CN106344925B - A kind of Mn2+Donor and chloroquine class drug cotransport the preparation and application of system - Google Patents
A kind of Mn2+Donor and chloroquine class drug cotransport the preparation and application of system Download PDFInfo
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- CN106344925B CN106344925B CN201610722078.3A CN201610722078A CN106344925B CN 106344925 B CN106344925 B CN 106344925B CN 201610722078 A CN201610722078 A CN 201610722078A CN 106344925 B CN106344925 B CN 106344925B
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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
Abstract
The present invention relates to a kind of Mn2+Donor and chloroquine class drug cotransport the preparation and application of system, it is low tumor therapeutic agent drug effect can effectively to be solved, required dosage is big, the problem that targeting is poor, toxic side effect is big, technical solution is: synthesizing the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow by hydro-thermal method, hyaluronic acid and the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow pass through chemistry key connection, nanometer layer is spontaneously formed in an aqueous medium, and then chloroquine series antineoplastic medicament is entered by physical action in the meso-hole structure of the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow；The drug collaboration system of cotransporting of the present invention can significantly reduce the dosage and toxic side effect of drug, improve the therapeutic efficiency of drug, effectively solve its solubility problem, realize drug payload and drug in the controlled release of tumour target area；Improve the dispersibility and biocompatibility of magnetic carrier, realizes the fixed point gate release of long circulating, active targeting, drug, and preparation process is simple, energy conservation and environmental protection, it is at low cost, it can be realized industrialized production, be the innovation in tumor therapeutic agent.
Description
Technical field
The invention belongs to field of medicine and chemical technology, especially a kind of Mn2+Donor and chloroquine class drug cotransport the preparation of system
And apply (i.e. a kind of hollow mesoporous door-control type Mn2+Donor cooperates with the preparation method for the system of cotransporting with chloroquine series antineoplastic medicament
And answer).
Background technique
1, hollow mesoporous door-control type Mn2+Donor and the collaboration of chloroquine series antineoplastic medicament cotransport and can significantly increase therapeutic effect
Chloroquine class drug (chloroquine, CQ) is a kind of antimalarial old medicine, and Recent study discovery is pressed down using chloroquine
The autophagy of system treatment induction can promote death of neoplastic cells, cause tumor regression to sexually revise, delay tumour growth.1992,
The report such as Djordevic, chloroquine can influence people MDA-MB231 cancer cell by radiation sensitization, make lysosome and cell
Film loss of stability.Therefore, chloroquine also has very strong lethal effect to tumour cell.
However chloroquine is to the IC of tumour cell50It is larger, therefore antitumor required dosage is big, drug effect is lower.Secondly, simple
Chloroquine is poor to tumor-targeting, low in tumor locus aggregate concentration, and effective treatment concentration is not achieved, and cannot cause tumour cell certainly
It bites and effectively plays antitumor action.In addition, chloroquine class drug is metabolized fastly in vivo.
So such drug how to be made to play antitumor action to the greatest extent? design Mn2+Donor and chloroquine class are anti-swollen
The tumor medicine collaboration system of cotransporting will effectively solve the problems, such as this.We test discovery Mn2+Carrier and chloroquine class drug cooperate with energy
Chloroquine is significantly increased to the toxicity of tumour cell, and tool inside the mesoporous manganese sesquioxide managnic oxide nanoparticle of the double layer hollow prepared by us
Have a biggish hollow structure, hollow and cellular structure can load drug, large specific surface area has very high Drug loadings energy
Power.And has the function of the drug release of tumour response type.In human body under property environment, manganese sesquioxide managnic oxide (HMn2O3) it is able to maintain structure
Integrality, and under tumor locus slant acidity and strong reducing property environment, HMn2O3Structure can gradually ablation, generate Mn2+Meanwhile
The drug of load discharges into tumour cell therewith, realizes the purpose of tumour target area fixed-point drug releasing, reduces the secondary work of poison of drug
With.Simultaneously because the protective effect of hollow sphere shell, drug can avoid and plasma protein or other biological point during transportation
Son interaction, therefore, can protect drug to avoid being digested.In addition, the high concentration Mn that the carrier is provided in tumor locus2+It can show
Enhancing magnetic resonance imaging is write, realizes the diagnosis and treatment integration of tumour.
2, the advantage of hyaluronic acid (HA) modification nano-carrier
HA because its hydrophily, good biocompatibility, biodegradability, non-immunogenic, tumor-targeting (by
Body is CD44) etc. advantages be used as pharmaceutical carrier or targeted molecular to be applied in drug novel Drug Delivery Systems, and have become in recent years
The hot spot for carrying out oncotherapy research is widely used in targeted molecular imaging, targeted drug and gene therapy etc..Gate
The nanoparticle of material HA modification can not only increase its hydrophily and stability, extend blood circulation time, reach Continuous slow release
The purpose of drug release, moreover it is possible to which the tumor-targeting for improving nanoparticle reduces its toxic side effect to normal cell.
