CN109224082A - A kind of macromolecular prodrug Nano medication, preparation method and applications - Google Patents
A kind of macromolecular prodrug Nano medication, preparation method and applications Download PDFInfo
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- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
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- A61K47/6931—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
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- A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
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Abstract
The invention discloses a kind of macromolecular prodrug Nano medications, preparation method and applications.Macromolecular prodrug Nano medication is that be bonded reduced form lipoic acid-polyethylene glycol amphipathic molecule of two hydrophobic drugs by forming the shell of intermolecular cross-linking cystine linkage be polyethylene glycol hydrophilic polymeric layer, the nano particle that kernel is hydrophobic drug, having a size of 10~1000 nanometers.The pharmaceutical composition nano particle can be used as liquid preparation, solid pharmaceutical preparation, semisolid preparation, and toxicity is low, can be used for oncotherapy.
Description
Technical field
The present invention is a kind of macromolecular prodrug Nano medication and its preparation method and application with oncotherapy effect, is related to
And pharmaceutical technology field.
Background technique
For many small-molecule chemical drugs because hydrophobicity is too strong or hydrophily is too strong, lipophilicity is too poor, it is difficult to through thin
After birth causes the effect for treating disease poor.
Some plant origin drugs with strong physiological activity have strong hydrophobicity, and administration is difficult, using limited.Happiness
Setting alkali (Camptothecin, CPT) and 10-hydroxycamptothecine (HCPT) has stronger cytotoxic activity.Camptothecine compounds
Greatest drawback for oncotherapy is water-soluble very poor, it is difficult to obtain the solution of high effective concentration.In order to improve CPT, HCPT
Hydrophobicity defect, there is research institution and enterprise to be modified the chemical structure of camptothecine, synthesized hundreds of camptothecines and spread out
Biology.So far there are 2 kinds there is certain hydrophilic camptothecin derivative to be approved for clinical cancer therapy, be her respectively
It is vertical to replace health and topotecan, but it is water-soluble still lower.
Taxol is also a kind of alkaloid, is that currently the only one kind can promote microtubule polymerization and stabilization to polymerize micro-pipe
Drug.Studies have shown that taxol is integrated in the micro-pipe of polymerization, not with unpolymerized tubulin dimerization precursor reactant.Taxol
It is primarily adapted for use in oophoroma and breast cancer, also has one to lung cancer, colorectal cancer, melanoma, head-neck carcinoma, lymthoma, brain tumor
Constant current modulation effect.But taxol soluble is poor, need to use Emulsifier EL-60 and ethyl alcohol hydrotropy, and Emulsifier EL-60 can
It can lead to allergic reaction, need pre- to take Claritin before patient medication.Studies have shown that the application of Emulsifier EL-60 reduces
The anti-tumor activity of taxol.Meanwhile taxol has stronger toxic effect due to poor selectivity, is also easy to produce drug resistance, and
The defects of blood-brain barrier can not be penetrated.
It is a kind of important administration mode that drug package, which is carried out control release into carrier,.Nano medication is by drug point
Attached bag is embedded in polymer nanoparticle drug carriers, has many advantages: 1) significantly improving the dissolubility of hydrophobic drug, extend drug body
Interior circulation time improves bioavilability；2) pass through passive target (EPR effect) or active targeting with making drug specificity target
To tumor tissues, its distribution in the normal tissue is reduced, to reduce poisonous side effect of medicine.For treating the anti-of kinds cancer
Cancer medicine Doxil is the liposome medicament for embedding adriamycin, and there is polyethylene glycol (PEG) hydrated sheath on surface.Clinic proves that Doxil can
It to extend the circulation time of drug in vivo, and is enriched with drug in tumor locus, reduces the cardiac toxic of drug.In addition,
Multiple high molecular nanometer drugs based on PEG have entered clinical or different clinical experimental stages.For example, polyethylene glycol-polylactic acid
The nano-micelle drug (Genexol-PM) of copolymer (PEG-PLA) paclitaxel loaded (PTX) was used in South Korea from 2007
Clinical treatment breast cancer, lung cancer and oophoroma etc..
But existing Nano medication is also faced with numerous challenges: 1) Nano medication contains low efficiency (< 10%), is injected into body
After interior, it is easy to decompose or gathers due to being diluted and with the effect of heterogeneity in blood, lead to the drug leakage contained
Or release too early；2) PEG Nano medication drug releasing rate after entering tumor tissues is too slow or discharges insufficient, drug utilization
It spends low.
Therefore, it is necessary to develop new Nano medication release system, drug solubility, stability, targeting are improved, and assign
The sensitive function of quickly releasing the drug of reduction is given, to achieve the purpose that reduce toxic side effect, improve bioavilability.
Summary of the invention
Technical problem: the present invention provides a kind of macromolecular prodrug Nano medication and preparation method and applications, hydrophobicity medicine
Object molecule is connected to form macromolecular prodrug by cystine linkage and low molecular poly hydrophilic high mol, and prodrug is assembled into nanometer
Drug, and kernel is cross-linked to form by cystine linkage, shell is low molecular poly hydrophilic high mol brush, and Nano medication has
The drug release function and better stability for restoring sensitive targets neoplastic cells, do not occur drug leakage.
Technical solution: macromolecular prodrug Nano medication of the invention, including two hydrophobic drugs are led to by cystine linkage
Cross lipoic acid and the amphiphilic macromolecular prodrug of general formula (1) that low molecular poly is connected to form, described amphipathic big point
Sub- prodrug is by self assembly and is cross-linked to form that kernel contains drug, shell is low molecular poly by intermolecular disulfides
The nano particle of hydrophilic high mol brush, having a size of 10~1000 nanometers:
In formula, X is serinol or 3- amino-glycerol, and D is hydrophobic drug, and Y is CH2CH2OCOO or CH2CH2OCONH, n
It is 6~80.
In the preferred embodiment of Nano medication of the present invention, above-mentioned hydrophobic drug be taxol, docetaxel, Cabazitaxel,
Adriamycin, Epi-ADM, daunorubicin, demethoxy daunorubicin, Aclarubicin, pirarubicin, zorubicin, camptothecine,
7-Ethyl-10-hydroxycamptothecin, hydroxycamptothecin, topotecan, Irinotecan, Rubitecan, Belotecan, cepehalotaxus fortunei ester
Alkali, isoharringtonin, rapamycin, maytansine, everolimus or Dasatinib.
In the preferred embodiment of Nano medication of the present invention, Nano medication further includes acceptable carrier in pharmacodynamics.
In the preferred embodiment of Nano medication of the present invention, Nano medication further includes auxiliary agent.In further preferred embodiment, auxiliary agent
It is fat or phosphatide.
In Nano medication preferred embodiment of the invention, Nano medication is liquid preparation, solid pharmaceutical preparation, semisolid preparation, glue
Wafer, granule, gelling agent, injection, sustained release preparation or controlled release preparation.
From the point of view of the screenings such as external pharmacological activity, good antitumor wait of macromolecular prodrug Nano medication performance of the present invention is given birth to
Object activity.Experiments have shown that the toxicity in vivo of macromolecular prodrug Nano medication of the present invention is less than raw medicine.Therefore it can be used as antitumor etc.
Drug is used for patient.
The preparation method of macromolecular prodrug Nano medication of the invention is the macromolecular prodrug by general formula (1) in aqueous solution
In to be assembled into diameter be 10-1000 nanometer of nano-micelle, addition hydrogen peroxide or in air sulfhydryl oxidase cause intermolecular
Crosslinking forms kernel and contains dewatering medicament, and outer layer is the crosslinked nano-particles of hydrophilic polyglycol brush, freeze-dried to obtain
The crosslinked nano-particles freeze-dried powder of packaging medicine.
