CN108619511A - A kind of preparation method and application of the metal organic frame drug-loading system based on cytarabine small molecule prodrugs - Google Patents
A kind of preparation method and application of the metal organic frame drug-loading system based on cytarabine small molecule prodrugs Download PDFInfo
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Abstract
The invention discloses a kind of preparation method and application of the metal organic frame drug-loading system of cytarabine prodrug, the present invention chooses the molecule that can be reacted with metallic ion coordination and cytarabine covalent bond, synthesize a kind of novel and multifunctional small molecule prodrugs, method is contained by a simple and environmentally-friendly step, so that prodrug is contained and forms drug-carrying nanometer particle in metal organic frame, after centrifuging washing and drying, the MOF intravenous formulations for carrying cytarabine small molecule prodrugs are obtained.By taking the Ara IR820 ZIF 8 of synthesis as an example, antitumor pharmacodynamics in Mice Body is the results show that 8 nano aqueous solutions of HA/Ara IR820 ZIF have good antitumous effect, lower system toxicity.Intravenous formulations drugloading rate is high, and preparation process simple economy can be mass, and small toxicity safety is good, is to realize high drug load of the cytarabine in metal organic frame and provide broad prospect of application for being injected intravenously drug treatment solid tumor.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of design and conjunction of novel cytarabine small molecule prodrugs
At further relating to the preparation and evaluation of the metal organic frame drug delivery system based on the Medicine small molecule prodrug.
Background technology
Continuous with morbidity and mortality is risen, and cancer has become the primary factor for threatening public health, cancer
It treats very urgent.Chemotherapy is the means to inhibit tumor cell proliferation, promote apoptosis of tumor cells by using chemicals,
It is the treatment means being most widely used at present.Cytarabine is clinically most common as typical pyrimidines antimetabolic medicine
One of chemotherapeutics is widely used in all kinds of leukemias for the treatment of.However since its molecular polarity is very big, fat-soluble low, film
Permeability is poor；In addition, the NH on pyrimidine ring2Inactive ara-U, therefore mouth are easily become by deaminase deamination inactivation
It is low to take bioavilability, internal plasma half-life is extremely short after intravenous injection.It is clinically main to use to reach effective blood drug concentration
Continuous intravenous dripping mode；Moreover, according to the literature, cytarabine is ineffective for treatment of solid tumors, significantly limit
The clinical application of cytarabine.
To improve the fat-soluble and biological permeable membrane of cytarabine, protecting the NH on drug pyrimidine ring2Not by deaminase generation
Thank to inactivation, it can be by different chain length hydrophobic chain (such as C6-C20Aliphatic chain etc.) covalent modification is in cytarabine NH2On to obtain prodrug small
Molecule.Monotherapy tumour is unable to reach satisfactory effect at present, clinically, in order to obtain more preferably treatment effect
Fruit is improved tumor cure rate, is often treated using the united means of two or more therapeutic modalities.By by drug molecule
(such as camptothecine, doxorubicin hydrochloride, taxol etc.), photo-thermal therapy photosensitizer (such as indocyanine green, new indocyanine green,
IR780 etc.), dynamic treatment photosensitizer (hypocrellin, the chlorin, derivatives of porphyrin etc.) covalent modification of light is in cytarabine NH2
On can prepare multi-functional prodrug small molecule, the wherein dynamic treatment of chemotherapy, photo-thermal therapy and light has respective mechanism of action and cell toxicant
Property, generally produce synergistic effect, moreover it is possible to weaken the side effect generated in therapeutic process, hence it is evident that enhancing antitumor curative effect.It is right at present
In the research of small molecule prodrugs, drug molecule self assembly may be implemented in limited drug graft, or free preceding liquid medicine is made
Solution or obtained greater particle size precipitation.There is non-targeted distribution in wherein free preceding aqueous solution, to meet drug to swollen
The therapeutic effect at tumor position need to select large dosage, increase general toxicity.Larger, irregular grain size can limit preparation to
Medicine approach：Oral administered dosage form preparation process is cumbersome, and production cost is high；Intratumor injection is unfavorable for clinical practice operation.
