CN106344925A - Preparation and application of cotransport system of Mn<2+> donor and chloroquine drugs - Google Patents
Preparation and application of cotransport system of Mn<2+> donor and chloroquine drugs Download PDFInfo
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- CN106344925A CN106344925A CN201610722078.3A CN201610722078A CN106344925A CN 106344925 A CN106344925 A CN 106344925A CN 201610722078 A CN201610722078 A CN 201610722078A CN 106344925 A CN106344925 A CN 106344925A
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- 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
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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Abstract
The invention relates to preparation and application of a cotransport system of a Mn<2+> donor and chloroquine drugs. According to the preparation and the application, the problems of low pesticide effect, large required dosage, poor targeting ability and serious toxic and side effects of tumor treating drugs can be effectively solved. According to the technical scheme, double-layer hollow mesoporous manganese sesquioxide nanoparticles are synthesized by virtue of a hydrothermal method, hyaluronic acid and the double-layer hollow mesoporous manganese sesquioxide nanoparticles are linked through chemical bonds so as to spontaneously form a nano-layer in a water medium, and then a chloroquine anti-tumor drug enters mesoporous structures of the double-layer hollow mesoporous manganese sesquioxide nanoparticles through a physical effect. According to the drug-cooperated cotransport system, the dosage and toxic and side effects of the drug can be effectively reduced, the treating efficiency of the drug can be improved, the solubility problem of the drug can be effectively solved, and the effective loading of the drug and the controlled release of the drug at target sites of tumors can be realized; the dispersity and biocompatibility of magnetic carriers are improved, the long circle, the active targeting and the fixed-point gate-controlled release of the drug are realized; and furthermore, the preparation process is simple, energy saving, environmentally friendly and low in cost, the industrial production can be realized, and the preparation process is the innovation of the tumor treating drugs.
Description
Technical field
The invention belongs to field of medicine and chemical technology, particularly a kind of mn2+Donor and chloroquine class medicine cotransport the preparation of system
And a kind of application (the i.e. mesoporous door-control type mn of hollow2+Donor and chloroquine series antineoplastic medicament work in coordination with the preparation method of the system of cotransporting
And should).
Background technology
1st, hollow mesoporous door-control type mn2+Donor and chloroquine series antineoplastic medicament are worked in coordination with to cotransport and can be significantly increased therapeutical effect
Chloroquine class medicine (chloroquine, cq) is the antimalarial old medicine of a class, and Recent study finds to control using chloroquine suppression
The autophagy treating induction can promote death of neoplastic cells, lead to tumor regression to sexually revise, delay tumour growth.1992,
Djordevic etc. reports, chloroquine can affect people's mda-mb231 cancerous cell by radiating sensitization, makes lysosome and cell
Film loss of stability.Therefore, chloroquine also has very strong lethal effect to tumor cell.
But the ic to tumor cell for the chloroquine50Larger, therefore antitumor required dosage is big, and drug effect is relatively low.Secondly, simple
Chloroquine is poor to tumor-targeting, low in tumor locus aggregate concentration, does not reach effectively treatment concentration it is impossible to cause tumor cell certainly
Bite and effectively play antitumor action.Additionally, chloroquine class medicine metabolism is fast in vivo.
Such medicine so how is made farthest to play antitumor action？Design mn2+Donor and chloroquine class are anti-swollen
Tumor medicine works in coordination with the system of cotransporting will this problem of effectively solving.We test discovery mn2+Energy worked in coordination with by carrier and chloroquine class medicine
Significantly increase the toxicity to tumor cell for the chloroquine, and tool inside our prepared double layer hollows mesoporous manganese sesquioxide managnic oxide nanoparticle
Have larger hollow structure, its hollow and pore passage structure all can load medicine, specific surface area is big, has very high Drug loadings energy
Power.And there is tumor response type release function.Under human body neutral environment, manganese sesquioxide managnic oxide (hmn2o3) being capable of holding structure
Integrity, and under tumor locus slant acidity and strong reducing property environment, hmn2o3Structure can progressively ablation, generate mn2+Meanwhile,
The medicine of load discharges into tumor cell therewith, realizes the purpose of tumor target site fixed-point drug releasing, reduces the secondary work of poison of medicine
With.Simultaneously because the protective effect of hollow ball shell, medicine can avoid dividing with plasma protein or other biological in course of conveying
Son interacts, and therefore, medicine can be protected to avoid being digested.Additionally, high concentration mn that this carrier provides in tumor locus2+Can show
Write and strengthen nuclear magnetic resonance, realize the diagnosis and treatment integration of tumor.