The present invention also provides a kind of above-mentioned macromolecular prodrug Nano medication application in preparations of anti-tumor drugs.
The preparation method of macromolecular prodrug Nano medication of the invention is big by macromolecular prodrug or the present invention of the invention
The mixture of molecule prodrug and auxiliary agent by film dispersion method, reverse phase evaporation, freeze-drying, ultrasonic dispersion, is sprayed
The preparation of the methods of seasoning, film extrusion or high pressure homogenization method.
The present invention utilizes amphipathic before macromolecular, is self-assembled into nano particle, sulfydryl in macromolecular is utilized to be crosslinked shape
At kernel, low molecular poly brush constitutes shell, is prepared into kernel crosslinking, and the hydrophilic Nano medication of shell improves nanometer
Drug loading rate, the stability of drug；Nano medication of the invention, long half time, antitumor isoreactivity are significantly better than raw medicine.
Macromolecular prodrug Nano medication of the invention is not only a kind of prodrug and pharmaceutical carrier, has long circulating, targeting
Tumour, sensitive release function, have less toxic side effect.
The utility model has the advantages that compared with prior art, the present invention having the advantage that
Macromolecular prodrug Nano medication of the invention, only there are two drug molecule group, hydrophilic segments in prodrugs
For the polyethylene glycol of low molecular weight, prodrugs molecular weight is low, clear in structure.
Macromolecular prodrug Nano medication of the invention is self-assembled into nano particle using the amphipathic of macromolecular prodrug, benefit
It is cross-linked to form kernel with the sulfydryl in macromolecular prodrug molecule, low molecular poly brush constitutes shell, is prepared into kernel friendship
Connection, the hydrophilic Nano medication of shell, drug loading rate are high.
Macromolecular prodrug Nano medication of the invention, shell are low molecular poly brush, and nanoparticles stable is good,
Circulating half-life in vivo is long.
Macromolecular prodrug Nano medication of the invention, hydrophobic drug are bonded on macromolecular chain by cystine linkage,
Drug molecule will not leak, and have glutathione reduction sensibility, mainly quickly release the drug in tumor tissues or tumour cell, just
Often drug molecule is difficult to discharge in tissue, has tumor-targeting.
Macromolecular prodrug Nano medication of the invention, macromolecular prodrug are cross-linked to form kernel by cystine linkage, in vivo not
Easily disintegrate, while there is reduction-sensitive, quickly disintegrate in tumor tissues or tumour cell, realizes quickly drug release.
Macromolecular prodrug Nano medication of the invention, macromolecular prodrug use low molecular poly, degradation in vivo
The residence time is short in vivo for the polyethylene glycol of the low molecular weight released afterwards, is easy and fast to excrete, not be detained in vivo, body
Polyethylene glycol antibody is not generated inside.
Macromolecular prodrug nano particle of the invention, overcome that drug in physically encapsulation type Nano medication easily leaks out lacks
Point.
The part containing drug of macromolecular prodrug Nano medication of the invention includes cystine linkage, can be by glutathione etc.
It degrades and fast fracture, sulfydryl in the fragment after fracture containing drug molecule etc. passes through the carbonyl of " inventing a charge against " attack molecule itself
Base leads to quick release raw medicine, overcomes the defect that general interval arm is difficult to fast fracture and is unable to quick release raw medicine, has
Stronger drug effect.
Macromolecular prodrug Nano medication of the invention has passive target effect, realizes Targeting delivery.
Macromolecular prodrug Nano medication of the invention, can be used as liquid preparation, solid pharmaceutical preparation, semisolid preparation.
Macromolecular prodrug Nano medication of the invention combines targeting group, has active targeting effect.
Nano particle is cross-linked by dioxygen oxidation after macromolecular prodrug assembling of the invention, preparation process is simple.
Detailed description of the invention
Fig. 1 lipoic acid-serinol-polyethylene glycol synthetic route
Bis- camptothecine-lipoic acid-serinol-polyethylene glycol the synthetic routes of Fig. 2
Bis- taxol-lipoic acid-serinol-polyethylene glycol the synthetic routes of Fig. 3
Bis- adriamycin-lipoic acid-serinol-polyethylene glycol the synthetic routes of Fig. 4
Bis- adriamycin-N- lipoic acid-serinol-polyethylene glycol the synthetic routes of Fig. 5
Bis- Cabazitaxel-lipoic acid-serinol-polyethylene glycol the synthetic routes of Fig. 6
Bis- harringtonine-lipoic acid-serinol-polyethylene glycol the synthetic routes of Fig. 7
Bis- maytansine-lipoic acid-serinol-polyethylene glycol the synthetic routes of Fig. 8
Bis- everolimus-lipoic acid-serinol-polyethylene glycol the synthetic routes of Fig. 9
Bis- Dasatinib-lipoic acid-serinol-polyethylene glycol the synthetic routes of Figure 10
Bis- Dasatinib-lipoic acid-amino-glycerol-polyethylene glycol the synthetic routes of Figure 11
Sulfhydryl oxidase in Figure 12 macromolecular prodrug is crosslinked schematic diagram
Figure 13 dynamic light scattering method measures double camptothecine-lipoic acid-serinol-polyethylene glycol macromolecular prodrug nano particles
Size (A) and its transmission electron microscope picture (B)
The external degradation of the bis- camptothecine-lipoic acid-serinol-polyethylene glycol macromolecular prodrug nano particles of Figure 14
The extracorporeal anti-tumor of the bis- camptothecine-lipoic acid-serinol-polyethylene glycol macromolecular prodrug nano particles of Figure 15 is living
Property, (A) breast cancer cell MCF-7, (B) HepG-2 cell
The blood concentration (A) of the bis- camptothecine-lipoic acid-serinol-polyethylene glycol macromolecular prodrug nano particles of Figure 16 with
Distribution (B) of the drug in tumour and tissue
It is antitumor in the bis- camptothecine-lipoic acid-serinols of Figure 17-polyethylene glycol macromolecular prodrug nano particle animal body
Effect (A) and the weight of animals variation (B).
Specific embodiment
Further details of the technical solution of the present invention with embodiment with reference to the accompanying drawings of the specification.
A kind of macromolecular prodrug Nano medication of the invention, which is characterized in that two hydrophobic drugs are by cystine linkage
The macromolecular prodrug of general formula (1), prodrug self assembly are connected to form by lipoic acid and low molecular poly hydrophilic high mol
And to be cross-linked to form kernel be the cross-linked structure containing drug, shell is low molecular poly hydrophilic high mol by cystine linkage
The nano particle of brush, having a size of 10~1000 nanometers.
In formula, X is serinol or 3- amino-glycerol, and D is hydrophobic drug, and Y is CH2CH2OCOO or CH2CH2OCONH, n
It is 6~80.
Above-mentioned hydrophobic drug B is that taxone includes taxol, docetaxel, Cabazitaxel, Anthraquinone
Including adriamycin, Epi-ADM, daunorubicin, demethoxy daunorubicin, Aclarubicin, pirarubicin, zorubicin, camplotheca acuminata
Bases drug includes that camptothecine, 7-Ethyl-10-hydroxycamptothecin, hydroxycamptothecin, topotecan, Irinotecan, Shandong ratio replace
Health, Belotecan, harringtonine as medicinal materials drug include harringtonine, isoharringtonin and maytansine, everolimus,
Dasatinib.
Macromolecular prodrug Nano medication of the present invention includes acceptable carrier or auxiliary agent in pharmacodynamics, and the auxiliary agent is rouge
One of fat, phosphatide.