Summary of the invention
In view of the above-mentioned problems, it is an object of the invention to provide a kind of Mn to solve the defect of the prior art2+Donor and chlorine
Quinoline class drug cotransports the preparation and application of system, can effectively solve that tumor therapeutic agent drug effect is low, and required dosage is big, targeting
The big problem of difference, toxic side effect.
The technical scheme is that a kind of Mn2+Donor and chloroquine class drug cotransport the preparation method of system, pass through water
Thermal method synthesizes the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow, and hyaluronic acid and the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow are logical
Chemistry key connection is crossed, spontaneously forms nanometer layer in an aqueous medium, then chloroquine series antineoplastic medicament is entered double by physical action
In the meso-hole structure of the hollow mesoporous manganese sesquioxide managnic oxide nanoparticle of layer；The Mn2+Donor and chloroquine class drug cotransport system
Partial size is 50-300nm；The hyaluronic acid is the high molecular weight hyaluronic acid that molecular weight is 12000 kd；
Specifically includes the following steps:
(1) 5-50g sucrose the synthesis of the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow: is added to 10-200mL deionization
In water, 2-8h is reacted in 140-300 DEG C of baking oven, 12000rpm is centrifuged 8-12min, by precipitating deionized water and dehydrated alcohol
It is dried at each washing 2-3 times, 60 DEG C, obtains black carbon powder；Weigh 0.1-5g carbon dust, ultrasonic disperse in 5-50mL deionized water,
10-50ml mass concentration is added dropwise as 50% manganese sesquioxide managnic oxide solution, after ultrasonic disperse 12-17min, impregnates 24-72h, stirs,
12000rpm is centrifuged 25-35min, and precipitating deionized water and dehydrated alcohol are respectively washed 2-3 times, dried at 50-70 DEG C,
2-10h is roasted at 300-700 DEG C, obtains the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow；
(2) hyaluronic acid and the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow react: weighing 1- ethyl-(3- bis- respectively
Dimethylaminopropyl) carbodiimide hydrochloride) 300-500mg, n-hydroxysuccinimide 150-300mg and double layer hollow it is mesoporous
Manganese sesquioxide managnic oxide nanoparticle 40-60mg, is dissolved in respectively in 5-20ml formamide, obtains 1- ethyl-(3- dimethylaminopropyl) carbon
Diimmonium salt hydrochlorate) formamide solution, n-hydroxysuccinimide formamide solution and the mesoporous manganese sesquioxide managnic oxide of double layer hollow receive
Grain of rice formamide solution, by 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide solution, N- hydroxyl amber
Amber acid imide formamide solution is slowly added into the mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution of double layer hollow, is stirred at room temperature
15min is reacted, mixed solution is obtained；It weighs 10-100mg hyaluronic acid to be dissolved in 1-20ml formamide, obtains hyaluronic acid formamide
Solution；Above-mentioned mixed solution is added dropwise in hyaluronic acid formamide solution, 12-24h is reacted at room temperature；The acetone of pre-cooling is added
Ice bath crystallization filters, and dialyse 48-72h, changes liquid every 8h, removes formamide and extra hyaluronic acid, be freeze-dried transparent
The mesoporous manganese sesquioxide managnic oxide nanoparticle of matter acid-double layer hollow；
(3) preparation of the mesoporous manganese sesquioxide managnic oxide nanometer particle loading chloroquine class drug of hyaluronic acid-double layer hollow: 5- is weighed
The mesoporous manganese sesquioxide managnic oxide nanoparticle of 20mg hyaluronic acid-double layer hollow, is added in 2-40ml deionized water, ultrasonic dissolution, with
The mixing of 5-60ml chloroquine class pharmaceutical aqueous solution removes organic solvent through ultrasound or high-pressure homogeneous processing, after being stirred at room temperature and dissociates
Drug is freeze-dried to obtain hollow mesoporous door-control type Mn2+Donor cooperates with the system of cotransporting with chloroquine series antineoplastic medicament.
The Mn of the method preparation2+Donor and chloroquine class drug cotransport system application in preparation of anti-tumor drugs,
The delivery system can be used for injection, oral or drug delivery implant.Wherein drug administration by injection optimizing injection, freeze-dried powder, take orally to
Medicine preferably is selected from tablet, capsule, pill, syrup, granule, and drug delivery implant preferably is selected from gelling agent, solution.
The Mn of the method preparation2+Donor and chloroquine class drug cotransport system preparation for tumor locus targeting to
Medicine, the acidity sensitivity drug release of tumor locus, the tumour multimachine system treatment of the chemotherapy of tumour and the diagnosis and treatment one chemical drug of tumour
Application in object.
Mn of the present invention2+Donor and the chloroquine class drug system of cotransporting can significantly reduce the dosage and the secondary work of poison of drug
With improving the therapeutic efficiency of drug, effectively solve its solubility problem, realize drug payload and drug in tumour target area
Controlled release；Improve magnetic carrier dispersibility and biocompatibility, realize long circulating, active targeting, drug fixed point gate release
It puts, and preparation process is simple, energy conservation and environmental protection is at low cost, can be realized industrialized production, is the wound in tumor therapeutic agent
Newly.
