288622B (en) The preparation method of chemotherapeutics and the cell membrane vesicles of optical dynamic therapy medicine is loaded simultaneously
CN110743012A (en) Preparation method and application of glucose oxidase modified mesoporous manganese dioxide pharmaceutical composition
Yuan et al. Protective effect of astaxanthin against La2O3 nanoparticles induced neurotoxicity by activating PI3K/AKT/Nrf-2 signaling in mice
Gao et al. Selective decoating-induced activation of supramolecularly coated toxic nanoparticles for multiple applications
Shanmugan et al. Chronotherapeutic drug delivery systems
Singh et al. Contemporary mesoporous materials for drug delivery applications: A review
CN105056244B (en) A kind of Fe of mesoporous door-control type2+Donor and Fe2+Dependence antineoplastic cotransports system and preparation method and application
Li et al. Chitosan-modified hollow manganese dioxide nanoparticles loaded with resveratrol for the treatment of spinal cord injury
Wang et al. Mitochondria-targeting folic acid-modified nanoplatform based on mesoporous carbon and a bioactive peptide for improved colorectal cancer treatment
CN104174036B (en) A kind of nano-micelle for realizing diagnosis and treatment integration and its preparation method and application
Fayyaz et al. Dextran-based oxygen nanobubbles for treating inner retinal hypoxia
Wang et al. Library screening to identify highly-effective autophagy inhibitors for improving photothermal cancer therapy
CN101229130B (en) Isomorellic acid polylactic acid nano particle preparation and preparing method thereof
CN107648612A (en) A kind of hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport the preparation and application of system
Gherasim et al. Biodistribution of essential oil-conjugated silver nanoparticles
CN113398135B (en) Nano system for HILI in-situ detection and drug release
CN106344925B (en) A kind of Mn2+Donor and chloroquine class drug cotransport the preparation and application of system
CN107970447A (en) Tool targeting and lipid-poly- anoxic radiotherapeutic sensitizer of radio therapy sensitization dual-use function
CN109481418A (en) Anti-tumor nano particle and its preparation method and application
Reiländer et al. Oral Use of Therapeutic Carbon Monoxide for Anyone, Anywhere, and Anytime

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