The preparation method of macromolecular prodrug Nano medication of the present invention is the macromolecular prodrug of general formula (1) or (2) in aqueous solution
In to be assembled into diameter be 10-1000 nanometer of nano-micelle, addition hydrogen peroxide or in air sulfhydryl oxidase cause intermolecular
Crosslinking forms kernel and contains dewatering medicament, and outer layer is the crosslinked nano-particles of hydrophilic polyglycol brush, freeze-dried to obtain
The crosslinked nano-particles freeze-dried powder of packaging medicine.
Macromolecular prodrug Nano medication application in preparation of anti-tumor drugs of the present invention.
In the preferred embodiment of pharmaceutical composition of the present invention, pharmaceutical composition is liquid preparation, solid pharmaceutical preparation, semisolid system
Agent, capsule, granule, gelling agent, injection, sustained release preparation or controlled release preparation.
From the point of view of the screenings such as external pharmacological activity, the good bioactivity such as antitumor of Nano medication of the present invention performance.Examination
It tests and shows that the toxicity in vivo of the compounds of this invention is less than raw medicine.Therefore it can be used as antitumor equal drugs for patient.
Nano medication prepared by the present invention, cross-film ability is strong, and liquid preparation, solid pharmaceutical preparation, semisolid system can be formed by having
The characteristic of agent has target function for the treatment such as tumour；Nano medication of the invention, degradation in vivo rapid delivery of pharmaceuticals,
Drug effect is played, there is less toxic side effect.
Nano medication of the invention is preparing the application in antitumor equal drugs, by the macromolecular prodrug Nano medication,
Medicament is prepared into carrier acceptable in pharmacodynamics.It can be by Nano medication of the present invention and one or more solids or liquid medicine
Excipient and/or adjuvant combine, and are made and can be used as administration form or dosage form appropriate that people's medicine uses.Usual medicine of the present invention
Compositions contain the Nano medication of the present invention of weight percent 0.1-100%.
Nano medication administration route of the present invention can be enteron aisle or non-bowel, and such as oral, muscle, subcutaneous, nasal cavity, oral cavity are viscous
Film, skin, peritonaeum or rectum etc..It can be drug administration by injection, including intravenous injection, intramuscular injection, subcutaneous injection, intracutaneous injection and cave
Position injection etc..Form of administration can be liquid dosage form, solid dosage forms.As liquid dosage form can be true solution class, colloidal type, particle
Dosage form, emulsion dosage form, mixed suspension form.Other dosage forms such as tablet, dripping pill, aerosol, pill, pulvis, solution, mixes capsule
Suspension, emulsion, granule, suppository, freeze drying powder injection etc..
The compounds of this invention can be made ordinary preparation, be also possible to sustained release preparation, controlled release preparation, targeting preparation and various
Particulate delivery system.
There are disulfide bond spacerarm or cross-bond in Nano medication of the invention.The spacerarm or cross-bond in tumor tissues or
The effects of intracellular glutathione and fast fracture, quick release proto-drug play drug effect.
Nano medication of the present invention improves the efficiency of drug package and the stability of drug, while Nano medication being made to be easy to take the photograph
Enter intracellular, performance drug effect.
Synthetic agent abbreviation is as follows in embodiment:
Tetrabutyl ammonium fluoride trihydrate: TBAF
2- (pyridyl group-disulphanes base) ethyl alcohol:
1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride: EDCHCl
Lipoic acid: LA
Diisopropyl ethyl amine: DIPEA
I-hydroxybenzotriazole: HOBt
4- (dimethylamino) pyridine: DMAP
Triphosgene: BTC
Tertbutyloxycarbonyl: BOC
Reference examples 1:
The synthesis of reduced form lipoic acid-serinol-polyethylene glycol (LA-SPEG) (synthetic route is shown in Fig. 1)
Dithio-octanoic acid-serinol ester (diLA-Ser) synthesis: 2.97g lipoic acid (LA), 3.31g 1- ethyl -3- (3- bis-
Dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl) is added in 100mL round-bottomed flask, 40mL CH is added2Cl2Dissolution is lived
Change 30min.20mL CH will be dissolved in2Cl21.25g Boc- serinol and 2.21g 4- (dimethylamino) pyridine (DMAP) plus
Enter into above-mentioned mixed liquor, reacts 12h.It filters after the reaction was completed, filtrate is sufficiently washed with excess 0.1mol/L hydrochloric acid, stand
After discard water phase.The dry oily phase of sodium sulphate, column chromatographic purifying (eluent: CHCl3/CH3OH=20/1, v/v), it obtains faint yellow
Oily liquids di-Boc-LA-Ser (3.19g, yield 86%).Take 1g di-Boc-LA-Ser in 10mL CH2Cl2In, it is cooled to 0
DEG C, it is slowly added dropwise 0.41g trifluoroacetic acid (TFA), reacts 2h.Mixture is concentrated in vacuo, diLA-Ser crude product is obtained.
The synthesis of reduced form lipoic acid-serinol-polyethylene glycol (LA-SPEG): diLA-Ser crude product is dissolved in 20mL
Anhydrous CH2Cl2, addition 3g methoxy poly (ethylene glycol) monomester succinate (molecular weight polyethylene glycol is respectively 4000,2000,1000,
300), 0.42g EDCHCl, 0.19g I-hydroxybenzotriazole (HOBt) and 0.85g diisopropyl ethyl amine (DIPEA), room
Temperature reaction 12h.50mL CH is added2Cl2Dilution, is washed 3 times with 0.1M HCl.It collects and merges organic phase, anhydrous Na2SO4It is dry,
Vacuum concentration.Through silica gel column chromatography (CH2Cl2/ MeOH=20/1, v/v) purifying, obtain yellow solid or liquid, about 3g.It will
Intermediate product is dissolved in 15mL methanol and water mixed liquid (1/4, v/v), is cooled to 0 DEG C, and 0.10g NaBH is added4, react 2 hours
Until solution becomes colorless.After reaction, pH to 3.0, dialysis purification oligomer are adjusted.Freeze-drying obtains white solid or viscous fluid
Each about 2.5g of body reduced form lipoic acid-serinol-polyethylene glycol (LA-SPEG),.According to molecular weight polyethylene glycol, product difference
It is denoted as LA-SPEG4K, LA-SPEG2K, LA-SPEG1K, LA-SPEG300.
Reference examples 1:
The synthesis of reduced form lipoic acid-amino-glycerol-polyethylene glycol (LA-GPEG)
Dithio-octanoic acid-amino-glycerol Lipase absobed: 3g lipoic acid (LA), 3.31g 1- ethyl -3- (3- dimethylamino third
Base) carbodiimide hydrochloride (EDCHCl) is added in 100mL round-bottomed flask, 40mL CH is added2Cl2Dissolution activation 30min.It will
It is dissolved in 20mL CH2Cl21.25g Boc-3- amino-glycerol and 2g 4- (dimethylamino) pyridine (DMAP) be added to it is above-mentioned mixed
It closes in liquid, reacts 12h.It filters after the reaction was completed, filtrate is sufficiently washed with excess 0.1mol/L hydrochloric acid, water is discarded after standing
Phase.The dry oily phase of sodium sulphate, column chromatographic purifying (eluent: CHCl3/CH3OH=20/1, v/v), obtain pale yellow oily liquid.
Intermediate product is dissolved in 10mL CH2Cl2In, it is cooled to 0 DEG C, is slowly added dropwise 0.41g trifluoroacetic acid (TFA), reacts 2h.Mixture is true
Sky concentration, obtains dithio-octanoic acid-amino-glycerol ester crude product.