Specific embodiment
It elaborates with reference to embodiments to a specific embodiment of the invention.
The present invention in specific implementation, is realized by following embodiment.
Embodiment 1
Hollow mesoporous door-control type Mn of the present invention2+Donor cooperates with the system for the system of cotransporting with chloroquine series antineoplastic medicament
Preparation Method, comprising the following steps:
(1) synthesis of the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow: 16g sucrose is added in 80mL deionized water,
Reacting 4h in 190 DEG C of baking ovens, 12000rpm is centrifuged 10min, precipitating deionized water and dehydrated alcohol are respectively washed 3 times, 60
It is dried at DEG C, obtains black carbon powder；1g carbon dust is weighed, for ultrasonic disperse in 10mL deionized water, it is 50% that 40ml mass concentration, which is added dropwise,
Manganese sesquioxide managnic oxide solution, after ultrasonic disperse 15min, impregnate 48h, stirring, 12000rpm is centrifuged 20min, by precipitating spend from
Sub- water and dehydrated alcohol respectively wash 3 times, dry at 60 DEG C, roast 6h at 450 DEG C, obtain the mesoporous manganese sesquioxide managnic oxide of double layer hollow and receive
The grain of rice；Obtained carbon dust average grain diameter is at 1.5 ~ 2 μm or so；The mesoporous manganese sesquioxide managnic oxide partial size of double layer hollow is in 200nm, dispersion
Property it is good, current potential be -28.4mv；
(2) hyaluronic acid and the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow react: weighing 1- ethyl-(3- bis- respectively
Dimethylaminopropyl) carbodiimide hydrochloride) 346mg, n-hydroxysuccinimide 206mg and double layer hollow it is mesoporous three oxidation two
Manganese nanoparticle 50mg, is dissolved in respectively in 15ml formamide, obtains 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride)
Formamide solution, n-hydroxysuccinimide formamide solution and the mesoporous manganese sesquioxide managnic oxide nanoparticle formamide of double layer hollow are molten
Liquid, by 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide solution, n-hydroxysuccinimide formyl
Amine aqueous solution is slowly added into the mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution of double layer hollow, and reaction 15min is stirred at room temperature, obtains
Mixed solution；It weighs 50mg hyaluronic acid to be dissolved in 10ml formamide, obtains hyaluronic acid formamide solution；Above-mentioned mixing is molten
Drop is added in hyaluronic acid formamide solution, reacts at room temperature 18h；The acetone ice bath crystallization of pre-cooling is added, filters, dialyse 56h,
Liquid is changed every 8h, removes formamide and extra hyaluronic acid, is freeze-dried to obtain mesoporous three oxidation two of hyaluronic acid-double layer hollow
Manganese nanoparticle；The HA-HMn of HA modification2O3Uniform particle diameter, average grain diameter are -23.8mv in 240nm, favorable dispersibility, current potential.
(3) preparation of the mesoporous manganese sesquioxide managnic oxide nanometer particle loading chloroquine class drug of hyaluronic acid-double layer hollow: 10mg is weighed
The mesoporous manganese sesquioxide managnic oxide nanoparticle of hyaluronic acid-double layer hollow, is added in 10ml deionized water, ultrasonic dissolution, with 20ml chlorine
The mixing of quinoline class pharmaceutical aqueous solution removes organic solvent and free drug, freezing through ultrasound or high-pressure homogeneous processing after being stirred at room temperature
Dry hollow mesoporous door-control type Mn2+Donor cooperates with the system of cotransporting with chloroquine series antineoplastic medicament.
