CN109293683A - A kind of drug delivery system of reduction response type camptothecine dimer and the reduction sensitivity based on the camptothecine dimer - Google Patents
A kind of drug delivery system of reduction response type camptothecine dimer and the reduction sensitivity based on the camptothecine dimer Download PDFInfo
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Abstract
A kind of drug delivery system of reduction sensitivity the invention discloses reduction response type camptothecine dimer and based on the camptothecine dimer, belongs to biological medicine and nanosecond medical science technical field.Technical solution of the present invention main points are as follows: successively reduction response type camptothecine dimer, the structural formula of the camptothecine dimer is made with triethylene glycol monomethyl ether, 2,2- dihydroxy ethyl disulphide, camptothecine reaction in dibromo-maleimide are as follows:The drug delivery system of reduction sensitivity the invention further particularly discloses the preparation method of the camptothecine dimer and based on the camptothecine dimer.Drug delivery system of the invention is compared with camptothecine transmission system, its drugloading rate is improved by 1wt% to 9.6wt%, and the drug delivery system has reduction-sensitive, good biocompatibility and the ability for inhibiting tumor cell proliferation, can be used for preparing the anticancer drug transmission system with slow controlled release and targeting.
Description
Technical field
The invention belongs to biological medicines and nanosecond medical science technical field, and in particular to a kind of reduction response type camptothecine dimerization
The drug delivery system of body and the reduction sensitivity based on the camptothecine dimer.
Background technique
Camptothecine (Camptothecin, CPT) is a kind of DNA topoisomerase (TOPO I) inhibitor, prevents DNA's
Duplication and the synthesis of RNA, eventually lead to cell death, as a kind of broad-spectrum anti-cancer drug, can effectively inhibit melanin
Tumor, breast cancer, prostate cancer, liver cancer and colon cancer etc..But due to it is water-soluble it is low, toxic side effect is big, lactonic ring it is unstable with
And the disadvantages of quickly removing, limits the application of camptothecine clinically.In order to overcome these problems, various camptothecines
Carrier micelle is developed to solve these problems, but since drugloading rate is low, stability is poor, uncontrollable drug release
Etc. factors cause it to be difficult to clinically realize.The drugloading rate of camptothecine carrier micelle reported in the literature is usually less than 5wt%, very
To less than 1wt%.The aggtegation of drug non-encapsulated in carrier micelle preparation process is to cause drugloading rate low most important
One of reason." σ " key for rotating freely will be introduced in drug and be prepared into dimer can be effectively reduced aggtegation, to mention
High drug load.Jiang Chen etc. is reported for the first time to be prepared into the sensitive dimer prodrug of reduction for camptothecine and is encapsulated with mPEG-PLA,
Compared with free camptothecine, drugloading rate and encapsulation rate have to be promoted significantly.Zhou Shaobing etc. is prepared for based on maleimide
The reduction response type camptothecine dimer of disulfide, drugloading rate are also obviously improved.
PCL is widely used in biological medicine as biodegradable polymer material, obtains with after polyethylene glycol polymeric
To there is preferably water-soluble and stability polymer, the carrier micelle which forms can be delivered by the method for physically trapping
Various hydrophobic anti-tumor small molecular drug, since good biodegradable properties are widely used in drug delivery system.
For the present invention using anti-tumor small molecular camptothecin drug as research object, design has synthesized a kind of reduction responsiveness Malaysia
The connected camptothecine dimer prodrug of acid imide thioether bond improves camplotheca acuminata buck under the embedding of mPEG-b-PCL carrier micelle
Dissolubility is poor, and drugloading rate is low, and normal tissue or organ have the problems such as larger toxic side effect.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of reduction response type camptothecine dimer and it is based on the camptothecine
The sensitive drug delivery system of the reduction of dimer, the drug delivery system compared with camptothecine transmission system, drugloading rate by
1wt% is improved to 9.6wt%, and the drug delivery system has reduction-sensitive, good biocompatibility and inhibits swollen
The ability of tumor cell proliferation can be used for preparing the anticancer drug transmission system with slow controlled release and targeting.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of reduction response type camptothecine dimer,
It is characterized by: dibromo-maleimide is successively reacted with triethylene glycol monomethyl ether, 2,2- dihydroxy ethyl disulphide, camptothecine
Reduction response type camptothecine dimer (CPT-Mal-CPT), the structural formula of the camptothecine dimer is made are as follows:
The preparation method of reduction response type camptothecine dimer of the present invention, it is characterised in that detailed process are as follows: will
Maleimide is reacted with triethylene glycol monomethyl ether is made intermediate 1, then by intermediate 1 and 2,2- dihydroxy ethyl disulphide reacts
Intermediate 2 is made, intermediate 2 is reacted with camptothecine then, camptothecine dimer 3, corresponding synthetic route is made are as follows:
The preparation method of reduction response type camptothecine dimer of the present invention, it is characterised in that specific steps are as follows:
Step S1: at -78 DEG C, using anhydrous tetrahydro furan as solvent, it is different that triphenylphosphine, azoformic acid two are sequentially added
Propyl ester, triethylene glycol monomethyl ether and neopentyl alcohol, are eventually adding dibromo-maleimide, and room temperature is transferred to after being uniformly mixed and is reacted
20h obtains intermediate 1 after purification；
Step S2: at room temperature, using methanol as solvent, TCEP.HCl, which is added, makes two sulphur of 2- hydroxyethyl disulfide
Key fracture, while triethylamine is added as acid binding agent, it is eventually adding intermediate 1, purifying obtains intermediate 2 after reaction overnight；
Step S3: at room temperature, using camptothecine and p-nitrophenyl chloro-formate as reactant, with 4- dimethylamino
Pyridine is catalyst, using methylene chloride as solvent, reacts 48h with intermediate 2 under protection of argon gas, crude product obtained is through column layer
Analysis purifying obtains camptothecine dimer 3.