Reduced form lipoic acid-amino-glycerol-polyethylene glycol synthesis: dithio-octanoic acid-amino-glycerol ester crude product is dissolved in
The anhydrous CH of 20mL2Cl2, addition 3g methoxy poly (ethylene glycol) monomester succinate (molecular weight polyethylene glycol is respectively 4000,2000,
1000,300), 0.42g EDCHCl, 0.19g I-hydroxybenzotriazole (HOBt) and 0.85g diisopropyl ethyl amine
(DIPEA), 12h is reacted at room temperature.50mL CH is added2Cl2Dilution, is washed 3 times with 0.1M HC1.It collects and merges organic phase, it is anhydrous
Na2SO4It is dry, vacuum concentration.Through silica gel column chromatography (CH2Cl2/ MeOH=20/1, v/v) purifying, obtain yellow solid or liquid
Methoxy poly (ethylene glycol) succinimidyl glycerol lipoate, about 3g.Intermediate product is dissolved in 15mL methanol and water mixed liquid
In (1/4, v/v), be cooled to 0 DEG C, 0.10g NaBH be added4, reaction 2 hours until solution becomes colorless.After reaction, it adjusts
PH to 3.0, dialysis purification oligomer.Freeze-drying obtains white solid or thick liquid reduced form lipoic acid-poly- second two of amino-glycerol-
The each about 2.5g of alcohol LA-GPEG.According to molecular weight polyethylene glycol, product is denoted as LA-GPEG4K, LA-GPEG2K, LA- respectively
GPEG1K, LA-GPEG300.
Embodiment 1:
The synthesis of double camptothecine-lipoic acid-serinol-polyethylene glycol (diCPTLA-SPEG) (synthetic route is shown in Fig. 2)
0.8g camptothecine (CPT) and the dissolution of 0.3g triphosgene (BTC) mixture are suspended in anhydrous 40mL CH2Cl2In, N2
The CH of 0.6g DMAP is slowly added dropwise under protection2Cl2Solution.2h is reacted at room temperature, 0.4g2- (pyridyl group-two is then added at one time
Sulfanyl) ethyl alcohol, it is stirred overnight.Reaction mixture body is washed with deionized, is concentrated in vacuo.Silica gel chromatography crude product
(eluent: EtOAc/DCM=1/1, v/v) obtains light yellow solid camptothecine dithiopyridines (CPT-SS-Pyr) 0.6g, yield
50%.
Take respectively control column 1 LA-SPEG4K, LA-SPEG2K, LA-SPEG1K, each 0.06g of LA-SPEG300, respectively plus
Enter to 0.1g CPT-SS-Pyr and be dissolved in 2mL methanol/dimethyl sulfoxide (2/3, v/v) mixed liquor, be stirred to react 48h at 37 DEG C, leads to
Dialyse 12h in the deionized water of nitrogen deoxygenation, and freeze-drying respectively obtains the double camptothecine-lipoic acid-serinols-of pale yellow powder
Polyethylene glycol, and the molecular weight according to polyethylene glycol is denoted as diCPTLA-SPEG4K, diCPTLA-SPEG2K, diCPTLA- respectively
SPEG1K, diCPTLA-SPEG300, respectively about 0.08g.
Embodiment 2:
The synthesis of double taxol-lipoic acid-serinol-polyethylene glycol (diPTXLA-SPEG) (synthetic route is shown in Fig. 3)
0.3g taxol -2 '-tertiary butyl dimethylsilane (PTX-2 '-TBDMS) and 0.12g triphosgene (BTC) is taken to mix
Object dissolves or is suspended in anhydrous 40mL CH2Cl2In, N2Under protection, the CH of 0.29g DMAP is slowly added dropwise2Cl2Solution, room temperature are anti-
Answer 2h.Then, it is added at one time 0.20g 2- (pyridyl group-disulphanes base) ethyl alcohol, is stirred overnight.Mixing is washed with deionized
Liquid system, vacuum concentration.Pass through silica gel chromatography crude product (EtOAc/DCM=1/1, v/v).Crude product is dissolved in 20mL bis-
In chloromethanes, 0.5 gram of tetrabutyl ammonium fluoride deprotection is added.Reaction solution concentration after, by silica gel chromatography (eluent:
EtOAc/DCM=1/1, v/v).Obtain light yellow solid taxol dithiopyridines (PTX-SS-Pyr) 0.35g.
Take respectively control column 1 LA-SPEG4K, LA-SPEG2K, LA-SPEG1K, each 0.06g of LA-SPEG300, respectively plus
Enter to 0.1g PTX-SS-Pyr and is dissolved in 2mL methanol/dimethyl sulfoxide (2/3, v/v) mixed liquor, after stirring 48h under the conditions of 37 DEG C,
Dialyse 12h in the deionized water of logical nitrogen deoxygenation.Freeze-drying respectively obtains the double taxol-lipoic acid-serinols-of white powder
Polyethylene glycol, and the molecular weight according to polyethylene glycol is denoted as diPTXLA-SPEG4K, diPTXLA-SPEG2K, diPTXLA- respectively
SPEG1K, diPTXLA-SPEG300, respectively about 0.07g.
Embodiment 3:
The synthesis of double adriamycin-lipoic acid-serinol-polyethylene glycol (diDOXLA-SPEG) (synthetic route is shown in Fig. 4)
0.20g 2- (pyridyl group-disulphanes base) ethyl alcohol is dissolved in anhydrous 40mL CH2Cl2, it is added 0.12g triphosgene (BTC)
In mixture, N2Under protection, the CH of 0.3g DMAP is slowly added dropwise2Cl2Solution reacts at room temperature 4h.0.3g adriamycin hydrochloric acid is added
The 40mL CH of salt (DOXHCl)2Cl2Suspension reacts 4 hours.Then, pass through silica gel chromatography crude product (EtOAc/
DCM=1/1, v/v), obtain red solid powder adriamycin dithiopyridines (DOX-SS-Pyr) 0.35g.
0.06g LA-SPEG1K and 0.1g DOX-SS-Pyr is weighed, 2mL methanol/dimethyl sulfoxide (2/3, v/v) is codissolved in
In mixed liquor, after stirring 48h under the conditions of 37 DEG C, dialyse 12h in the deionized water of logical nitrogen deoxygenation.Freeze-drying, obtains red
Double adriamycin-lipoic acid-serinol-the polyethylene glycol (diDOXLA-SPEG1K) of solid powder.
Embodiment 4:
The synthesis of double adriamycin-N- lipoic acid-serinol-polyethylene glycol (diDOXLA-SPEG) (synthetic route is shown in Fig. 5)
0.20g 2- (pyridyl group-disulphanes base) ethyl alcohol is dissolved in anhydrous 40mL CH2Cl2, it is added 0.12g triphosgene (BTC)
In mixture, N2Under protection, the CH of 0.3g DMAP is slowly added dropwise2Cl2Solution reacts at room temperature 4h.It is added 0.3g adriamycin (DOX)
40mL CH2Cl2Suspension reacts 4 hours.Then, pass through silica gel chromatography crude product (EtOAc/DCM=1/1, v/
V), red solid powder adriamycin dithiopyridines (DOX-SS-Pyr) 0.35g is obtained.
0.06g LA-SPEG1K and 0.1g DOX-SS-Pyr is weighed, 2mL methanol/dimethyl sulfoxide (2/3, v/v) is codissolved in
In mixed liquor, after stirring 48h under the conditions of 37 DEG C, dialyse 12h in the deionized water of logical nitrogen deoxygenation.Freeze-drying, obtains red
Double adriamycin-N- lipoic acid-serinol-the polyethylene glycol (diDOXNLA-SPEG1K) of solid powder.