Embodiment 2
Hollow mesoporous door-control type Mn of the present invention2+Donor cooperates with the system for the system of cotransporting with chloroquine series antineoplastic medicament
Preparation Method, comprising the following steps:
(1) synthesis of the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow: 5g sucrose is added in 10mL deionized water,
2h is reacted in 140 DEG C of baking ovens, 12000rpm is centrifuged 8min, precipitating deionized water and dehydrated alcohol are respectively washed at 2 times, 60 DEG C
Drying, obtains black carbon powder；0.1g carbon dust is weighed, for ultrasonic disperse in 5mL deionized water, it is 50% that 10ml mass concentration, which is added dropwise,
Manganese sesquioxide managnic oxide solution, after ultrasonic disperse 12min, for 24 hours, stirring, 12000rpm is centrifuged 25min to dipping, by precipitating deionization
Water and dehydrated alcohol respectively wash 2 times, dry at 50 DEG C, roast 2h at 300 DEG C, obtain the mesoporous manganese sesquioxide managnic oxide nanometer of double layer hollow
Grain；
(2) hyaluronic acid and the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow react: weighing 1- ethyl-(3- bis- respectively
Dimethylaminopropyl) carbodiimide hydrochloride) 300mg, n-hydroxysuccinimide 150mg and double layer hollow it is mesoporous three oxidation two
Manganese nanoparticle 40mg, is dissolved in respectively in 5ml formamide, obtains 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) first
Amide solution, n-hydroxysuccinimide formamide solution and the mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution of double layer hollow,
By 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide solution, n-hydroxysuccinimide formamide be molten
Liquid is slowly added into the mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution of double layer hollow, and reaction 15min is stirred at room temperature, must mix
Solution；It weighs 10mg hyaluronic acid to be dissolved in 1ml formamide, obtains hyaluronic acid formamide solution；Above-mentioned mixed solution is added dropwise
Enter into hyaluronic acid formamide solution, reacts at room temperature 12h；The acetone ice bath crystallization of pre-cooling is added, filters, dialyse 48h, every
8h changes liquid, removes formamide and extra hyaluronic acid, be freeze-dried the mesoporous manganese sesquioxide managnic oxide of hyaluronic acid-double layer hollow is received
The grain of rice；
(3) preparation of the mesoporous manganese sesquioxide managnic oxide nanometer particle loading chloroquine class drug of hyaluronic acid-double layer hollow: 5mg is weighed
The mesoporous manganese sesquioxide managnic oxide nanoparticle of hyaluronic acid-double layer hollow, is added in 2ml deionized water, ultrasonic dissolution, with 5ml chloroquine
The mixing of class pharmaceutical aqueous solution removes organic solvent and free drug through ultrasound or high-pressure homogeneous processing after being stirred at room temperature, freezing is dry
It is dry to obtain hollow mesoporous door-control type Mn2+Donor cooperates with the system of cotransporting with chloroquine series antineoplastic medicament.
Embodiment 3
Hollow mesoporous door-control type Mn of the present invention2+Donor cooperates with the system for the system of cotransporting with chloroquine series antineoplastic medicament
Preparation Method, comprising the following steps:
(1) synthesis of the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow: 50g sucrose is added in 200mL deionized water,
Reacting 8h in 300 DEG C of baking ovens, 12000rpm is centrifuged 12min, precipitating deionized water and dehydrated alcohol are respectively washed 3 times, 60
It is dried at DEG C, obtains black carbon powder；5g carbon dust is weighed, for ultrasonic disperse in 50mL deionized water, it is 50% that 50ml mass concentration, which is added dropwise,
Manganese sesquioxide managnic oxide solution, after ultrasonic disperse 17min, impregnate 72h, stirring, 12000rpm is centrifuged 35min, by precipitating spend from
Sub- water and dehydrated alcohol respectively wash 3 times, dry at 70 DEG C, roast 10h at 700 DEG C, obtain the mesoporous manganese sesquioxide managnic oxide of double layer hollow
Nanoparticle；
(2) hyaluronic acid and the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow react: weighing 1- ethyl-(3- bis- respectively
Dimethylaminopropyl) carbodiimide hydrochloride) 500mg, n-hydroxysuccinimide 300mg and double layer hollow it is mesoporous three oxidation two
Manganese nanoparticle 60mg, is dissolved in respectively in 20ml formamide, obtains 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride)
Formamide solution, n-hydroxysuccinimide formamide solution and the mesoporous manganese sesquioxide managnic oxide nanoparticle formamide of double layer hollow are molten
Liquid, by 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide solution, n-hydroxysuccinimide formyl
Amine aqueous solution is slowly added into the mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution of double layer hollow, and reaction 15min is stirred at room temperature, obtains
Mixed solution；It weighs 100mg hyaluronic acid to be dissolved in 20ml formamide, obtains hyaluronic acid formamide solution；Above-mentioned mixing is molten
Drop is added in hyaluronic acid formamide solution, and room temperature reaction is for 24 hours；The acetone ice bath crystallization of pre-cooling is added, filters, dialysis
72h changes liquid every 8h, removes formamide and extra hyaluronic acid, be freeze-dried to obtain mesoporous three oxygen of hyaluronic acid-double layer hollow
Change two manganese nanoparticles；
(3) preparation of the mesoporous manganese sesquioxide managnic oxide nanometer particle loading chloroquine class drug of hyaluronic acid-double layer hollow: 20mg is weighed
The mesoporous manganese sesquioxide managnic oxide nanoparticle of hyaluronic acid-double layer hollow, is added in 40ml deionized water, ultrasonic dissolution, with 60ml chlorine
The mixing of quinoline class pharmaceutical aqueous solution removes organic solvent and free drug, freezing through ultrasound or high-pressure homogeneous processing after being stirred at room temperature
Dry hollow mesoporous door-control type Mn2+Donor cooperates with the system of cotransporting with chloroquine series antineoplastic medicament.