It is to enhance drug to the inhibiting effect of tumour and reduce its toxicity that pharmaceutical preparation needs the main problem solved now：
The effect of tumor locus increases drug is conducted drugs to, and the whole body of drug is avoided to be distributed, reduces its normal tissue
Damage, lethal effect of the enhancing drug to tumour cell.Therefore exploitation drugloading rate it is high, safely and effectively, have the function of Targeting distribution
Medicament nano delivery system have important research significance and clinical value.Existing drug carrier material is broadly divided into
Inorganic material and organic material：Make carrier using inorganic material, material itself has certain toxicity, and since its structure is excessively steady
Cause biological degradability poor, material effectively can not be degraded and excreted by organism surely.Although organic material bio-compatible
Property is preferable, and material surface is modified after can also carrying out, and still, material drug carrier amount is limited；Moreover, because its thermal stability and chemistry
Stability is weaker, and there may be phenomenon of burst release in release for drug.Therefore, it is most important to develop novel effective pharmaceutical carrier.
Metal-organic framework materials (Metal Organic Frameworks, MOFs) (such as ZIF series, MIL are serial, UiO is serial,
IRMOF series etc.) be one is using metal ion as hybridised center, oxygen-containing or organic compounds containing nitrogen as ligand self assembly and
At the co-ordination complex crystalline material with periodical reticular structure.MOF have duct controllability, superhigh specific surface area,
The structure features such as modified, show in drug delivery field behind skeleton Diversity, composition designability, excellent surface
Huge application prospect is expected to become excellent pharmaceutical carrier.But due to the stability of MOF material self structures and not
With the specificity of drug molecular structure, the medicament categories that can be contained by MOF materials being currently known are very limited, anticancer of the present invention
Medicine cytarabine is easy to reveal from the apertures MOF, it is difficult to which realization contains, it would therefore be highly desirable to develop one kind since molecular structure is smaller
The metal organic frame that height carries small-molecule drug carries medicine transmission system.
Invention content
In conjunction with the above problem, the MOF preparations that the present invention is directed to load small molecule prodrugs for the first time are studied, especially arabinose born of the same parents
Glycosides small molecule prodrugs.Anticancer drug cytarabine and hydrophobic chain, drug molecule, photo-thermal therapy photosensitizer, light are moved and are controlled by the present invention
It treats photosensitizer to combine, utilizes carboxylic group, the sulphur in hydrophobic chain, drug molecule, photo-thermal therapy photosensitizer, the dynamic treatment photosensitizer of light
Metal is coordinated in acid groups, ester group and metal organic frame, to which cytarabine to be drawn in MOF cavitys, realizes two
Kind compound equimolar further realizes the characteristic compared with high drug load than total load.For for example, Selection utilization of the present invention is close
In the new indocyanine green of IR dyes (IR820), sulfonic acid group and metal organic frame zeolitic imidazolate framework material (ZIF-8)
The coordination of metal realizes MOF effectively containing to small molecule anticancer drug cytarabine.
To achieve the above object, specifically, the present invention relates to following technical schemes：
A kind of novel cytarabine of present invention synthesis and new indocyanine green small molecule prodrugs (Ara-IR820), IR820 and change
Treatment drug cytarabine is obtained by the reaction prodrug Ara-IR820, Ara-IR820 by amide and not only increases cytarabine to entity
The effect of tumor, also improves its stability, in addition, the Ara-IR820 prodrugs of synthesis are dispersed in water since structural polarity is larger
The aqueous solution of high concentration can be prepared, realizes that the drug delivery system of high drug load lays the foundation to be follow-up.
To realize the purpose, specifically, the present invention relates to following technical schemes：
The present invention provides a kind of novel cytarabine and new indocyanine green small molecule prodrugs (Ara-IR820), structures
Formula is as follows：
The present invention also provides the preparation sides of above-mentioned cytarabine and new indocyanine green small molecule prodrugs (Ara-IR820)
Method, preparation method are：
New indocyanine green is reacted with 6-aminocaprolc acid, the upper carboxyl of modification in new indocyanine green, after product separating-purifying, with
Cytarabine carries out amide and product is obtained by the reaction.