Embodiment 5:
Double Cabazitaxel-lipoic acid-serinol-polyethylene glycol synthesis (synthetic route is shown in Fig. 6)
0.3g Cabazitaxel (CAB) and the dissolution of 0.12g triphosgene mixture are suspended in anhydrous 40mL CH2Cl2In, in N2
It protects under atmosphere, the CH of 0.29g DMAP is slowly added dropwise2Cl2Solution, the hydroxyl of Cabazitaxel is reacted with triphosgene at room temperature.With
Afterwards, it is added at one time 0.20g 2- (pyridyl group-disulphanes base) ethyl alcohol, is stirred overnight.Mixture system is washed with deionized,
Vacuum concentration.Pass through silica gel chromatography crude product (EtOAc/DCM=1/1, v/v).Obtain two sulphur of light yellow solid adriamycin
For pyridine (CAB-SS-Pyr) 0.25g.
0.06g LA-SPEG1K and 0.1g CAB-SS-Pyr is weighed, 2mL methanol/dimethyl sulfoxide (2/3, v/v) is codissolved in
In mixed liquor, after stirring for 24 hours under the conditions of 37 DEG C, dialyse 12h in the deionized water of logical nitrogen deoxygenation.Freeze-drying, obtains white
Double Cabazitaxel-lipoic acid-serinol-polyethylene glycol the 1K (diCABLA-SPEG1K) of powder.
Embodiment 6:
Double harringtonine-lipoic acid-serinol-polyethylene glycol synthesis (synthetic route is shown in Fig. 7)
0.3g harringtonine (HAR) and 0.12g triphosgene mixture is taken to dissolve or be suspended in anhydrous 40mL CH2Cl2In,
In N2It protects under atmosphere, the CH of 0.29g DMAP is slowly added dropwise2Cl2Solution, hydroxyl at room temperature are reacted with triphosgene.Then, one
0.20g 2- (pyridyl group-disulphanes base) ethyl alcohol is added in secondary property, is stirred overnight.Mixture system, vacuum is washed with deionized
Concentration.Pass through silica gel chromatography crude product (EtOAc/DCM=1/1, v/v).Obtain two sulphur of light yellow solid harringtonine
For pyridine (HAR-SS-Pyr) 0.25g.
0.06g LA-SPEG1K and 0.1g HAR-SS-Pyr is weighed, 2mL methanol/dimethyl sulfoxide (2/3, v/v) is codissolved in
In mixed liquor, after stirring for 24 hours under the conditions of 37 DEG C, dialyse 12h in the deionized water of logical nitrogen deoxygenation.Freeze-drying, obtains white
Double harringtonine-lipoic acid-serinol-polyethylene glycol the 1K (diHARLA-SPEG1K) of powdered product.
Embodiment 7:
Double maytansine-lipoic acid-serinol-polyethylene glycol 1K synthesis (synthetic route is shown in Fig. 8)
0.3g maytansine (MAY) is taken to be dissolved in anhydrous 40mL CH2Cl2In, in N2It protects under atmosphere, 0.29g is slowly added dropwise
The CH of DMAP2Cl2Solution is added 2,2 '-two sulphur of 0.20g, two pyridine, is stirred overnight.Mixture system is washed with deionized,
Vacuum concentration.Pass through silica gel chromatography crude product (EtOAc/DCM=1/1, v/v).Obtain two sulphur of light yellow solid maytansine
For pyridine (MAY-SS-Pyr) 0.25g.
0.06gLA-SPEG1K- and 0.1g MAY-SS-Pyr is weighed, 2mL methanol/dimethyl sulfoxide (2/3, v/v) is codissolved in
In mixed liquor, after stirring for 24 hours under the conditions of 37 DEG C, dialyse 12h in the deionized water of logical nitrogen deoxygenation.Freeze-drying, obtains white
Double maytansine-lipoic acid-serinol-polyethylene glycol the 1K (diMAYLA-SPEG1K) of powdered product.
Embodiment 8:
The synthesis of double everolimus-lipoic acid-serinol-polyethylene glycol (diEVELA-SPEG) (synthetic route is shown in Fig. 9)
Take 0.3g tertiary butyl dimethyl siloxane protect everolimus (EVE) and 0.12g triphosgene mixture dissolve or
It is suspended in anhydrous 40mL CH2Cl2In, in N2It protects under atmosphere, the CH of 0.29g DMAP is slowly added dropwise2Cl2Solution, at room temperature according to
The hydroxyl of Wei Mosi is reacted with triphosgene.Then, it is added at one time 0.20g 2- (pyridyl group-disulphanes base) ethyl alcohol, it is stirred
Night.Mixture system is washed with deionized, is concentrated in vacuo.Crude product is dissolved in 20mL methylene chloride, and 0.5 gram of tetrabutyl is added
Ammonium fluoride deprotection.After reaction solution concentration, pass through silica gel chromatography (eluent: EtOAc/DCM=1/1, v/v).It obtains shallowly
Yellow solid everolimus dithiopyridines (EVE-SS-Pyr) 0.25g.
0.06g LA-SPEG1K- and 0.1g EVE-SS-Pyr is weighed, 2mL methanol/dimethyl sulfoxide (2/3, v/v) is codissolved in
In mixed liquor, after stirring for 24 hours under the conditions of 37 DEG C, dialyse 12h in the deionized water of logical nitrogen deoxygenation.Freeze-drying, obtains white
Double everolimus-lipoic acid-serinol-polyethylene glycol the 1K (diEVELA-SPEG1K) of powdered product.
Embodiment 9:
The synthesis of double Dasatinibs-lipoic acid-polyethylene glycol (diDASLA-SPEG) (synthetic route is shown in Figure 10)
0.3g Dasatinib (DAS) and 0.12g triphosgene mixture is taken to dissolve or be suspended in anhydrous 40mL CH2Cl2In,
N2It protects under atmosphere, the CH of 0.29g DMAP is slowly added dropwise2Cl2Solution, the hydroxyl of Dasatinib is reacted with triphosgene at room temperature.
Then, it is added at one time 0.20g 2- (pyridyl group-disulphanes base) ethyl alcohol, is stirred overnight.Mixing liquid is washed with deionized
System, vacuum concentration.Pass through silica gel chromatography crude product (EtOAc/DCM=1/1, v/v).Obtain light yellow solid Dasatinib
Dithiopyridines (DAS-SS-Pyr) 0.25g.
0.06g LA-SPEG1K- and 0.1g DAS-SS-Pyr is weighed, 2mL methanol/dimethyl sulfoxide (2/3, v/v) is codissolved in
In mixed liquor, after stirring for 24 hours under the conditions of 37 DEG C, dialyse 12h in the deionized water of logical nitrogen deoxygenation.Freeze-drying, obtains white
Double Dasatinib-lipoic acid-serinol-polyethylene glycol the 1K (diDASLA-SPEG1K) of powdered product.
Embodiment 10:
(synthetic route is shown in figure for the synthesis of double Dasatinib-lipoic acid-amino-glycerol-polyethylene glycol (diDASLA-GPEG)
11)
0.3g Dasatinib (DAS) and 0.12g triphosgene mixture is taken to dissolve or be suspended in anhydrous 40mL CH2Cl2In,
N2It protects under atmosphere, the CH of 0.29g DMAP is slowly added dropwise2Cl2Solution, the hydroxyl of Dasatinib is reacted with triphosgene at room temperature.
Then, it is added at one time 0.20g 2- (pyridyl group-disulphanes base) ethyl alcohol, is stirred overnight.Mixing liquid is washed with deionized
System, vacuum concentration.Pass through silica gel chromatography crude product (EtOAc/DCM=1/1, v/v).Obtain light yellow solid Dasatinib
Dithiopyridines (DAS-SS-Pyr) 0.25g.