2nd, hyaluronic acid (ha) modifies the advantage of nano-carrier
Because of its hydrophilic, good biocompatibility, biodegradability, non-immunogenic, tumor-targeting, (receptor is ha
) etc. cd44 advantage is applied in medicine novel Drug Delivery Systems as pharmaceutical carrier or targeted molecular, and has become swollen in recent years
The focus of tumor Therapy study, is widely used in the aspects such as targeted molecular imaging, targeted drug and gene therapy.Gate material
The nanoparticle that ha modifies not only can increase its hydrophilic and stability, extend blood circulation time, reach Continuous slow release release
Purpose moreover it is possible to improve nanoparticle tumor-targeting, reduce its toxic and side effects to normal cell.
Content of the invention
For the problems referred to above, for solving the defect of prior art, it is an object of the invention to provide a kind of mn2+Donor and chlorine
Quinoline class medicine cotransports the preparation of system and application, can effectively solving anti-tumor medicine drug effect low, required dosage is big, targeting
The big problem of difference, toxic and side effects.
The technical scheme is that a kind of mn2+Donor and chloroquine class medicine cotransport the preparation method of system, by water
Full-boiled process synthesizes double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle, and hyaluronic acid is led to double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle
Cross chemical bonded, aqueous medium spontaneously forms nanometer layer, then chloroquine series antineoplastic medicament is double by physical action entrance
In the meso-hole structure of layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle；Described mn2+Donor and chloroquine class medicine cotransport system
Particle diameter is 50-300nm；The high molecular weight hyaluronic acid that described hyaluronic acid is 12000 kd for molecular weight；
Specifically include following steps:
(1) synthesis of double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle: 5-50g sucrose is added to 10-200ml deionized water
In, 140-300 DEG C of baking oven reacts 2-8h, 12000rpm is centrifuged 8-12min, will be each to precipitate with deionized water and dehydrated alcohol
Washing 2-3 time, dries at 60 DEG C, obtains black carbon powder；Weigh 0.1-5g carbon dust, ultrasonic disperse, in 5-50ml deionized water, drips
Plus the manganese sesquioxide managnic oxide solution that 10-50ml mass concentration is 50%, after ultrasonic disperse 12-17min, impregnate 24-72h, stir,
12000rpm is centrifuged 25-35min, and precipitate with deionized water and dehydrated alcohol are respectively washed 2-3 time, dries at 50-70 DEG C,
Roasting 2-10h at 300-700 DEG C, obtains double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle；
(2) reaction of hyaluronic acid and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle: weigh 1- ethyl-(3- dimethyl respectively
Aminopropyl) carbodiimide hydrochloride) 300-500mg, n- N-Hydroxysuccinimide 150-300mg and mesoporous three oxygen of double layer hollow
Change two manganese nanoparticle 40-60mg, be dissolved in respectively in 5-20ml Methanamide, obtain 1- ethyl-(3- dimethylaminopropyl) carbon two sub-
Amine hydrochlorate) formamide solution, n- N-Hydroxysuccinimide formamide solution and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle
Formamide solution, by 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide solution, n- hydroxysuccinimidyl acyl
Imines formamide solution is slowly added in double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution, and reaction is stirred at room temperature
15min, obtains mixed solution；Weigh 10-100mg hyaluronic acid to be dissolved in 1-20ml Methanamide, obtain hyaluronic acid Methanamide molten
Liquid；Above-mentioned mixed solution is added dropwise in hyaluronic acid formamide solution, room temperature reaction 12-24h；Add the acetone ice of pre-cooling
Bath crystallize, sucking filtration, dialyse 48-72h, changes liquid every 8h, removes Methanamide and unnecessary hyaluronic acid, and lyophilization obtains hyalomitome
Acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle；
(3) preparation of hyaluronic acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanometer particle loading chloroquine class medicine: weigh 5-20mg
Hyaluronic acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle, is added in 2-40ml deionized water, ultrasonic dissolution, with 5-
60ml chloroquine class pharmaceutical aqueous solution mixes, and processes through ultrasonic or high pressure homogenize, removes organic solvent and free medicine after being stirred at room temperature
Thing, lyophilization obtains hollow mesoporous door-control type mn2+Donor works in coordination with, with chloroquine series antineoplastic medicament, the system that cotransports.
The mn of methods described preparation2+Donor and chloroquine class medicine cotransport application in preparing antitumor drug for the system,
This delivery system can be used for injection, oral or drug delivery implant.Wherein drug administration by injection optimizing injection, freeze-dried powder, be administered orally to
Medicine preferably is selected from tablet, capsule, pill, syrup, granule, and drug delivery implant preferably is selected from gel, solution.