Preferably, new indocyanine green is with cytarabine reaction process：New indocyanine green under the conditions of triethylamine is added, with
6-aminocaprolc acid reacts, and generates first step product；After product separating-purifying, it is catalyzed through triethylamine, ethyl chloroformate, with arabinose born of the same parents
Glycosides reaction generates above-mentioned cytarabine and new indocyanine green small molecule prodrugs (Ara-IR820).
Specifically reaction step includes：(1) a certain amount of new indocyanine green is dissolved in anhydrous n,N-Dimethylformamide (DMF)
In, triethylamine is added, a certain amount of 6-aminocaprolc acid is dissolved in anhydrous DMF, is added in above-mentioned reaction solution, inert gas is protected
It is reacted under the conditions of shield, 85 DEG C of oil baths, prepares IR820-COOH.
The new indocyanine green：6-aminocaprolc acid：Triethylamine molar ratio is 1:5:5.
Further including the steps that IR820-COOH purifies (2) later in preferred embodiment.
Specifically, the step of purifying (2), is：Vacuum rotary steam removes reaction dissolvent anhydrous DMF, and vacuum drying is slightly produced
Object；Crude product is dissolved in methanol, silica gel column chromatography purification, ethyl acetate and methanol elution gradient (10:1-3:1) it, obtains
IR820-COOH sterlings are blue solid.
(3) a certain amount of IR820-COOH is dissolved in anhydrous DMF, and triethylamine and ethyl chloroformate is added, and inert gas is protected
It is reacted under shield, condition of ice bath；
(4) a certain amount of cytarabine is dissolved in anhydrous DMF, is added in step (3) described reaction solution, prepares
State cytarabine and new indocyanine green small molecule prodrugs (Ara-IR820).
The IR820-COOH：Cytarabine：Triethylamine：Ethyl chloroformate molar ratio is 1:3:3:3.
Further including the steps that Ara-IR820 purifies (5) later in preferred embodiment.
Specifically, the step of purifying (5), is：Vacuum rotary steam removes reaction dissolvent anhydrous DMF, and vacuum drying is slightly produced
Object；Crude product is dissolved in methanol, silica gel column chromatography purification, ethyl acetate and methanol elution gradient (4:1-2.5:1) it, obtains
Ara-IR820 sterlings are blue solid.
The present invention also provides the use of cytarabine and new indocyanine green small molecule prodrugs (Ara-IR820) in antitumor
On the way, it can be used for treating or alleviating the cancer of a certain tissue or organ, cancer includes but not limited to leukaemia, solid tumor etc..
The present invention, which also synthesizes a kind of metal with active targeting function based on cytarabine small molecule prodrugs, machine frame
Frame drug delivery system.
To realize the purpose, specifically, the present invention relates to following technical schemes：
The invention discloses a kind of, and the metal with active targeting function based on cytarabine small molecule prodrugs has machine frame
The preparation method of frame drug delivery system, including：The Ara prodrugs of synthesis is soluble in water, it is added dropwise to metal salt under stirring condition
In the aqueous solution of ion, mixed liquor is added dropwise under agitation in ligand aqueous solution；The suspension of above-mentioned formation is centrifuged,
Washing, is dried to obtain solid, that is, contains the metal organic frame drug delivery system of cytarabine small molecule prodrugs；
The metal organic frame for containing cytarabine small molecule prodrugs, which is dispersed in, has the function of tumor-targeting
Ligand aqueous solution in, be stirred at room temperature, the suspension of formation centrifuged, washing is dried to obtain solid, that is, it is small to be based on cytarabine
The metal organic frame drug delivery system with active targeting function of molecule prodrug.
The present invention utilize part of compounds in sulfonic acid group, carboxylic acid group, ester group can in metal organic frame
Metal coordination is to realize that the characteristic compared with high drug load, related compound are covalently tied with anticancer drug cytarabine by amido bond
It closes cytarabine being drawn in MOF cavitys, two kinds of molecule equimolars realize than total load and contain small molecule prodrugs
Has the structure of the metal organic frame drug delivery system of target function.