Take respectively control column 2 LA-GPEG4K, LA-GPEG2K, LA-GPEG1K, each 0.06g of LA-GPEG300, respectively plus
Enter to 0.1g DAS-SS-Pyr and be dissolved in 2mL methanol/dimethyl sulfoxide (2/3, v/v) mixed liquor, be stirred to react 12h at 37 DEG C, leads to
Dialyse 12h in the deionized water of nitrogen deoxygenation, and it is sweet that freeze-drying respectively obtains the double Dasatinib-lipoic acid-amino of white powder
Oil-polyethylene glycol, and the molecular weight according to polyethylene glycol be denoted as respectively diDASLA-GPEG4K, diDASLA-GPEG2K,
DiDASLA-GPEG1K, diDASLA-GPEG300, respectively about 0.08g.
Embodiment 12:
The preparation of macromolecular prodrug nano particle
Double camptothecine-lipoic acid-the serinols-of the macromolecular prodrug of the different molecular weight polyethylene glycols of embodiment 1~11 are poly-
Ethylene glycol (diCPTLA-SPEG), double taxol-lipoic acids-serinol-polyethylene glycol (diPTXLA-SPEG), double adriamycins-
Lipoic acid-serinol-polyethylene glycol (diDOXLA-SPEG), double adriamycin-N- lipoic acid-serinol-polyethylene glycol
(diDOXNLA-SPEG), double Cabazitaxel-lipoic acids-serinol-polyethylene glycol (diCBALA-SPEG), double harringtonines-
Lipoic acid-serinol-polyethylene glycol (diHARLA-SPEG), double maytansine-lipoic acid-serinol-polyethylene glycol (diMAYLA-
SPEG), double everolimus-lipoic acid-serinol-polyethylene glycol (diEVELA-SPEG), double poly- second of Dasatinib-lipoic acid-
Glycol (diDASLA-SPEG), double Dasatinib-lipoic acids-amino-glycerol-polyethylene glycol (diDASLA-GPEG) each 0.05g,
It is scattered in the 10mL water of letting nitrogen in and deoxidizing gas, mixes slowly 20 minutes respectively.Lead to a small amount of oxygen, makes the sulfydryl in macromolecular prodrug
Oxidation cross-linked (crosslinking schematic diagram is shown in Figure 12), obtains macromolecular prodrug nanoparticles solution.Freeze-drying, obtains macromolecular prodrug
Powder of nanometric particles.
Dynamic light scattering (DLS) method detects nano particle diameter, as the result is shown all various macromolecular prodrug nanometers
Grain average grain diameter is 50~100 nanometers.Transmission electron microscope measures the form of nano particle, as the result is shown all macromolecular prodrug nanometers
Particle shows spherical structure.Figure 13 (A) is that dynamic light scattering method measures double camptothecine-lipoic acid-serinol-polyethylene glycol
The average grain diameter of 1K macromolecular prodrug nano particle, value 75nm, Figure 13 (B) are its nano particle forms, in regular ball
Shape.
Embodiment 13:
Double camptothecine-lipoic acids-serinol-polyethylene glycol (diCPTLA-SPEG) macromolecular prodrug nano particle is external
Degradation
Sample: double camptothecine-lipoic acid-serinol-polyethylene glycol 1K (diCPTLA-SPEG1K) prepared by embodiment 12
Macromolecular prodrug nano particle is dissolved in suitable PBS solution and is configured to the solution that concentration is 0.1mmol.
Above-mentioned sample is respectively classified into 2 parts, and PBS buffer solution 0.5mL (the GSH concentration of glutathione (GSH) is added in a copy of it
20mM), PBS buffer solution is added in another, places and is incubated in incubator 37 DEG C, is contained with high performance liquid chromatography detection camptothecine
Amount (Agilent 1100LC, Zorbax reverse phase C18 column, 150 × 4.6mm, 5 μm, sample volume 20 μ L, 25 DEG C of column temperature, Detection wavelength
λ=254nm；Gradient elution: 2-90% buffer solution B/A, flow velocity 1.0mL/min, buffer solution A: the deionized water of 0.1%TFA is delayed
The acetonitrile of fliud flushing B:0.1%TFA).
The result shows that: the result is shown in Figure 14.Double camptothecine-lipoic acid-serinol-polyethylene glycol (diCPTLA- of GSH processing
SPEG1K) the camptothecine raw medicine that the PBS solution of macromolecular prodrug nano particle releases after 0.5 hour reaches total amount
The camptothecine raw medicine released after 70%, 1 hour reaches the 90% of total amount；Macromolecular prodrug nano particle without GSH processing
The camptothecine raw medicine that solution releases after 1 hour is only the 10% of total amount.
Obviously, diCPTLA-SPEG1K macromolecular prodrug nano particle has GSH sensibility.Under GSH effect,
The cystine linkage of diCPTLA-SPEG1K macromolecular prodrug nano particle is broken, and by post-rift end group sulfydryl attack carbonic acid ester bond
Carbonyl, so that quick release goes out camptothecine raw medicine.
Embodiment 14:
The external degradation of adriamycin macromolecular prodrug nano particle
Sample: double adriamycin-lipoic acid-serinol-polyethylene glycol 1K (diDOXLA-SPEG1K) of the preparation of embodiment 12,
Double adriamycin-N- lipoic acid-serinol-polyethylene glycol 1K (diDOXNLA-SPEG1K) macromolecular prodrug nano particles are dissolved in suitable
The PBS solution of amount is configured to the solution that concentration is 0.1mmol.
Above two sample is respectively classified into 2 parts, and the PBS buffer solution 0.5mL (GSH of glutathione (GSH) is added in a copy of it
Concentration 20mM), PBS buffer solution is added in another, places and is incubated in incubator 37 DEG C, with high performance liquid chromatography detection camplotheca acuminata
(Agilent 1100LC, Zorbax reverse phase C18 column, 150 × 4.6mm, 5 μm, 20 μ L of sample volume, is detected alkali content by 25 DEG C of column temperature
Wavelength X=254nm；Gradient elution: 2-90% buffer solution B/A, flow velocity 1.0mL/min, buffer solution A: the deionization of 0.1%TFA
Water, buffer solution B: the acetonitrile of 0.1%TFA).
The result shows that: diDOXLA-SPEG1K, diDOXNLA-SPEG1K macromolecular prodrug nano particle of GSH processing
The camptothecine raw medicine that PBS solution releases after 0.1 hour reaches the 70% of total amount, the adriamycin raw medicine released after 1 hour
Reach the 85% of total amount；The adriamycin raw medicine released behind macromolecular prodrug nanoparticles solution 1 hour without GSH processing is low
In the 10% of total amount.
Obviously, diDOXLA-SPEG1K, diDOXNLA-SPEG1K macromolecular prodrug nano particle have GSH sensibility.?
Under GSH effect, the cystine linkage of diDOXLA-SPEG1K, diDOXNLA-SPEG1K macromolecular prodrug nano particle is broken, and by breaking
The carbonyl of end group sulfydryl attack carbonic acid ester bond after splitting or urethane bond, so that quick release goes out adriamycin raw medicine.
Experimental example 15:
Pharmacological evaluation: mtt assay cancer cell vitality test
Double camptothecine-lipoic acid-serinols-polyethylene glycol 1K (diCPTLA-SPEG1K) macromolecular prodrug nano particle
Anti-tumor activity
MCF-7 human breast cancer cell, hepatocellular carcinoma H22 are with 8 × 103The inoculum concentration in a/hole is inoculated in 96 well culture plates,
5%CO2, cultivate for 24 hours in 37 DEG C of incubators after, the diCPTLA-SPEG1K macromolecular of the embodiment 12 of various concentration is added in every hole
Prodrug nanoparticles solution, control camptothecin drug solution (camptothecine is dissolved in physiological saline, with DMSO solubilising) each 100 μ L, make
The drug final concentration finally screened is respectively 1,2,5,10,20 μ g/mL, after continuing culture for 24 hours；It is separately added into 50 μ LMTT incubation
4h discards culture medium, and 150 μ LDMSO are added, shake up on plate shaker, microplate reader 495nm read plate, according to the absorbance measured
Value calculates cell inhibitory rate.Data are expressed as average ± SD (n=6).