The mn of methods described preparation2+Donor and chloroquine class medicine cotransport system preparation for tumor locus targeting to
Medicine, the acidity sensitivity release of tumor locus, chemotherapeutical tumor many mechanism treatment of tumor and the diagnosis and treatment one chemical medicine of tumor
Application in thing.
Mn of the present invention2+Donor and the chloroquine class medicine system of cotransporting can significantly reduce using dosage and the secondary work of poison of medicine
With improving the therapeutic efficiency of medicine, its solubility problem of effectively solving, realizing drug payload and medicine in tumor target site
Controlled release；Improve dispersibility and the biocompatibility of magnetic carrier, realize long circulating, active targeting, medicine fixed point gate release
Put, and preparation process is simple, energy-conserving and environment-protective, low cost, it is capable of industrialized production, be the wound on anti-tumor medicine
Newly.
Specific embodiment
With reference to embodiments the specific embodiment of the present invention is elaborated.
The present invention, in being embodied as, is to be realized by following examples.
Embodiment 1
The mesoporous door-control type mn of hollow of the present invention2+Donor and chloroquine series antineoplastic medicament work in coordination with the preparation of the system of cotransporting
Method, comprises the following steps:
(1) synthesis of double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle: 16g sucrose is added in 80ml deionized water, 190
React 4h in DEG C baking oven, 12000rpm is centrifuged 10min, precipitate with deionized water and each washing of dehydrated alcohol 3 times are dried at 60 DEG C
Dry, obtain black carbon powder；Weigh 1g carbon dust, in 10ml deionized water, Deca 40ml mass concentration is 50% three oxygen to ultrasonic disperse
Change two manganese solutions, after ultrasonic disperse 15min, impregnate 48h, stirring, 12000rpm is centrifuged 20min, by precipitate with deionized water and
The each washing of dehydrated alcohol 3 times, dries at 60 DEG C, roasting 6h at 450 DEG C, obtains double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle；
Obtained carbon dust mean diameter is at 1.5 ~ 2 μm about；Double layer hollow mesoporous manganese sesquioxide managnic oxide particle diameter in 200nm, good dispersion,
Current potential is -28.4mv；
(2) reaction of hyaluronic acid and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle: weigh 1- ethyl-(3- dimethyl respectively
Aminopropyl) carbodiimide hydrochloride) 346mg, n- N-Hydroxysuccinimide 206mg and the mesoporous manganese sesquioxide managnic oxide of double layer hollow receive
Grain of rice 50mg, is dissolved in 15ml Methanamide respectively, obtains 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) formyl
Amine aqueous solution, n- N-Hydroxysuccinimide formamide solution and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution, will
1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide solution, n- N-Hydroxysuccinimide formamide solution
It is slowly added in double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution, reaction 15min is stirred at room temperature, must mix molten
Liquid；Weigh 50mg hyaluronic acid to be dissolved in 10ml Methanamide, obtain hyaluronic acid formamide solution；By above-mentioned mixed solution Deca
Enter in hyaluronic acid formamide solution, room temperature reaction 18h；Add the acetone ice bath crystallize of pre-cooling, sucking filtration, dialyse 56h, every 8h
Change liquid, remove Methanamide and unnecessary hyaluronic acid, lyophilization obtains hyaluronic acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanometer
Grain；The ha-hmn that ha modifies2o3Uniform particle diameter, in 240nm, favorable dispersibility, current potential is -23.8mv to mean diameter.
(3) preparation of hyaluronic acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanometer particle loading chloroquine class medicine: weigh 10mg
Hyaluronic acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle, is added in 10ml deionized water, ultrasonic dissolution, with 20ml chlorine
Quinoline class pharmaceutical aqueous solution mixes, and processes through ultrasonic or high pressure homogenize, removes organic solvent and free drug, freezing after being stirred at room temperature
Dry hollow mesoporous door-control type mn2+Donor works in coordination with, with chloroquine series antineoplastic medicament, the system that cotransports.