The sensitive drug delivery system of reduction of the present invention based on camptothecine dimer, it is characterised in that: utilize
Camptothecine dimer is encapsulated into amphipathic nature block polymer polyethylene glycol-polycaprolactone (mPEG-b-PCL) and is made by dialysis
The sensitive drug delivery system of the reduction of high drug load, the camptothecine dimer have the maleic amide thioether of reduction-sensitive
Key group, the disulfide bonds under reductive condition, camptothecine are released from prodrug, and the amphipathic nature block polymer is poly-
Ethylene glycol-polycaprolactone number-average molecular weight is 7000-10000.
The preparation method of the sensitive drug delivery system of reduction of the present invention based on camptothecine dimer, feature
It is detailed process are as follows: using camptothecine dimer as drug model, be with amphipathic nature block polymer polyethylene glycol-polycaprolactone
Carrier prepares drug delivery system by dialysis, and the drugloading rate of the drug delivery system is increased to 9.6wt%.
Preferably, the specific synthesis process of the amphipathic nature block polymer polyethylene glycol-polycaprolactone are as follows: be with mPEG
Macromole evocating agent, using stannous octoate as catalyst, the poly- second two of amphipathic nature block polymer is made in caprolactone ontology ring-opening polymerisation
Alcohol-polycaprolactone.
Preferably, the dialysis prepares the molecular cut off of bag filter used during drug delivery system and is
14000。
The sensitive drug delivery system of reduction of the present invention has stimuli responsive release and targeting antitumor in preparation
Application in drug.
Compared with the prior art, the invention has the following beneficial effects:
1, the present invention provides the camptothecine dimer that a kind of maleimide thioether bond is connected, which has reduction
Sensibility.
2, the present invention provides a kind of method of drugloading rate that drug delivery system is improved using camptothecine dimer, the medicines
For object transmission system compared with camptothecine transmission system, drugloading rate is increased to 9.6wt% by 1wt%.
3, for the present invention using polyethylene glycol-polycaprolactone as pharmaceutical carrier, degradability is excellent, water-soluble and stable
Property enhancing, blood circulation time extend, can by EPR effect enhancing tumor tissues position drug-rich.In tumor locus, horse
Carry out acid imide disulfide reproducibility in the presence of glutathione to respond, to play excellent antitumous effect, have preferable
Application prospect.
4, reduction responsiveness thioether bond provided by the invention connected camptothecine dimer and polyethylene glycol-polycaprolactone
Pharmaceutical carrier preparation is simple, significant effect.
Detailed description of the invention
Fig. 1 is the nuclear magnetic resonance spectroscopy spectrogram of 1 synthetic intermediate 1 of embodiment；
Fig. 2 is the nuclear magnetic resonance spectroscopy spectrogram that embodiment 3 synthesizes camptothecine dimer；
Fig. 3 is the cumulative release amount curve of drug delivery system in embodiment 6.