As a result as shown in figure 15, diCPTLA-SPEG1K macromolecular prodrug nano particle is to breast cancer cell MCF-7 and liver
Cancer cell HepG-2 has good growth inhibition and lethal effect, remains camptothecine powerful antitumor activity, corresponds to two kinds and swells
The IC50 value of oncocyte is respectively 2.06 μ g/mL and 1.89 μ g/mL, and cytotoxicity enhances with the increase of drug concentration,
With concentration dependent.Under identical drug dose, diCPTLA-SPEG1K macromolecular prodrug nano particle shows cell toxicant
Property is weak compared with the camptothecine raw medicine of free state.This is because double camptothecine-lipoic acids-polyethylene glycol 1K macromolecular prodrug nano particle
Self assembly is stable nano particle in PBS (pH 7.4), and the camptothecin drug compared to free state discharges, and may be had certain
Slow releasing function.Therefore it is lower to show opposite free state drug in for 24 hours for diCPTLA-SPEG1K macromolecular prodrug nano particle
Anti-tumor activity.
Experimental example 16:
Pharmacological evaluation: mtt assay cancer cell vitality test
The anti-tumor activity of adriamycin macromolecular prodrug nano particle
MCF-7 human breast cancer cell, hepatocellular carcinoma H22 are with 8 × 103The inoculum concentration in a/hole is inoculated in 96 well culture plates,
5%CO2, cultivate for 24 hours in 37 DEG C of incubators after, double adriamycin-lipoic acid-silk ammonia of the embodiment 12 of various concentration are added in every hole
Alcohol-polyethylene glycol 1K (diDOXLA-SPEG1K), double adriamycin-N- lipoic acid-serinol-polyethylene glycol 1K (diDOXNLA-
SPEG1K) macromolecular prodrug nanoparticles solution, control Doxorubicin solution (adriamycin is dissolved in physiological saline, with DMSO solubilising) are each
100 μ L, making the drug final concentration finally screened is respectively 1,2,5,10,20 μ g/mL, after continuing culture for 24 hours；It is separately added into 50 μ
LMTT incubates 4h, discards culture medium, and 150 μ LDMSO are added, shake up on plate shaker, microplate reader 495nm read plate, according to measuring
Absorbance value calculate cell inhibitory rate.Data are expressed as average ± SD (n=6).
The result shows that double adriamycin-lipoic acid-serinols-polyethylene glycol 1K (diDOXLA-SPEG1K), double adriamycins-
N- lipoic acid-serinol-polyethylene glycol 1K (diDOXNLA-SPEG1K) macromolecular prodrug nano particle is to breast cancer cell MCF-
7 and HepG-2 cell there is good growth inhibition and lethal effect, remain adriamycin powerful antitumor activity, correspond to two
The IC50 value of kind of tumour cell is close with adriamycin, and cytotoxicity enhances with the increase of drug concentration, with concentration according to
Lai Xing.Under identical drug dose, it is weak compared with the adriamycin raw medicine of free state that macromolecular prodrug nano particle shows cytotoxicity.
This is because the self assembly in PBS (pH 7.4) of macromolecular prodrug nano particle is stable nano particle, compared to free state
Adriamycin drug release may have certain slow releasing function.Therefore diDOXLA-SPEG1K, diDOXNLA-SPEG1K macromolecular
Prodrug nano particle shows the opposite lower anti-tumor activity of free state drug in 48h.
Embodiment 17:
Double camptothecine-lipoic acid-serinols-polyethylene glycol 1K (diCPTLA-SPEG1K) macromolecular prodrug nano particle
Pharmacokinetic
By implantation tumor having a size of 100-150mm3The female BAl BIc of MCF-7/c nude mice, be randomly divided into Irinotecan and
DiCPTLA-SPEG1K macromolecular prodrug nano particle group (n=3).By tail vein injection 5mg CPT/kg Irinotecan and
DiCPTLA-SPEG1K macromolecular prodrug nanoparticles solution, respectively in 0.5h, 1h, 2h, 4h, 6h, 8h and for 24 hours collect blood
Sample, and with 3,000rpm centrifugation 10min to obtain blood plasma.Then, Irinotecan in blood plasma is extracted using acetonitrile and do not hydrolyze
DiCPTLA-SPEG1K macromolecular prodrug amount.Specific steps: by 100 μ L plasma samples in 2mL centrifuge tube, 1mL is added
Acetonitrile containing 0.5% acetic acid is uniformly mixed.Mixture is centrifuged after ten minutes through 11,000rpm, and the supernatant of acquisition is carried out
HPLC analysis.
In order to assess the biological distribution of pharmaceutical preparation, the BALB/c nude mice of load MCF-7 tumour is in injection 5mg
It is de- by cervical vertebra after CPT/kg Irinotecan and diCPTLA-SPEG1K macromolecular prodrug nanoparticles solution 0.5h, 2h and 6h
Position method puts to death nude mice, and cutting off includes heart, liver, spleen, lungs, and the major organs including kidney and tumour are raw with 0.9%
Reason saline rinse is simultaneously weighed, and is homogenized.CPT, HPLC measurement are extracted from tissue homogenate using the identical program extracted with blood plasma
Drug concentration, and correspondingly corresponding CPT content in computation organization.
The result is shown in Figure 13 (A).Upon administration in 4-8 hours, free Irinotecan can be significantly clear from blood circulation
It removes.The result and diCPTLA-SPEG1K macromolecular prodrug nano particle form significant comparison, extend the blood circulation of drug
When.This is because diCPTLA-SPEG1K macromolecular prodrug nano particle is conducive to avoid the quick of reticuloendothelial system (RES)
Intake.Second, diCPTLA-SPEG1K macromolecular prodrug keep its good stability without decomposing in physiological environment.The
The presence of three, PEG will further extend blood circulation.Moreover, short chain PEG, which does not easily lead to body, generates PEG antibody, to reduce
The blood plasma supersession rate of drug.
Figure 16 (B) is shown in distribution of the nano particle in the BALB/c nude mouse tumor and other organs of transplanting MCF-7 tumour.It can
To see, diCPTLA-SPEG1K macromolecular prodrug nano particle is mainly distributed to reticuloendothelial system (RES) organ after 2 hours,
Such as lung, spleen, especially liver, and corresponding Irinotecan level is lower.DiCPTLA-SPEG1K macromolecular prodrug nanometer
Larger accumulation of the grain in these organs may be the nanoscale features due to preparation, can provide long-term treatment effects.More
Importantly, being shown in tumour than her with the experimental group that diCPTLA-SPEG1K 1K macromolecular prodrug nano particle is handled
It is vertical to replace the higher CPT concentration of health treatment group (p < 0.01).As it can be seen that diCPTLA-SPEG1K macromolecular prodrug nano particle can be with
It reduces the fast Acquisition of RES system and is passively accumulated in tumour due to EPR effect.Therefore, it is replaced with individual Yi Li
Health is compared, and can be extended in plasma half-life and significant reinforcement from diCPTLA-SPEG1K macromolecular prodrug nano particle to tumour
The distribution of tissue.