Embodiment 2
The mesoporous door-control type mn of hollow of the present invention2+Donor and chloroquine series antineoplastic medicament work in coordination with the preparation of the system of cotransporting
Method, comprises the following steps:
(1) synthesis of double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle: 5g sucrose is added in 10ml deionized water, 140
React 2h in DEG C baking oven, 12000rpm is centrifuged 8min, precipitate with deionized water and each washing of dehydrated alcohol 2 times are dried at 60 DEG C
Dry, obtain black carbon powder；Weigh 0.1g carbon dust, in 5ml deionized water, Deca 10ml mass concentration is the three of 50% to ultrasonic disperse
Aoxidize two manganese solutions, after ultrasonic disperse 12min, impregnate 24h, stirring, 12000rpm is centrifuged 25min, by precipitate with deionized water
With dehydrated alcohol respectively washing 2 times, dry at 50 DEG C, roasting 2h at 300 DEG C, obtain double layer hollow mesoporous manganese sesquioxide managnic oxide nanometer
Grain；
(2) reaction of hyaluronic acid and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle: weigh 1- ethyl-(3- dimethyl respectively
Aminopropyl) carbodiimide hydrochloride) 300mg, n- N-Hydroxysuccinimide 150mg and the mesoporous manganese sesquioxide managnic oxide of double layer hollow receive
Grain of rice 40mg, is dissolved in 5ml Methanamide respectively, obtains 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) Methanamide
Solution, n- N-Hydroxysuccinimide formamide solution and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution, by 1-
Ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide solution, n- N-Hydroxysuccinimide formamide solution delay
Slowly it is added in double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution, reaction 15min is stirred at room temperature, must mix molten
Liquid；Weigh 10mg hyaluronic acid to be dissolved in 1ml Methanamide, obtain hyaluronic acid formamide solution；Above-mentioned mixed solution is added dropwise to
To in hyaluronic acid formamide solution, room temperature reaction 12h；Add the acetone ice bath crystallize of pre-cooling, sucking filtration, dialyse 48h, every 8h
Change liquid, remove Methanamide and unnecessary hyaluronic acid, lyophilization obtains hyaluronic acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanometer
Grain；
(3) preparation of hyaluronic acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanometer particle loading chloroquine class medicine: weigh 5mg transparent
Matter acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle, is added in 2ml deionized water, ultrasonic dissolution, with 5ml chloroquine class medicine
Thing aqueous solution, is processed through ultrasonic or high pressure homogenize, removes organic solvent and free drug after being stirred at room temperature, and lyophilization obtains
Hollow mesoporous door-control type mn2+Donor works in coordination with, with chloroquine series antineoplastic medicament, the system that cotransports.
Embodiment 3
The mesoporous door-control type mn of hollow of the present invention2+Donor and chloroquine series antineoplastic medicament work in coordination with the preparation of the system of cotransporting
Method, comprises the following steps:
(1) synthesis of double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle: 50g sucrose is added in 200ml deionized water,
8h is reacted, 12000rpm is centrifuged 12min in 300 DEG C of baking ovens, by each to precipitate with deionized water and dehydrated alcohol washing 3 times, 60 DEG C
Lower drying, obtains black carbon powder；Weigh 5g carbon dust, in 50ml deionized water, Deca 50ml mass concentration is 50% to ultrasonic disperse
Manganese sesquioxide managnic oxide solution, after ultrasonic disperse 17min, impregnates 72h, stirring, 12000rpm is centrifuged 35min, by precipitation deionization
Water and dehydrated alcohol respectively washing 3 times, dry at 70 DEG C, roasting 10h at 700 DEG C, obtain the mesoporous manganese sesquioxide managnic oxide of double layer hollow and receive
The grain of rice；
(2) reaction of hyaluronic acid and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle: weigh 1- ethyl-(3- dimethyl respectively
Aminopropyl) carbodiimide hydrochloride) 500mg, n- N-Hydroxysuccinimide 300mg and the mesoporous manganese sesquioxide managnic oxide of double layer hollow receive
Grain of rice 60mg, is dissolved in 20ml Methanamide respectively, obtains 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) formyl
Amine aqueous solution, n- N-Hydroxysuccinimide formamide solution and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution, will
1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide solution, n- N-Hydroxysuccinimide formamide solution
It is slowly added in double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution, reaction 15min is stirred at room temperature, must mix molten
Liquid；Weigh 100mg hyaluronic acid to be dissolved in 20ml Methanamide, obtain hyaluronic acid formamide solution；By above-mentioned mixed solution Deca
Enter in hyaluronic acid formamide solution, room temperature reaction 24h；Add the acetone ice bath crystallize of pre-cooling, sucking filtration, dialyse 72h, every
8h changes liquid, removes Methanamide and unnecessary hyaluronic acid, and lyophilization obtains the mesoporous manganese sesquioxide managnic oxide of hyaluronic acid-double layer hollow and receives
The grain of rice；
(3) preparation of hyaluronic acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanometer particle loading chloroquine class medicine: weigh 20mg saturating
Bright matter acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle, is added in 40ml deionized water, ultrasonic dissolution, with 60ml chloroquine
Class pharmaceutical aqueous solution mixes, and processes through ultrasonic or high pressure homogenize, removes organic solvent and free drug after being stirred at room temperature, and freezing is dry
Dry hollow mesoporous door-control type mn2+Donor works in coordination with, with chloroquine series antineoplastic medicament, the system that cotransports.