Specifically, with cytarabine and new indocyanine green small molecule prodrugs (Ara-IR820), ZIF-8 metal organic frames
For, preparation method is as follows：
Ara-IR820 prodrugs is soluble in water, zinc nitrate hexahydrate (Zn (NO are added dropwise under stirring condition3)2·6H2O) water-soluble
In liquid, mixed liquor is added dropwise under agitation in 2-methylimidazole aqueous solution；The suspension of above-mentioned formation is centrifuged, water
It washes, is dried to obtain blue solid, i.e., the metal organic frame drug based on cytarabine and new indocyanine green small molecule prodrugs is passed
Send system Ara-IR820@ZIF-8；
Ara-IR820@ZIF-8 are dispersed in the aqueous solution of hyaluronic acid (HA), are stirred at room temperature, by the mixed of formation
Suspension centrifuges, and washing is dried to obtain blue solid, that is, is based on cytarabine and new indocyanine green small molecule prodrugs (Ara-
IR820 the metal organic frame drug delivery system HA/Ara-IR820@ZIF-8 with active targeting function).
The Micelle-like Nano-structure of Two intravenous formulations of the present invention form through experiment and stablize suspension concentration up to 10mg/mL
More than.
The metal organic frame drug delivery system HA/Ara- with active targeting function that above-mentioned preparation method obtains
IR820@ZIF-8 are also protection scope of the present invention.
The invention also discloses above-mentioned, and the metal with active targeting function based on cytarabine small molecule prodrugs is organic
The application of frame drug delivery system, can be used for treating or alleviate the cancer of a certain tissue or organ, and cancer includes but unlimited
In leukaemia, solid tumor etc..
Preferably, the application be will the metal with active targeting function based on cytarabine small molecule prodrugs it is organic
Frame drug delivery system ultrasound, which is dispersed in water, is made targeted vein ejection preparation.The intravenous formulations pass through letter
Single, quick, green method obtains, and has good stability, is easy to preserve, is provided simultaneously with excellent internal antitumous effect.
The present invention achieves following advantageous effect：
(1) present invention synthesizes cytarabine and new indocyanine green small molecule prodrugs Ara-IR820 for the first time, and prodrugs are not only
It solves the shortcomings of Ara is easily metabolized inactivation in vivo, improves toxicity of the drug to solid tumor, and improve Ara stabilizations
Property, extend the antitumor application thereof range of Ara.
(2) Ara-IR820 can be contained the hole of metal organic frame ZIF-8 by the present invention by simple and rapid method
Intracavitary is made nanoparticle and realizes active targeting HA modifications, not only economic and environment-friendly, also can be mass, solid is easy to preserve and transport
It is defeated, provide possibility for industrial production.
(3) first passage of the present invention generates prodrug with compound graft reaction and cytarabine is contained metal organic frame
The hole intracavitary of ZIF-8 is simultaneously prepared into the metal organic frame drug delivery system with active targeting function, for research base later
It lays the foundation in the metal organic frame drug delivery system of Ara small molecule prodrugs.
(4) HA/Ara-IR820@ZIF-8 nanoparticles intravenous formulations toxicity is low, and safety is good, and solid tumor cancer inhibits
Rate is high, and possibility is provided to realize that cytarabine is injected intravenously drug treatment solid tumor.
Description of the drawings
The nuclear magnetic spectrum of Fig. 1 IR820-COOH and Ara-IR820；
Fig. 2 HA/Ara-IR820@ZIF-8 nanoparticles transmission electron microscope (TEM) image；
Gross tumor volume, mouse in Fig. 3 HA/Ara-IR820@ZIF-8 nanoparticle intravenous medical treatment solid tumor effect experiments
Changes of weight curve and tumor control rate result.
Specific implementation mode
In conjunction with specific example, the present invention is further illustrated, and following instance is not right merely to the explanation present invention
Its content is defined.If the experiment actual conditions being not specified in example, usually according to normal condition, or according to Reagent Company
The condition recommended；Reagent as used in the following examples, consumptive material etc., are commercially available unless otherwise specified.