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
Triphenylphosphine 511mg (1.95mmol) is dissolved in the anhydrous THF of 5mL and is stirred.By azo dimethylbenzene diisopropyl ester
0.38mL (1.95mmol) is added dropwise in the above solution, stirs 5min at -78 DEG C.By 0.25 mL of triethylene glycol monomethyl ether
After (1.56mmol) is dissolved in the anhydrous THF of 5mL, it is added dropwise and added in azo dimethylbenzene diisopropyl ester reaction solution, at -78 DEG C
Continue to stir 5min.Neopentyl alcohol 121mg (1.37mmol) is dissolved in 2mL anhydrous THF addition and added triethylene glycol monomethyl ether later
In, 5min is stirred at -78 DEG C.Finally dibromo-maleimide 497mg (1.95mmol) is added in above-mentioned reaction solution, -78 DEG C
It is transferred to room temperature after lower stirring 10min, at room temperature magnetic agitation 20h.Crude product column chromatographic purifying (volume ratio EA:PA=1:10-1:
4), then in passing through preparative separation is pressed to obtain rice white target product i.e. 1 325mg of intermediate, yield 52.2%.1H NMR
(400MHz,CDCl3)δ3.82(t,2H),3.66(t,2H),3.64–3.56(m,6H), 3.54–3.50(m,2H),3.37(s,
3H)。
Embodiment 2
Weigh 2- hydroxyethyl disulfide 123.2mg (0.8mmol), triethylamine 323.6mg (3.2mmol) and TCEP.HCl
230mg (0.8mmol) is dissolved in the methanol that 50mL is handled through anaerobic, stirs 20min at room temperature.It weighs intermediate made from embodiment
1 319.1mg of body (0.8mmol) is added in above-mentioned reaction solution after being dissolved in the methanol that 25mL is handled through anaerobic, and color is become from colourless
Turmeric.Magnetic stirrer over night at room temperature.Crude product column chromatographic purifying (vol/vol methanol: methylene chloride=1:200-1:50), obtains
To 2 243.3mg of buff oily target pure product intermediate, yield 77%.1H NMR(600MHz, CDCl3)δ3.91–3.81
(m,2H),3.72(d,2H),3.69–3.57(m,5H),3.54(s,1H),3.48–3.42(m, 2H),3.38(s,2H),
2.28–1.96(m,1H)。
Embodiment 3
It weighs CPT 835.4mg (2.4mmol) to be dissolved in 25mL anhydrous methylene chloride, is added with stirring p-nitrophenyl chlorine
Formic acid esters 482.35mg (2.4mmol) and DMAP 585.9mg (4.8mmol) stirs 4h under oxygen free condition.Then it weighs
Intermediate 2 made from 395.1mg (1.0mmol) embodiment 2 is dissolved in 16mL (anhydrous THF/CH2Cl2) in solution.Magnetic force at room temperature
It is stirred to react 36h.Crude product column chromatographic purifying (vol/vol methanol: methylene chloride=1:250-1:100), obtains yellow green target
3 525.9mg of product camptothecine dimer, yield 64%.1H NMR(600MHz,CDCl3)δ 8.38(s,2H),8.20(d,
2H),7.93(d,2H),7.82(t,2H),7.66(t,2H),7.29(s,2H),5.69(d,2H),5.36 (d,2H),5.29
(d,4H),4.17(m,4H),3.51(m,12H),3.38(m,6H),2.25(m,2H),2.12(m,2H), 0.98(t,6H).13C
NMR(151MHz,CDCl3)δ167.25(s),157.27(s),153.21(s),152.38(s),145.43 (s),134.84
(s), 131.17 (s), 130.72 (s), 129.69 (s), 128.60 (s), 128.58-128.04 (m), 120.26 (d, J=
0.9Hz), 95.92 (s), 78.01 (s), 71.89 (s), 70.53 (s), 70.02 (s), 67.63 (d, J=11.6Hz), 67.12
(s), 59.01(s),50.04(s),37.84(s),31.94(s),29.68(s),7.62(s),0.00(s)。
Embodiment 4
Take mPEG5000526mg (12mmol) and 6-caprolactone 232mg (2mmol) add 1wt ‰ in polymerization pipe
Sn(Oct)246 μ L of anhydrous toluene solution (10mg/mL), dry overnight for 35 DEG C in vacuum oven, after taking-up, oil pump is vacuumized
More than 4h, vacuum degree is extracted into about 1Pa, and alcohol blast burner calcines tube sealing, system is transferred in 140 DEG C of oil bath pans and is polymerize, after 100h,
It is cooled to room temperature, DMF dissolution, solution is transferred in bag filter (MWCO 14000) and dialyses, water saturating time about 48h, 3-4h
It is primary to change water, takes reaction solution in bag filter, is centrifuged, freeze-drying obtains target product mPEG-b-PCL about 0.54g, and yield is about
71.1%, nuclear magnetic resonance1H NMR(400MHz,CDCl3)δ4.05 (t,CH3OCH2CH2CH2-),3.64(s,CH3OCH2CH2-
O-),2.30(t,-COCH3CH2-),1.70–1.59(m, -COCH2CH2CH2CH2CH2COCH3),1.38(t,-
COCH2CH2CH2CH2CH2COCH3)。
Embodiment 5
It weighs polyethylene glycol-polycaprolactone 75mg and camptothecine dimer 7.5mg to be dissolved in 20mL DMF, stir at room temperature
Then solution is transferred in bag filter (MWCO 3500) by about 30min, for 24 hours with deionized water dialysis, change once every 3-4 h
Water, after dialysis, centrifugation takes supernatant, and freeze-drying obtains the sensitive drug delivery system of the reduction based on camptothecine dimer.