The invention provides a kind of simple, effective mn2+Donor and chloroquine series antineoplastic medicament work in coordination with corotation delivery medicine body
System.By mn2+Donor (hmn2o3Carrier) and chloroquine class medicine (being represented with oxychloroquine hcq) composition；The hmn of load hcq2o3Pass through
Endocytosiss enter tumor cell, are further distributed among in the acidic organelles such as endosome and lysosome, hmn2o3In sour environment
Lower decomposition, generates and discharges mn2+, mn2+Synergism is produced with hcq by non-enzymatic reaction, thus effectively killing cancerous cell,
Significantly enhance the antitumous effect of hcq.
The present invention is in hmn2o3Surface chemical modification on hyaluronic acid (ha)；Ha is connected to hmn2o3Surface, closure
Its meso-hole structure, after reaching tumor locus, the hyaluronidase of tumor locus makes ha decomposition slough, and discharges medicine, realizes door
Control effect.Reduce release before reaching tumor target site of action for the medicine, realize the fixed point conveying of medicine, farthest improve
The curative effect of medicine.Be finally reached improve its dispersibility and biocompatibility, increase medicine-carried system in vivo circulation time, improve right
The targeting ability of tumor, realize medicine fixed point assemble release purpose.Meanwhile, the mn that tumor locus are assembled2+Core can be significantly increased
Magnetic imaging function, realizes the diagnosis and treatment integration of tumor.
Present invention warp is repeatedly tested repeatedly, all achieves identical effect, related experiment data is as follows:
First, hmn2o3Mn under sour environment2+Generate and measure
Prepare the hmn of 100 μ g/ml2o3Aqueous solution, solvent is respectively the phosphate pbs buffer (7.4: simulation is just of different ph values
Often body fluid and 4.0: simulation lysosome) in, 100r/min, shakes under the conditions of 37 DEG C, takes out part at regular intervals, adopt
mn2+Kit measurement mn2+Concentration.Result shows hmn2o3It is easier to decompose under sour environment and produce mn2+, this shows hmn2o3
Release mn in acidic cancer position meeting environmental sensitivity2+, produce synergism with chloroquine series antineoplastic medicament (as hcq).
2nd, ha-hmn2o3Medicine controlled releasing under the sour environment for/hcq
By ha-hmn2o3/ hcq is placed in (molecular cut off mw=3500 da) in bag filter, the phosphate of immersion different ph values
Pbs buffer (7.4: simulation normal body fluid, 6.5: simulation tumor tissues and 4.0: simulation lysosome) in, 100r/min, 37 DEG C
Under the conditions of shake, at regular intervals take out part, using hplc method measure hcq, measure its concentration and calculate rate of release.Knot
Fruit shows that said preparation release has obvious acidity sensitivity, and drug release rate is: ph4.0 > ph6.5 > ph7.4.
3rd, ha-hmn2o3The antitumor cytolytic activity of/hcq medicine-carried system
Anti tumor activity in vitro (with Mouse mammary cells strain 4t-1 as object of study): time effect: use ha-hmn2o3/ hcq pair
Cell carries out single treatment, and (srb method or other method are surveyed to investigate its inhibitory action to growth of tumour cell in different time points
Fixed)；Dosage effect: use various dose ha-hmn2o3/ hcq processes cell, investigates its inhibitory action to growth of tumour cell
(srb method or other method measure).
Above experiment is all provided with different experiments group: hmn2o3、ha-hmn2o3、hcq、hmn2o3/hcq、ha-hmn2o3/ hcq etc..
Result shows ha-hmn2o3/ hcq has obvious time dependence and concentration dependent to the inhibitory action of cell, and hcq and
ha-hmn2o3Have and significantly work in coordination with tumor-inhibiting action；
Anti-tumor in vivo activity: 4t-1 cell is inoculated into the subcutaneous of nude mice flank, monitors the growing state of tumor every other day, and
The general status of record nude mice.When gross tumor volume reaches 100-300mm3When, by animal random packet and start to process (vein note
Penetrate): 1. hcq；②hmn2o3；③ha-hmn2o3；④hmn2o3/hcq；⑤ha-hmn2o3/hcq.Set saline control group simultaneously
And positive controls.Continuous monitoring gross tumor volume is till animal execution.During by the 7th week, put to death all mices, take out swollen
Tumor, weighs.According to Relative tumor rate of increase t/c evaluation effect.