Embodiment 1Ara-IR820 prodrugs synthesize
Assay balance precision weighs a certain amount of IR820, is dissolved in anhydrous DMF and is placed in round-bottomed flask, assay balance essence
It is close to weigh a certain amount of 6-aminocaprolc acid, it is dissolved in anhydrous DMF, the DMF solution of above-mentioned IR820, stirring bar are added under stirring condition
Triethylamine is added under part, reacts 4h under the conditions of nitrogen protection, 85 DEG C of oil baths.Wherein mole is IR820：Triethylamine：6- amino
Caproic acid=1:5:5, monitor reaction process using lamellae.After reaction, vacuum rotary steam removes anhydrous DMF, is dried in vacuo
Night obtains crude product.Crude product is dissolved in methanol, a little column layer chromatography silicone rubber mixes sample, silica gel column chromatography purification, ethyl acetate
With methanol elution gradient (10:1-3:1) it is blue solid, yield 48.8%, to obtain IR820-COOH sterlings.
Assay balance precision weighs a certain amount of IR820-COOH, is dissolved in anhydrous DMF and is placed in round-bottomed flask, stirring bar
Triethylamine and ethyl chloroformate are added under part, reacts 20min under nitrogen protection, condition of ice bath.It is molten to weigh a certain amount of cytarabine
In anhydrous DMF, above-mentioned reaction solution is slowly dropped under stirring condition, wherein mole is IR820-COOH：Triethylamine：Chloromethane
Acetoacetic ester：Cytarabine=1:3:3:3, reacting recovery the reaction was continued to room temperature and under the conditions of nitrogen protection 72h utilize thin layer
Plate monitors reaction process.After reaction, vacuum rotary steam removes anhydrous DMF, is dried in vacuum overnight, obtains crude product.It will slightly produce
Object is dissolved in methanol, and a little column layer chromatography silicone rubber mixes sample, silica gel column chromatography purification, ethyl acetate and methanol elution gradient (4:1-
2.5:1) Ara-IR820, is obtained, sterling is blue solid, yield 61.2%.
2 nuclear magnetic resonance spectroscopy of embodiment (1H-NMR IR820-COOH and Ara-IR820 prodrug chemical structures) are identified
IR820-COOH and Ara-IR820 prodrugs about 5mg is weighed respectively, and deuterated dimethyl sulfoxide (DMSO-d6) dissolves juxtaposition
In in nuclear magnetic tube, using its hydrogen nuclear magnetic resonance spectrogram of 400MHz nuclear magnetic resonance hydrogen spectruming determinings, using tetramethylsilane as internal standard compound, remember
Record the chemical displacement value (ppm) of compound.The results are shown in Figure 1, and nuclear-magnetism result is it can be confirmed that arabinose born of the same parents in newly synthesized molecule
The molar ratio of glycosides and IR820 are close to 1:1, at the same on amido bond the characteristic peak of H appearance, it was demonstrated that the synthesis of amido bond.Pass through1H-NMR spectrum can confirm the successful synthesis of Ara-IR820 prodrugs.
What embodiment 3 was based on cytarabine and new indocyanine green small molecule prodrugs (Ara-IR820) has active targeting work(
The metal organic frame drug delivery system of energy is prepared as intravenous formulations
Precision weighs Ara-IR820 prodrugs about 50mg, is dissolved in 2mL water, and the Zn of 0.5mL is instilled under stirring condition
(NO3)2·6H2It in O aqueous solutions, then will be instilled in the 2-methylimidazole aqueous solution of 5mL under above-mentioned suspension stirring condition, carry medicine
MOF nanoparticles spontaneously form, and suspension is centrifuged, and washing discards supernatant, and vacuum drying obtains blue solid Ara-IR820@
ZIF-8。
Ara-IR820@ZIF-8 are dispersed in the aqueous solution of 3mg/mL hyaluronic acids (HA), 48h is stirred at room temperature；It will
The suspension of formation centrifuges, and washing is dried to obtain blue solid, its ultrasound is dispersed in water and obtains targeted vein note
Penetrate preparation.
The Micelle-like Nano-structure of Two intravenous formulations of the present invention form through experiment and stablize suspension concentration up to 10mg/mL
More than.
Sulfonic acid group in nir dye IR820 of the present invention can with metal coordination in metal organic frame to realize compared with
Cytarabine is drawn to anticancer drug cytarabine by amido bond covalent bond by the characteristic of high drug load, IR820
In MOF cavitys, two kinds of drug equimolars realize the metal organic frame drug of the target function of small molecule prodrugs than total load
The structure of delivery system.