The present invention provides a kind of simple, effective Mn2+Donor and chloroquine series antineoplastic medicament collaboration corotation deliver medicine body
System.By Mn2+Donor (HMn2O3Carrier) and chloroquine class drug (with hydroxychloroquine HCQ representative) form；The HMn of load HCQ2O3Pass through
Endocytosis enters tumour cell, is further distributed among in the acidic organelles such as endosome and lysosome, HMn2O3In acidic environment
Lower decomposition, generates and discharges Mn2+, Mn2+Synergistic effect is generated by non-enzymatic reaction and HCQ, so that cancer cell is effectively killed,
Significantly enhance the antitumous effect of HCQ.
The present invention is in HMn2O3Surface chemical modification on hyaluronic acid (HA)；HA is connected to HMn2O3Surface, block
Its meso-hole structure, after reaching tumor locus, the hyaluronidase of tumor locus sloughs HA decomposition, discharges drug, realizes door
Control effect.Release of the drug before reaching tumor target site of action is reduced, the fixed point conveying of drug is realized, improves to the greatest extent
The curative effect of drug.Be finally reached improvement its dispersibility and biocompatibility, increase medicine-carried system in vivo circulation time, improve pair
The targeting ability of tumour, the fixed point aggregation release purpose for realizing drug.Meanwhile the Mn of tumor locus aggregation2+Core can be significantly increased
Magnetic imaging function realizes the diagnosis and treatment integration of tumour.
The present invention is repeatedly tested repeatedly, achieves identical effect, related experiment data is as follows:
One, HMn2O3Mn under acidic environment2+Generate measurement
Prepare the HMn of 100 μ g/ml2O3Aqueous solution, solvent are respectively the phosphate PBS buffer solution (7.4: mould of different pH value
Quasi- normal 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
Use Mn2+Kit measurement Mn2+Concentration.The result shows that HMn2O3It is easier to decompose under acidic environment and generates Mn2+, this shows
HMn2O3In the release Mn of acidic cancer position meeting environmental sensitivity2+, work is cooperateed with chloroquine series antineoplastic medicament (such as HCQ) generation
With.
Two, HA-HMn2O3Medicine controlled releasing of/the HCQ under acidic environment
By HA-HMn2O3/ HCQ is placed in bag filter in (Da of molecular cut off MW=3500), immerses the phosphoric acid of different pH value
In salt PBS buffer solution (7.4: simulation normal body fluid, 6.5: simulation tumor tissues and 4.0: simulation lysosome), 100r/min, 37
It is shaken under the conditions of DEG C, takes out part at regular intervals, HCQ is measured using HPLC method, its concentration is measured and calculates rate of release.
The result shows that said preparation drug release has apparent acidity sensibility, drug release rate are as follows: pH4.0 > pH6.5 > pH7.4.
Three, HA-HMn2O3The antitumor cytolytic activity of/HCQ medicine-carried system
Anti tumor activity in vitro (using Mouse mammary cells strain 4T-1 as research object): time effect: HA-HMn is used2O3/
HCQ carries out single treatment to cell, and investigating its inhibiting effect to growth of tumour cell in different time points, (srb assay is other
Method measurement)；Dosage effect: various dose HA-HMn is used2O3/ HCQ handles cell, investigates its inhibition to growth of tumour cell
Effect (srb assay or the measurement of other methods).
The above experiment is all provided with different experiments group: HMn2O3、HA-HMn2O3、HCQ、HMn2O3/HCQ、HA-HMn2O3/ HCQ etc..
The result shows that HA-HMn2O3/ HCQ has apparent time dependence and a concentration dependent to the inhibiting effect of cell, and HCQ and
HA-HMn2O3With significant collaboration tumor-inhibiting action；
Internal anti-tumor activity: by 4T-1 cell inoculation to the subcutaneous of nude mice flank, the growth feelings of tumour are monitored every other day
Condition, and record the general status of nude mice.When gross tumor volume reaches 100-300mm3When, animal is grouped and is started to process at random
(intravenous injection): 1. HCQ；②HMn2O3；③HA-HMn2O3；④HMn2O3/HCQ；⑤HA-HMn2O3/HCQ.Physiology salt is set simultaneously
Water control group and positive controls.Continuous monitoring gross tumor volume is until animal is put to death.When by the 7th week, put to death all small
Mouse takes out tumour, weighing.According to Relative tumor proliferation rate T/C evaluation effect.
Test result shows compared to other groups, HA-HMn2O3/ HCQ achieves significant Suppressive effect in vivo, relatively
Tumour appreciation rate is minimum.