Result of the test shows compared to other groups, ha-hmn2o3/ hcq achieves significant Suppressive effect in vivo, relatively
Tumor appreciation rate is minimum.
The invention provides a kind of mn2+Donor and chloroquine class medicine cotransport system, select to have high Drug loadings amount and
The hollow mesoporous manganese sesquioxide managnic oxide nanoparticle (hmn of biocompatibility2o3) as matrix material, with chloroquine class medicine as model drug
Thing, builds one kind and has NMR (Nuclear Magnetic Resonance) imaging function, mesoporous door-control type transport of drug system；The particle diameter of this nanometer system is 50-
300nm, size uniformity, good dispersion；This system mainly has the following characteristics that 1) this carrier is in tumor faintly acid and reproducibility
Can be used as mn under specific environment2+Donor, realizes chloroquine series antineoplastic medicament and mn2+Donor is worked in coordination with and is cotransported, and strengthens chloroquine class medicine
Thing antitumor action；2) mn that tumor locus generate2+Nuclear magnetic resonance can be significantly increased, realize the diagnosis and treatment integration of tumor；3)
Chloroquine class drugs against tumor required dosage is big, hmn2o3The high drug capacity of double layer hollow loose structure, can effectively solving chloroquine class
The problem that antitumor drug dissolubility is poor, dosage is big, and medicine can be made in target site slow release；4) carrier has gate release and master
Dynamic target function.
Claims (6)
1. a kind of mn2+Donor and chloroquine class medicine cotransport system preparation method it is characterised in that by hydro-thermal method synthesis pair
Layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle, hyaluronic acid is bonded by chemistry with double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle
Connect, aqueous medium spontaneously forms nanometer layer, then chloroquine series antineoplastic medicament is mesoporous by physical action entrance double layer hollow
In the meso-hole structure of manganese sesquioxide managnic oxide nanoparticle；Described mn2+The cotransport particle diameter of system of donor and chloroquine class medicine is 50-
300nm；The high molecular weight hyaluronic acid that described hyaluronic acid is 12000 kd for molecular weight；
Specifically include following steps:
(1) synthesis of double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle: 5-50g sucrose is added to 10-200ml deionized water
In, 140-300 DEG C of baking oven reacts 2-8h, 12000rpm is centrifuged 8-12min, will be each to precipitate with deionized water and dehydrated alcohol
Washing 2-3 time, dries at 60 DEG C, obtains black carbon powder；Weigh 0.1-5g carbon dust, ultrasonic disperse, in 5-50ml deionized water, drips
Plus the manganese sesquioxide managnic oxide solution that 10-50ml mass concentration is 50%, after ultrasonic disperse 12-17min, impregnate 24-72h, stir,
12000rpm is centrifuged 25-35min, and precipitate with deionized water and dehydrated alcohol are respectively washed 2-3 time, dries at 50-70 DEG C,
Roasting 2-10h at 300-700 DEG C, obtains double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle；
(2) reaction of hyaluronic acid and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle: weigh 1- ethyl-(3- dimethylamino
Propyl group) carbodiimide hydrochloride) 300-500mg, n- N-Hydroxysuccinimide 150-300mg and double layer hollow mesoporous three oxidation two
Manganese nanoparticle 40-60mg, is dissolved in 5-20ml Methanamide respectively, obtains 1- ethyl-(3- dimethylaminopropyl) carbodiimide salt
Hydrochlorate) formamide solution, n- N-Hydroxysuccinimide formamide solution and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle formyl
Amine aqueous solution, by 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide solution, n- N-Hydroxysuccinimide
Formamide solution is added in double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution, reaction 15min is stirred at room temperature, obtains
Mixed solution；Weigh 10-100mg hyaluronic acid to be dissolved in 1-20ml Methanamide, obtain hyaluronic acid formamide solution；Will be above-mentioned
Mixed solution is added dropwise in hyaluronic acid formamide solution, room temperature reaction 12-24h；Add the acetone ice bath crystallize of pre-cooling, take out
Filter, dialyse 48-72h, changes liquid every 8h, removes Methanamide and unnecessary hyaluronic acid, lyophilization, obtains hyaluronic acid-bilayer
Hollow mesoporous manganese sesquioxide managnic oxide nanoparticle；
(3) preparation of hyaluronic acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanometer particle loading chloroquine class medicine: weigh 5-20mg
Hyaluronic acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle, is added in 2-40ml deionized water, ultrasonic dissolution, with 5-
60ml chloroquine class pharmaceutical aqueous solution mixes, and processes through ultrasonic or high pressure homogenize, removes organic solvent and free drug, lyophilization
Obtain hollow mesoporous door-control type mn2+Donor works in coordination with, with chloroquine series antineoplastic medicament, the system that cotransports.