Embodiment 4HA/Ara-IR820@ZIF-8 Micelle-like Nano-structure of Two morphologic observations
It takes the Micelle-like Nano-structure of Two after a small amount of drying in 1.5mL Ep pipes, 200 μ L distilled water is added to be suspended.A drop is drawn to be suspended
For drop on carbon film copper mesh, filter paper sucks surplus liquid, and drying at room temperature is placed under transmission electron microscope and observes HA/Ara-
IR820@ZIF-8 Micelle-like Nano-structure of Two forms.As a result electromicroscopic photograph such as Fig. 2 shows that HA/Ara-IR820@ZIF-8 can divide in water
The more rounding nanoparticle structure that diameter is about 100-200nm is dissipated into, form is uniform, favorable dispersibility, and nanoparticle scale is applicable in
It is administered in intravenous injection, and meets enhancing infiltration and be detained requirement of (EPR) effect to grain size.Nanoparticle preparation process does not need
Organic solvent, surfactant is added, need not heat, reaction is more simple and fast.
Pharmacodynamic study in embodiment 5HA/Ara-IR820 ZIF-8 intravenous medical treatment solid tumor bodies
1. the structure of breast cancer mouse model
The BALB/C mouse 25 for taking healthy 6-8 week old, are placed in suitable environment, raise 1 week.Wait for that mouse adapts to environment
Afterwards, in its right fore oxter, inoculation 0.1mL density is 2 × 107Mouse breast cancer (4T1) cell suspension of/mL, after inoculating cell
Continue to raise.The growing state of mouse right fore oxter tumour is checked daily.When gross tumor volume (V=1/2 × length ×
width2) reach about 150mm3Afterwards, inhibiting tumor assay is proceeded by.
2. tumor inhibition
This experiment probes into HA/Ara- using female BAl BIc/C mice of lotus 4T1 mouse mastopathy cells as animal model
The internal antitumous effect of IR820@ZIF-8.Mouse is randomly divided into 5 groups, every group 5.Tail vein injection respectively
Normal saline solution, cytarabine aqueous solution, IR820 aqueous solutions, Ara-IR820@ZIF-8 nanoparticle aqueous solutions, HA/Ara-
IR820@ZIF-8 nanoparticle aqueous solutions.Wherein IR820 aqueous solutions group, Ara-IR820@ZIF-8 nanoparticle aqueous solutions and HA/
The dosage of IR820 is 2mg/kg in Ara-IR820 ZIF-8 nanoparticle aqueous solution groups, and cytarabine aqueous solution group gives medicament
Amount is consistent with preparation group, every three days to a medicine, IR820 aqueous solutions, Ara-IR820 ZIF-8 nanoparticle aqueous solutions and
After the administration of HA/Ara-IR820@ZIF-8 nanoparticle aqueous solution groups, mouse receives near-infrared laser and irradiates 5 minutes, power 1W/
cm2, administration time point is denoted as the 1st, 4,7,10,13,16 day respectively.The weight and knurl of mouse are accumulated every two days and are measured once.It gives
Mouse can free diet, drinking-water during medicine.
In order to evaluate the antitumor efficacies of HA/Ara-IR820@ZIF-8 in vivo, compare by animal model of tumor-bearing mice
Physiological saline group (as a contrast), cytarabine aqueous solution group, IR820 aqueous solutions group, Ara-IR820@ZIF-8 nanoparticle water
The variation of the mouse tumor volume and weight of solution group and HA/Ara-IR820@ZIF-8 nanoparticle aqueous solution groups.It is swollen by measuring
The long and short diameter of tumor and the weight of mouse, calculate gross tumor volume and relative body weight (measures weight W/ original body mass W in real time0), as a result
As shown in Figure 3.