The present invention provides a kind of Mn2+Donor and chloroquine class drug cotransport system, selection have high Drug loadings amount and
The hollow mesoporous manganese sesquioxide managnic oxide nanoparticle (HMn of biocompatibility2O3) it is used as basis material, using chloroquine class drug as model drug
Object, constructing one kind has the function of NMR imaging, mesoporous door-control type drug transport system；The partial size of the nanometer system is 50-
300nm, size uniformity, good dispersion；The system mainly has the following characteristics that the 1) carrier in tumour faintly acid and reproducibility
It can be used as Mn under specific environment2+Donor realizes chloroquine series antineoplastic medicament and Mn2+Donor collaboration cotransports, and enhances chloroquine class medicine
Object antitumor action；2) Mn that tumor locus generates2+Magnetic resonance imaging can be significantly increased, realizes the diagnosis and treatment integration of tumour；3)
Dosage needed for chloroquine class drugs against tumor is big, HMn2O3The high drug capacity of double layer hollow porous structure can effectively solve chloroquine class
The problem that anti-tumor drug dissolubility is poor, dosage is big, and drug can be made to be sustained in target area；4) carrier has gate drug release and master
Dynamic target function.
Claims (6)
1. a kind of Mn2+Donor and chloroquine class drug cotransport the preparation method of system, which is characterized in that it is double to pass through hydro-thermal method synthesis
The hollow mesoporous manganese sesquioxide managnic oxide nanoparticle of layer, hyaluronic acid and the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow are connected by chemical bond
It connects, spontaneously forms nanometer layer in an aqueous medium, then it is mesoporous by physical action to enter double layer hollow for chloroquine series antineoplastic medicament
In the meso-hole structure of manganese sesquioxide managnic oxide nanoparticle；The Mn2+The cotransport partial size of system of donor and chloroquine class drug is 50-
300nm；The hyaluronic acid is the high molecular weight hyaluronic acid that molecular weight is 12000 kDa；
Specifically includes the following steps:
(1) 5-50g sucrose the synthesis of the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow: is added to 10-200mL deionized water
In, 2-8h is reacted in 140-300 DEG C of baking oven, 12000rpm is centrifuged 8-12min, and precipitating deionized water and dehydrated alcohol is each
It is dried at washing 2-3 times, 60 DEG C, obtains black carbon powder；0.1-5g carbon dust is weighed, ultrasonic disperse is in 5-50mL deionized water, drop
Adding 10-50ml mass concentration is 50% manganese sesquioxide managnic oxide solution, after ultrasonic disperse 12-17min, impregnates 24-72h, stirring,
12000rpm is centrifuged 25-35min, and precipitating deionized water and dehydrated alcohol are respectively washed 2-3 times, dried at 50-70 DEG C,
2-10h is roasted at 300-700 DEG C, obtains the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow；
(2) hyaluronic acid and the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow react: weighing 1- ethyl-(3- dimethylamino
Propyl) carbodiimide hydrochloride) 300-500mg, n-hydroxysuccinimide 150-300mg and double layer hollow it is mesoporous three oxidation two
Manganese nanoparticle 40-60mg, is dissolved in respectively in 5-20ml formamide, obtains 1- ethyl-(3- dimethylaminopropyl) carbodiimide salt
Hydrochlorate) formamide solution, n-hydroxysuccinimide formamide solution and the mesoporous manganese sesquioxide managnic oxide nanoparticle formyl of double layer hollow
Amine aqueous solution, by 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide solution, n-hydroxysuccinimide
Formamide solution is added in the mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution of double layer hollow, and reaction 15min is stirred at room temperature, obtains
Mixed solution；It weighs 10-100mg hyaluronic acid to be dissolved in 1-20ml formamide, obtains hyaluronic acid formamide solution；It will be above-mentioned
Mixed solution is added dropwise in hyaluronic acid formamide solution, reacts at room temperature 12-24h；The acetone ice bath crystallization of pre-cooling is added, takes out
Filter, dialyse 48-72h, changes liquid every 8h, removes formamide and extra hyaluronic acid, and freeze-drying obtains hyaluronic acid-bilayer
Hollow mesoporous manganese sesquioxide managnic oxide nanoparticle；
(3) preparation of the mesoporous manganese sesquioxide managnic oxide nanometer particle loading chloroquine class drug of hyaluronic acid-double layer hollow: 5-20mg is weighed
The mesoporous manganese sesquioxide managnic oxide nanoparticle of hyaluronic acid-double layer hollow, is added in 2-40ml deionized water, ultrasonic dissolution, with 5-
The mixing of 60ml chloroquine class pharmaceutical aqueous solution removes organic solvent and free drug, freeze-drying through ultrasound or high-pressure homogeneous processing
Obtain hollow mesoporous door-control type Mn2+Donor cooperates with the system of cotransporting with chloroquine series antineoplastic medicament.