Experimental example 18:
Double camptothecine-lipoic acid-serinols-polyethylene glycol 1K (diCPTLA-SPEG1K) macromolecular prodrug alloy granular solids
Interior drug effect and toxicity test
The preparation of nude mice model: collecting the HepG2 cell suspension of culture, and concentration is 1 × 107A/ml, with every 0.1ml
It is subcutaneous to be inoculated in armpit on the right side of nude mouse.Grouping and administration: transplanted tumor in nude mice vernier caliper measurement transplantable tumor diameter, tumour are raw
It grows to 75mm3When animal is grouped at random.Meanwhile each group nude mice starts to be administered, dosage regimen is shown in group and dosage regimen, uses
The method for measuring knurl footpath, the anti-tumor effect of dynamic observation given the test agent.The calculation formula of gross tumor volume (TV) are as follows: TV=1/2
×a×b2(formula 3-2), wherein a, b respectively indicate length and width.
Group and dosage regimen: blank group: physiological saline, intravenous injection, injection is primary every three days, volume 0.2ml, even
It is 3 weeks continuous.
Control group: Irinotecan is dissolved in physiological saline (micro DMSO hydrotropy, dosage 10mg/kg), intravenous injection, and every three
Its injection is primary, volume 0.2ml, and continuous 3 weeks.
Medicine group: (dosage is equivalent to happiness to the diCPTLA-SPEG1K macromolecular prodrug nanoparticles solution of embodiment 12
Set alkali 10mg/kg), intravenous injection, injection is primary every three days, volume 0.2ml, and continuous 3 weeks.Period measures changes of weight.
Anti-tumor activity and changes of weight the result is shown in Figure 17.From the point of view of anti-tumor activity (Figure 17 A), diCPTLA- of the present invention
SPEG1K macromolecular prodrug nano particle has inhibits tumour growth effect well, and the weight of animals does not decline (Figure 14 B),
Display is non-toxic.
Experimental example 19:
Drug effect and toxicity test in double adriamycin-lipoic acid-serinols-polyethylene glycol macromolecular prodrug nano particle body
The preparation of nude mice model: collecting the HepG2 cell suspension of culture, and concentration is 1 × 107A/ml, with every 0.1ml
It is subcutaneous to be inoculated in armpit on the right side of nude mouse.Grouping and administration: transplanted tumor in nude mice vernier caliper measurement transplantable tumor diameter, tumour are raw
It grows to 75mm3When animal is grouped at random.Meanwhile each group nude mice starts to be administered, dosage regimen is shown in group and dosage regimen, uses
The method for measuring knurl footpath, the anti-tumor effect of dynamic observation given the test agent.The calculation formula of gross tumor volume (TV) are as follows: TV=1/2
×a×b2(formula 3-2), wherein a, b respectively indicate length and width.
Group and dosage regimen: blank group: physiological saline, intravenous injection, injection is primary every three days, volume 0.2ml, even
It is 3 weeks continuous.
Control group: adriamycin is dissolved in physiological saline (micro DMSO hydrotropy, dosage 10mg/kg), intravenous injection, every three days
Injection is primary, volume 0.2ml, and continuous 3 weeks.
Medicine group: double adriamycin-lipoic acid-serinol-polyethylene glycol 1K (diDOXLA-SPEG1K) of embodiment 12, double
(the administration of adriamycin-N- lipoic acid-serinol-polyethylene glycol 1K (diDOXNLA-SPEG1K) macromolecular prodrug nanoparticles solution
Amount is equivalent to camptothecine 10mg/kg), intravenous injection, injection is primary every three days, volume 0.2ml, and continuous 3 weeks.Period, measurement
Changes of weight.
The result shows that the double adriamycin-lipoic acid-serinol-polyethylene glycol 1K (diDOXLA-SPEG1K) of the present invention, double Ah
The animal of mycin-N- lipoic acid-serinol-polyethylene glycol 1K (diDOXNLA-SPEG1K) macromolecular prodrug nano particle administration
Gross tumor volume is much smaller than adriamycin control group, and display macromolecular prodrug nano particle has inhibits tumour growth effect well；
Nano particle administration group the weight of animals does not decline (Figure 14 B), and display toxicity is lower than adriamycin；Animal cardiac muscle immunohistochemistry is aobvious
Show, macromolecular prodrug nano particle group animal cardiac muscle tissue has significant histology to change without significant change, adriamycin group animal cardiac muscle
Become.
Embodiment 20:
The preparation of macromolecular prodrug nano particle
Double camptothecine-lipoic acid-the serinols-of the macromolecular prodrug of the different molecular weight polyethylene glycols of embodiment 1,2,3 are poly-
Ethylene glycol (diCPTLA-SPEG), double taxol-lipoic acids-serinol-polyethylene glycol (diPTXLA-SPEG), double adriamycins-
Lipoic acid-serinol-polyethylene glycol (diDOXLA-SPEG) each 0.05g, be separately added into egg yolk lecithin, fatty glyceride or
It 0.05 gram of distearyl phosphocholine, is scattered in the 10mL water of letting nitrogen in and deoxidizing gas, mixes slowly 20 minutes.Lead to a small amount of oxygen,
So that the sulfhydryl oxidase in macromolecular prodrug is crosslinked (crosslinking schematic diagram is shown in Figure 12), obtains 3 class macromolecular prodrug nanoparticles solutions.
Freeze-drying, obtains 3 class macromolecular prodrug powder of nanometric particles.Dynamic light scattering (DLS) method detects nano particle diameter, knot
Fruit shows that all various macromolecular prodrug nano particle average grain diameters are 50~300 nanometers.
Claims (6)
1. a kind of macromolecular prodrug Nano medication, which is characterized in that the Nano medication includes two hydrophobic drugs by double
The amphiphilic macromolecular prodrug for the general formula (1) that sulfide linkage is connected to form by lipoic acid and low molecular poly, the amphiphilic
Property macromolecular prodrug by self assembly and by intermolecular disulfides be cross-linked to form kernel contain drug, shell be low molecular weight gather
The nano particle of ethylene glycol hydrophilic high mol brush, having a size of 10~1000 nanometers:
In formula, X is serinol or 3- amino-glycerol, and D is hydrophobic drug, and Y is CH2CH2OCOO or CH2CH2OCONH, n be 6~
80。
2. macromolecular prodrug Nano medication according to claim 1, which is characterized in that the hydrophobic drug is Japanese yew
Alcohol, docetaxel, Cabazitaxel, camptothecine, 7-Ethyl-10-hydroxycamptothecin, hydroxycamptothecin, topotecan, Yi Li are replaced
Health, Rubitecan, Belotecan, adriamycin, Epi-ADM, daunorubicin, demethoxy daunorubicin, Aclarubicin, pyrrole are soft
Than star, zorubicin, harringtonine, isoharringtonin, maytansine, everolimus or Dasatinib.
3. macromolecular prodrug Nano medication according to claim 1, which is characterized in that the Nano medication further includes pharmacodynamics
Upper acceptable carrier or auxiliary agent, the auxiliary agent are fat or phosphatide.
4. according to claim 1,2 or 3 macromolecular prodrug Nano medication, which is characterized in that the Nano medication be liquid preparation,
Solid pharmaceutical preparation or semisolid preparation.
5. a kind of preparation method of macromolecular prodrug Nano medication, which is characterized in that the preparation method is by big point of general formula (1)
Sub- prodrug is assembled into the nano-micelle that diameter is 10-1000 nanometers in aqueous solution, and hydrogen peroxide or in air sulfydryl is added
Oxidation leads to intermolecular cross-linking, forms kernel and contains dewatering medicament, and outer layer is the crosslinked nano-particles of hydrophilic polyglycol brush,
The freeze-dried crosslinked nano-particles freeze-dried powder for obtaining packaging medicine:
In formula, X is serinol or 3- amino-glycerol, and D is hydrophobic drug, and Y is CH2CH2OCOO or CH2CH2OCONH, n be 6~
80。
6. macromolecular prodrug Nano medication application in preparation of anti-tumor drugs described in a kind of claim 1,2,3 or 4.
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