The gross tumor volume of bulk pharmaceutical chemicals group and preparation group is significantly less than physiological saline group, shows bulk pharmaceutical chemicals and preparation to tumour
Growth have apparent inhibiting effect；Moreover, it can be seen from the results that HA/Ara-IR820@ZIF-8 nanoparticle aqueous solution groups pass through
Non-targeted Ara-IR820@ZIF-8 nanoparticle aqueous solutions are apparently higher than to the tumor control rate of mammary gland of mouse tumor after tail vein injection
Group, cytarabine bulk pharmaceutical chemicals group, IR820 bulk pharmaceutical chemicals group and physiological saline group, antitumous effect are optimal.
The changes of weight of mouse can be as measurement drug to the index of animal system toxicity.As seen from Figure 3, physiology
The relative body weight self administration of medication of brine group and preparation group occurs slowly constantly increasing day.And the opposite bank of two bulk pharmaceutical chemicals groups
Weight is but constantly in apparent reduction state.Raw material medicine solution group mouse weight is substantially reduced, shows that it will produce serious system
System toxicity；And preparation group changes of weight is not much different with physiological saline group, shows drug prodrug is made and is contained, targets and pass
The system toxicity of drug can effectively be mitigated after sending to tumor tissues.
The present invention synthesizes cytarabine and new indocyanine green small molecule prodrugs Ara-IR820 for the first time, and prodrugs not only solve
The shortcomings of Ara that determined easily is metabolized inactivation in vivo, and toxicity of the drug to solid tumor is improved, extend the anti-swollen of Ara
Tumor application range.The hole intracavitary that Ara-IR820 is contained to metal organic frame ZIF-8 by simple and rapid method is made and receives
The grain of rice simultaneously realizes active targeting HA modifications, not only economic and environment-friendly, also can be mass, and solid is easy to preserve and transport, for industry
Production provides may.HA/Ara-IR820@ZIF-8 nanoparticle intravenous formulations toxicity is low, and safety is good, solid tumor cancer suppression
Rate processed is high, and possibility is provided to realize that cytarabine is injected intravenously drug treatment solid tumor.In addition, the present invention with compound by connecing
Branch generates prodrug and cytarabine is contained the hole intracavitary of metal organic frame and is prepared into the metal with active targeting function
Organic frame drug delivery system is established for metal organic frame drug delivery system of the research based on Ara small molecule prodrugs later
Fixed basis.
Finally illustrate, the foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, to the greatest extent
Present invention has been described in detail with reference to the aforementioned embodiments for pipe, for those skilled in the art, still can be with
It modifies to the technical solution recorded in previous embodiment, or equivalent replacement is carried out to which part.It is all the present invention
Within spirit and principle, any modification, equivalent replacement, improvement and so on should all be included in the protection scope of the present invention.
Above-mentioned, although the foregoing specific embodiments of the present invention is described with reference to the accompanying drawings, not to the limit of the scope of the present invention
System, those skilled in the art should understand that, based on the technical solutions of the present invention, those skilled in the art need not pay
Go out various modifications or changes that creative work can be made still within protection scope of the present invention.
Claims (10)
1. a kind of metal organic frame drug delivery system with active targeting function based on cytarabine small molecule prodrugs
Preparation method, which is characterized in that prodrug is soluble in water, be added dropwise in ionizable metal salt aqueous solution, will mix under stirring condition
Liquid is closed to be added dropwise under agitation in ligand aqueous solution；The suspension of above-mentioned formation is centrifuged, washing is dried to obtain solid,
That is the metal organic frame drug delivery system based on cytarabine small molecule prodrugs；
The metal organic frame medicaments uniformity for containing cytarabine small molecule prodrugs, which is scattered in, has the function of tumor-targeting
Ligand aqueous solution in be stirred at room temperature；The suspension of formation is centrifuged, washing is dried to obtain solid, that is, it is small to be based on cytarabine
The metal organic frame drug delivery system with active targeting function of molecule prodrug.
2. the gold with active targeting function based on cytarabine small molecule prodrugs that preparation method described in claim 1 obtains
Belong to organic frame drug delivery system, which is characterized in that it is described based on cytarabine small molecule prodrugs include cytarabine with it is thin
Dynamic treatment photosensitizer of water chain, drug molecule, photo-thermal therapy photosensitizer, light etc. combines the small molecule prodrugs formed.