2. Mn according to claim 12+Donor and chloroquine class drug cotransport the preparation method of system, which is characterized in that
The following steps are included:
(1) synthesis of the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow: 16g sucrose is added in 80mL deionized water, 190
4h is reacted in DEG C baking oven, 12000rpm is centrifuged 10min, precipitating deionized water and dehydrated alcohol are respectively washed 3 times, dried at 60 DEG C
It is dry, obtain black carbon powder；1g carbon dust is weighed, three oxygen that 40ml mass concentration is 50% are added dropwise in 10mL deionized water in ultrasonic disperse
Change two manganese solutions, after ultrasonic disperse 15min, impregnate 48h, stirring, 12000rpm is centrifuged 20min, by precipitating deionized water and
Dehydrated alcohol respectively washs 3 times, dries at 60 DEG C, roasts 6h at 450 DEG C, obtains the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow；
(2) hyaluronic acid and the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow react: weighing 1- ethyl-(3- dimethylamino
Propyl) carbodiimide hydrochloride) 346mg, n-hydroxysuccinimide 206mg and the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow
50mg is dissolved in respectively in 15ml formamide, obtains 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide is molten
Liquid, n-hydroxysuccinimide formamide solution and the mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution of double layer hollow, by 1- second
Base-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide solution, the addition of n-hydroxysuccinimide formamide solution
Into the mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution of double layer hollow, reaction 15min is stirred at room temperature, obtains mixed solution；It weighs
50mg hyaluronic acid is dissolved in 10ml formamide, obtains hyaluronic acid formamide solution；Above-mentioned mixed solution is added dropwise to hyalomitome
In sour formamide solution, 18h is reacted at room temperature；The acetone ice bath crystallization of pre-cooling is added, filters, dialyse 56h, changes liquid every 8h, removes
Formamide and extra hyaluronic acid are removed, is freeze-dried, obtains the mesoporous manganese sesquioxide managnic oxide nanoparticle of hyaluronic acid-double layer hollow；
(3) it is saturating the preparation of the mesoporous manganese sesquioxide managnic oxide nanometer particle loading chloroquine class drug of hyaluronic acid-double layer hollow: to weigh 10mg
The bright mesoporous manganese sesquioxide managnic oxide nanoparticle of matter acid-double layer hollow, is added in 10ml deionized water, ultrasonic dissolution, with 20ml chloroquine
The mixing of class pharmaceutical aqueous solution removes organic solvent and free drug, is freeze-dried to obtain hollow Jie through ultrasound or high-pressure homogeneous processing
Hole door-control type Mn2+Donor cooperates with the system of cotransporting with chloroquine series antineoplastic medicament.
3. Mn according to claim 12+Donor and chloroquine class drug cotransport the preparation method of system, which is characterized in that
The following steps are included:
(1) synthesis of the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow: 5g sucrose is added in 10mL deionized water, 140
2h is reacted in DEG C baking oven, 12000rpm is centrifuged 8min, precipitating deionized water and dehydrated alcohol are respectively washed 2 times, dried at 60 DEG C
It is dry, obtain black carbon powder；0.1g carbon dust is weighed, three that 10ml mass concentration is 50% are added dropwise in 5mL deionized water in ultrasonic disperse
Aoxidize two manganese solutions, after ultrasonic disperse 12min, for 24 hours, stirring, 12000rpm is centrifuged 25min to dipping, by precipitating deionized water
It respectively washs with dehydrated alcohol 2 times, is dried at 50 DEG C, roast 2h at 300 DEG C, obtain the mesoporous manganese sesquioxide managnic oxide nanometer of double layer hollow
Grain；
(2) hyaluronic acid and the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow react: weighing 1- ethyl-(3- dimethylamino
Propyl) carbodiimide hydrochloride) 300mg, n-hydroxysuccinimide 150mg and the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow
40mg is dissolved in respectively in 5ml formamide, obtains 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide is molten
Liquid, n-hydroxysuccinimide formamide solution and the mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution of double layer hollow, by 1- second
Base-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide solution, the addition of n-hydroxysuccinimide formamide solution
Into the mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution of double layer hollow, reaction 15min is stirred at room temperature, obtains mixed solution；It weighs
10mg hyaluronic acid is dissolved in 1ml formamide, obtains hyaluronic acid formamide solution；Above-mentioned mixed solution is added dropwise to transparent
In matter acid formamide solution, 12h is reacted at room temperature；The acetone ice bath crystallization of pre-cooling is added, filters, dialyse 48h, liquid is changed every 8h,
Formamide and extra hyaluronic acid are removed, freeze-drying obtains the mesoporous manganese sesquioxide managnic oxide nanoparticle of hyaluronic acid-double layer hollow；
(3) it is transparent the preparation of the mesoporous manganese sesquioxide managnic oxide nanometer particle loading chloroquine class drug of hyaluronic acid-double layer hollow: to weigh 5mg
The mesoporous manganese sesquioxide managnic oxide nanoparticle of matter acid-double layer hollow, is added in 2ml deionized water, ultrasonic dissolution, with 5ml chloroquine class medicine
The mixing of object aqueous solution removes organic solvent and free drug, is freeze-dried to obtain hollow mesoporous door through ultrasound or high-pressure homogeneous processing
Control type Mn2+Donor cooperates with the system of cotransporting with chloroquine series antineoplastic medicament.