2. mn according to claim 12+Donor and chloroquine class medicine cotransport system preparation method it is characterised in that
Comprise the following steps:
(1) synthesis of double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle: 16g sucrose is added in 80ml deionized water, 190
React 4h in DEG C baking oven, 12000rpm is centrifuged 10min, precipitate with deionized water and each washing of dehydrated alcohol 3 times are dried at 60 DEG C
Dry, obtain black carbon powder；Weigh 1g carbon dust, in 10ml deionized water, Deca 40ml mass concentration is 50% three oxygen to ultrasonic disperse
Change two manganese solutions, after ultrasonic disperse 15min, impregnate 48h, stirring, 12000rpm is centrifuged 20min, by precipitate with deionized water and
The each washing of dehydrated alcohol 3 times, dries at 60 DEG C, roasting 6h at 450 DEG C, obtains double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle；
(2) reaction of hyaluronic acid and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle: weigh 1- ethyl-(3- dimethylamino
Propyl group) carbodiimide hydrochloride) 346mg, n- N-Hydroxysuccinimide 206mg and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle
50mg, is dissolved in 15ml Methanamide respectively, obtains 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) Methanamide is molten
Liquid, n- N-Hydroxysuccinimide formamide solution and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution, by 1- second
Base-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide solution, n- N-Hydroxysuccinimide formamide solution add
To in double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution, reaction 15min is stirred at room temperature, obtains mixed solution；Weigh
50mg hyaluronic acid is dissolved in 10ml Methanamide, obtains hyaluronic acid formamide solution；Above-mentioned mixed solution is added dropwise to hyalomitome
In sour formamide solution, room temperature reaction 18h；Add the acetone ice bath crystallize of pre-cooling, sucking filtration, dialyse 56h, changes liquid every 8h, removes
Go Methanamide and unnecessary hyaluronic acid, lyophilization, obtain hyaluronic acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle；
(3) preparation of hyaluronic acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanometer particle loading chloroquine class medicine: weigh 10mg saturating
Bright matter acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle, is added in 10ml deionized water, ultrasonic dissolution, with 20ml chloroquine
Class pharmaceutical aqueous solution mixes, and processes through ultrasonic or high pressure homogenize, removes organic solvent and free drug, and lyophilization obtains hollow and is situated between
Hole door-control type mn2+Donor works in coordination with, with chloroquine series antineoplastic medicament, the system that cotransports.
3. mn according to claim 12+Donor and chloroquine class medicine cotransport system preparation method it is characterised in that
Comprise the following steps:
(1) synthesis of double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle: 5g sucrose is added in 10ml deionized water, 140
React 2h in DEG C baking oven, 12000rpm is centrifuged 8min, precipitate with deionized water and each washing of dehydrated alcohol 2 times are dried at 60 DEG C
Dry, obtain black carbon powder；Weigh 0.1g carbon dust, in 5ml deionized water, Deca 10ml mass concentration is the three of 50% to ultrasonic disperse
Aoxidize two manganese solutions, after ultrasonic disperse 12min, impregnate 24h, stirring, 12000rpm is centrifuged 25min, by precipitate with deionized water
With dehydrated alcohol respectively washing 2 times, dry at 50 DEG C, roasting 2h at 300 DEG C, obtain double layer hollow mesoporous manganese sesquioxide managnic oxide nanometer
Grain；
(2) reaction of hyaluronic acid and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle: weigh 1- ethyl-(3- dimethylamino
Propyl group) carbodiimide hydrochloride) 300mg, n- N-Hydroxysuccinimide 150mg and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle
40mg, is dissolved in 5ml Methanamide respectively, obtains 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) Methanamide is molten
Liquid, n- N-Hydroxysuccinimide formamide solution and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution, by 1- second
Base-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide solution, n- N-Hydroxysuccinimide formamide solution add
To in double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution, reaction 15min is stirred at room temperature, obtains mixed solution；Weigh
10mg hyaluronic acid is dissolved in 1ml Methanamide, obtains hyaluronic acid formamide solution；Above-mentioned mixed solution is added dropwise to transparent
In matter acid formamide solution, room temperature reaction 12h；Add the acetone ice bath crystallize of pre-cooling, sucking filtration, dialyse 48h, changes liquid every 8h,
Remove Methanamide and unnecessary hyaluronic acid, lyophilization, obtain hyaluronic acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle；
(3) preparation of hyaluronic acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanometer particle loading chloroquine class medicine: weigh 5mg transparent
Matter acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle, is added in 2ml deionized water, ultrasonic dissolution, with 5ml chloroquine class medicine
Thing aqueous solution, processes through ultrasonic or high pressure homogenize, removes organic solvent and free drug, lyophilization obtains the mesoporous door of hollow
Control type mn2+Donor works in coordination with, with chloroquine series antineoplastic medicament, the system that cotransports.