3. the metal with active targeting function of a kind of cytarabine and new indocyanine green small molecule prodrugs (Ara-IR820) has
The preparation method of machine frame drug delivery system, which is characterized in that prodrug Ara-IR820 is soluble in water, it is dripped under stirring condition
It adds in zinc nitrate hexahydrate aqueous solution, mixed liquor is added dropwise under agitation in 2-methylimidazole aqueous solution；By above-mentioned shape
At suspension centrifugation, washing, be dried to obtain blue solid, the i.e. gold based on cytarabine and new indocyanine green small molecule prodrugs
Belong to organic frame drug delivery system Ara-IR820@ZIF-8；
Ara-IR820@ZIF-8 are dispersed in the aqueous solution of hyaluronic acid (HA) and are stirred at room temperature；By the suspension of formation
Centrifugation, washing, is dried to obtain blue solid, that is, is based on cytarabine and new indocyanine green small molecule prodrugs (Ara-IR820)
Metal organic frame drug delivery system HA/Ara-IR820@ZIF-8 with active targeting function.
4. preparation method described in claim 3 obtain based on cytarabine and new indocyanine green small molecule prodrugs (Ara-
IR820 the metal organic frame drug delivery system with active targeting function).
5. the system application in preparation of anti-tumor drugs of claim 2 or 4, which is characterized in that for treating or alleviating
The cancer of a certain tissue or organ, cancer includes but not limited to leukaemia, solid tumor.
6. application according to claim 5, which is characterized in that the system ultrasound described in claim 2 or 4 is evenly dispersed
Intravenous formulations are made in Yu Shuizhong.
7. preparation method according to claim 3, which is characterized in that the following institute of structural formula of the prodrug Ara-IR820
Show：
8. the preparation method according to claim 3 or 7, which is characterized in that the preparation method of the prodrug Ara-IR820 is
New indocyanine green is combined with cytarabine with amido bond, realizes the chemical modification to cytarabine amino.
9. preparation method according to claim 8, which is characterized in that the reaction process of cytarabine and new indocyanine green
For：New indocyanine green is reacted under the conditions of triethylamine is added with 6-aminocaprolc acid, and first step product is generated；Product separating-purifying
Afterwards, it is catalyzed, is reacted with cytarabine before generating above-mentioned cytarabine and new indocyanine green small molecule through triethylamine, ethyl chloroformate
Medicine (Ara-IR820).
10. preparation method according to claim 9, which is characterized in that preparation method includes the following steps：
(1) a certain amount of new indocyanine green is dissolved in anhydrous DMF, and triethylamine is added, a certain amount of 6-aminocaprolc acid is dissolved in anhydrous
It in DMF, is added in above-mentioned reaction solution, is reacted under the conditions of inert gas shielding, 85 DEG C of oil baths, prepare IR820-COOH；
(2) IR820-COOH is purified：Vacuum rotary steam removes reaction dissolvent anhydrous DMF, and vacuum drying obtains crude product；It will slightly produce
Object is dissolved in methanol, silica gel column chromatography purification, and ethyl acetate and methanol elution gradient, it is that blue is solid to obtain IR820-COOH sterlings
Body；The ethyl acetate and methanol volume ratio gradient are 10:1-3:1；
(3) a certain amount of IR820-COOH is dissolved in anhydrous DMF, and triethylamine and ethyl chloroformate, inert gas shielding, ice is added
It is reacted under the conditions of bath；
(4) a certain amount of cytarabine is dissolved in anhydrous DMF, is added in step (3) described reaction solution, prepare above-mentioned Ah
Sugared cytidine and new indocyanine green small molecule prodrugs (Ara-IR820)；
(5) the step of Ara-IR820 is purified (5)：Vacuum rotary steam removes reaction dissolvent anhydrous DMF, and vacuum drying is slightly produced
Object；Crude product is dissolved in methanol, silica gel column chromatography purification, ethyl acetate and methanol elution gradient obtain Ara-IR820 sterlings
For blue solid；The ethyl acetate and methanol volume ratio gradient are 4:1-2.5:1；
In the step (1), new indocyanine green：6-aminocaprolc acid：Triethylamine molar ratio is 1:5:5；
The IR820-COOH, cytarabine and triethylamine：Ethyl chloroformate molar ratio is 1:3:3:3.
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