4. Mn according to claim 12+Donor and chloroquine class drug cotransport the preparation method of system, which is characterized in that
The following steps are included:
(1) synthesis of the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow: 50g sucrose is added in 200mL deionized water,
8h is reacted in 300 DEG C of baking ovens, 12000rpm is centrifuged 12min, precipitating deionized water and dehydrated alcohol are respectively washed 3 times, 60 DEG C
Lower drying, obtains black carbon powder；5g carbon dust is weighed, for ultrasonic disperse in 50mL deionized water, it is 50% that 50ml mass concentration, which is added dropwise,
Manganese sesquioxide managnic oxide solution after ultrasonic disperse 17min, impregnates 72h, stirring, 12000rpm is centrifuged 35min, by precipitating deionization
Water and dehydrated alcohol respectively wash 3 times, dry at 70 DEG C, roast 10h at 700 DEG C, obtain the mesoporous manganese sesquioxide managnic oxide of double layer hollow and receive
The grain of rice；
(2) hyaluronic acid and the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow react: weighing 1- ethyl-(3- dimethylamino
Propyl) carbodiimide hydrochloride) 500mg, n-hydroxysuccinimide 300mg and the mesoporous manganese sesquioxide managnic oxide nanoparticle of double layer hollow
60mg is dissolved in respectively in 20ml formamide, obtains 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide is molten
Liquid, n-hydroxysuccinimide formamide solution and the mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution of double layer hollow, by 1- second
Base-(3- dimethylaminopropyl) carbodiimide hydrochloride) formamide solution, the addition of n-hydroxysuccinimide formamide solution
Into the mesoporous manganese sesquioxide managnic oxide nanoparticle formamide solution of double layer hollow, reaction 15min is stirred at room temperature, obtains mixed solution；It weighs
100mg hyaluronic acid is dissolved in 20ml formamide, obtains hyaluronic acid formamide solution；Above-mentioned mixed solution is added dropwise to
In bright matter acid formamide solution, room temperature reaction is for 24 hours；The acetone ice bath crystallization of pre-cooling is added, filters, dialyse 72h, changes every 8h
Liquid, removes formamide and extra hyaluronic acid, and freeze-drying obtains the mesoporous manganese sesquioxide managnic oxide nanometer of hyaluronic acid-double layer hollow
Grain；
(3) it is saturating the preparation of the mesoporous manganese sesquioxide managnic oxide nanometer particle loading chloroquine class drug of hyaluronic acid-double layer hollow: to weigh 20mg
The bright mesoporous manganese sesquioxide managnic oxide nanoparticle of matter acid-double layer hollow, is added in 40ml deionized water, ultrasonic dissolution, with 60ml chloroquine
The mixing of class pharmaceutical aqueous solution removes organic solvent and free drug, is freeze-dried to obtain hollow Jie through ultrasound or high-pressure homogeneous processing
Hole door-control type Mn2+Donor cooperates with the system of cotransporting with chloroquine series antineoplastic medicament.
5. the Mn of any one of claims 1 or 2-4 the method preparation2+Donor and chloroquine class the drug system that cotransports are anti-in preparation
Application in tumour medicine.
6. the Mn of any one of claims 1 or 2-4 the method preparation2+Donor and chloroquine class drug cotransport system in preparation use
In the target administration of tumor locus, the acidity sensitivity drug release of tumor locus, the chemotherapy of tumour the treatment of tumour multimachine system and
Application in the diagnosis and treatment integration drug of tumour.
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| CN105762349A (en) * | 2016-01-29 | 2016-07-13 | 中国科学院过程工程研究所 | Multi-shell metal oxide hollow sphere synthesized based on anion adsorption and preparation method as well as application thereof |
| CN105770904A (en) * | 2016-03-16 | 2016-07-20 | 深圳大学 | Composite nano medicament-loading material for treating cancer and preparation method thereof |
| CN108434462A (en) * | 2018-03-13 | 2018-08-24 | 中山大学 | A kind of multifunctional nano diagnosis and treatment agent and the preparation method and application thereof of mesoporous poly-dopamine load manganese carbonyl |
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| CN105762349A (en) * | 2016-01-29 | 2016-07-13 | 中国科学院过程工程研究所 | Multi-shell metal oxide hollow sphere synthesized based on anion adsorption and preparation method as well as application thereof |
| CN105770904A (en) * | 2016-03-16 | 2016-07-20 | 深圳大学 | Composite nano medicament-loading material for treating cancer and preparation method thereof |
| CN108434462A (en) * | 2018-03-13 | 2018-08-24 | 中山大学 | A kind of multifunctional nano diagnosis and treatment agent and the preparation method and application thereof of mesoporous poly-dopamine load manganese carbonyl |
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| Biocompatible and pH-Sensitive PLGA Encapsulated MnO Nanocrystals for Molecular and Cellular MRI;Margaret F. Bennewitz et al.;《ACSNANＯ》;20110415;第５卷(第５期);第3438-3446页 |
| Synthesis of Manganese Oxide Hollow Urchins with a Reactive Template of Carbon Spheres;Nan Wang et al.;《Eur. J. Inorg. Chem.》;20080709;第3827-3832页 |
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