4. mn according to claim 12+Donor and chloroquine class medicine cotransport system preparation method it is characterised in that
Comprise the following steps:
(1) synthesis of double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle: 50g sucrose is added in 200ml deionized water,
8h is reacted, 12000rpm is centrifuged 12min in 300 DEG C of baking ovens, by each to precipitate with deionized water and dehydrated alcohol washing 3 times, 60 DEG C
Lower drying, obtains black carbon powder；Weigh 5g carbon dust, in 50ml deionized water, Deca 50ml mass concentration is 50% to ultrasonic disperse
Manganese sesquioxide managnic oxide solution, after ultrasonic disperse 17min, impregnates 72h, stirring, 12000rpm is centrifuged 35min, by precipitation deionization
Water and dehydrated alcohol respectively washing 3 times, dry at 70 DEG C, roasting 10h at 700 DEG C, obtain the mesoporous manganese sesquioxide managnic oxide of double layer hollow and receive
The grain of rice；
(2) reaction of hyaluronic acid and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle: weigh 1- ethyl-(3- dimethylamino
Propyl group) carbodiimide hydrochloride) 500mg, n- N-Hydroxysuccinimide 300mg and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle
60mg, is dissolved in 20ml Methanamide respectively, obtains 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) Methanamide is molten
Liquid, n- N-Hydroxysuccinimide formamide solution and double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution, by 1- second
Base-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide solution, n- N-Hydroxysuccinimide formamide solution add
To in double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution, reaction 15min is stirred at room temperature, obtains mixed solution；Weigh
100mg hyaluronic acid is dissolved in 20ml Methanamide, obtains hyaluronic acid formamide solution；Above-mentioned mixed solution is added dropwise to
In bright matter acid formamide solution, room temperature reaction 24h；Add the acetone ice bath crystallize of pre-cooling, sucking filtration, dialyse 72h, changes every 8h
Liquid, removes Methanamide and unnecessary hyaluronic acid, lyophilization, obtains hyaluronic acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanometer
Grain；
(3) preparation of hyaluronic acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanometer particle loading chloroquine class medicine: weigh 20mg saturating
Bright matter acid-double layer hollow mesoporous manganese sesquioxide managnic oxide nanoparticle, is added in 40ml deionized water, ultrasonic dissolution, with 60ml chloroquine
Class pharmaceutical aqueous solution mixes, and processes through ultrasonic or high pressure homogenize, removes organic solvent and free drug, and lyophilization obtains hollow and is situated between
Hole door-control type mn2+Donor works in coordination with, with chloroquine series antineoplastic medicament, the system that cotransports.
5. the mn of claim 1 or the preparation of 2-4 any one methods described2+The donor and chloroquine class medicine system that cotransports is anti-in preparation
Application in tumour medicine.
6. the mn of claim 1 or the preparation of 2-4 any one methods described2+Donor and chloroquine class medicine cotransport system in preparation use
In the target administration of tumor locus, the acidity sensitivity release of tumor locus, chemotherapeutical tumor many mechanism treatment of tumor and
Application in the diagnosis and treatment integration medicine of tumor.
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| CN107648612A (en) * | 2017-10-16 | 2018-02-02 | 郑州大学 | A kind of hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport the preparation and application of system |
| CN111956627A (en) * | 2020-09-25 | 2020-11-20 | 郑州大学 | Preparation method and application of drug compound with nano targeting effect for improving II type diabetes pancreatic microenvironment |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107648612A (en) * | 2017-10-16 | 2018-02-02 | 郑州大学 | A kind of hollow mesoporous door-control type Mn2+Donor and qinghaosu cotransport the preparation and application of system |
| CN107648612B (en) * | 2017-10-16 | 2020-01-10 | 郑州大学 | Hollow mesoporous gated Mn2+Preparation and application of donor and artemisinin co-transport system |
| CN111956627A (en) * | 2020-09-25 | 2020-11-20 | 郑州大学 | Preparation method and application of drug compound with nano targeting effect for improving II type diabetes pancreatic microenvironment |
| CN111956627B (en) * | 2020-09-25 | 2022-02-18 | 郑州大学 | Preparation method and application of drug compound with nano targeting effect for improving II type diabetes pancreatic microenvironment |
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