Embodiment 6
It weighs 4.99mg drug delivery system to be dissolved into the 0.1M PH=7.40 phosphate buffer of 20mL, be vortexed concussion
It is bright to clarifying, it is transferred in bag filter (MWCO 14000), dialyses under the conditions of 37 DEG C in 100r/min shaking table.Every
A period of time takes 2mL solution, is then adding 2mL phosphate buffer, calculates drug release amount by HPLC.
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (8)
1. a kind of reduction response type camptothecine dimer, it is characterised in that: by dibromo-maleimide successively with triethylene glycol list first
Reduction response type camptothecine dimer is made in ether, 2,2- dihydroxy ethyl disulphide, camptothecine reaction, the camptothecine dimer
Structural formula are as follows:
2. a kind of preparation method of reduction response type camptothecine dimer described in claim 1, it is characterised in that detailed process
Are as follows: maleimide is reacted with triethylene glycol monomethyl ether, intermediate 1 is made, then by intermediate 1 and 2,2- dihydroxy ethyl curing
Object, which reacts, is made intermediate 2, then reacts intermediate 2 with camptothecine and camptothecine dimer 3, corresponding synthetic route is made
Are as follows:
3. the preparation method of reduction response type camptothecine dimer according to claim 2, it is characterised in that specific steps
Are as follows:
Step S1: at -78 DEG C, using anhydrous tetrahydro furan as solvent, triphenylphosphine, azoformic acid diisopropyl are sequentially added
Ester, triethylene glycol monomethyl ether and neopentyl alcohol, are eventually adding dibromo-maleimide, and room temperature is transferred to after being uniformly mixed and is reacted
20h obtains intermediate 1 after purification；
Step S2: at room temperature, using methanol as solvent, TCEPHCl, which is added, makes the disulfide bond of 2- hydroxyethyl disulfide
Fracture, while triethylamine is added as acid binding agent, it is eventually adding intermediate 1, purifying obtains intermediate 2 after reaction overnight；
Step S3: at room temperature, using camptothecine and p-nitrophenyl chloro-formate as reactant, with 4-dimethylaminopyridine
48h is reacted with intermediate 2 under protection of argon gas using methylene chloride as solvent for catalyst, crude by column chromatography obtained is pure
Change obtains camptothecine dimer 3.
4. the sensitive drug delivery system of the reduction based on camptothecine dimer described in claim 1, it is characterised in that: utilize
Camptothecine dimer is encapsulated into and going back for high drug load is made in amphipathic nature block polymer polyethylene glycol-polycaprolactone by dialysis
Former sensitive drug delivery system, the camptothecine dimer have the maleic amide thioether bond group of reduction-sensitive, also
Disulfide bonds under the conditions of originality, camptothecine are released from prodrug, the amphipathic nature block polymer polyethylene glycol oneself
The number-average molecular weight of lactone is 7000-10000.
5. a kind of preparation method for the drug delivery system that reduction as claimed in claim 4 is sensitive, it is characterised in that detailed process
Are as follows: using camptothecine dimer as drug model, using amphipathic nature block polymer polyethylene glycol-polycaprolactone as carrier, by saturating
Analysis method prepares drug delivery system, and the drugloading rate of the drug delivery system is increased to 9.6wt%.
6. the preparation method of the sensitive drug delivery system of reduction according to claim 5, it is characterised in that the amphiphilic
The specific synthesis process of property block copolymer polyethylene glycol-polycaprolactone are as follows: using mPEG as macromole evocating agent, with stannous octoate
For catalyst, amphipathic nature block polymer polyethylene glycol-polycaprolactone is made in caprolactone ontology ring-opening polymerisation.
7. the preparation method of the sensitive drug delivery system of reduction according to claim 5, it is characterised in that: the dialysis
The molecular cut off that method prepares bag filter used during drug delivery system is 14000.
8. the sensitive drug delivery system of reduction as claimed in claim 4 has stimuli responsive release and targeting antitumor in preparation
Application in drug.
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| CN112321615B (en) * | 2020-10-30 | 2021-11-09 | 华中科技大学 | Camptothecin-based dimer compound, and preparation and application thereof |
| WO2022088679A1 (en) * | 2020-10-30 | 2022-05-05 | 华中科技大学 | Method for removing tumor stem cells, anti-cancer drug, drug delivery system, and use thereof |
| CN114163458A (en) * | 2021-10-31 | 2022-03-11 | 南京碳硅人工智能生物医药技术研究院有限公司 | Design synthesis and activity evaluation of ROS (reactive oxygen species) -responsive dimeric camptothecin prodrug |
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Application publication date: 20190201 |