CN107669626A - A kind of preparation method and applications of the drug delivery system of the reduction sensitivity of high drug load - Google Patents
A kind of preparation method and applications of the drug delivery system of the reduction sensitivity of high drug load Download PDFInfo
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- CN107669626A CN107669626A CN201710782782.2A CN201710782782A CN107669626A CN 107669626 A CN107669626 A CN 107669626A CN 201710782782 A CN201710782782 A CN 201710782782A CN 107669626 A CN107669626 A CN 107669626A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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Abstract
The invention discloses a kind of preparation method and applications of the sensitive drug delivery system of the reduction of high drug load, belong to biological medicine and nanometer pharmaceutical technology field.Technical scheme main points are：By 2,2 dihydroxy ethyl disulphide are bonded the camptothecine dimer of structure reduction-sensitive by carbonic acid ester bond with camptothecine, secondly camptothecine dimer is encapsulated into the drug delivery system for the reduction sensitivity that high drug load is made in amphipathic nature block polymer polyethylene glycol polycaprolactone using dialysis, the structural formula of wherein camptothecine dimer is：The invention further particularly discloses the sensitive drug delivery system of the reduction of the high drug load to prepare with the application in slow controlled release and targeting antitumor medicine.The drug delivery system of the present invention compared with camptothecine transmission system, by 1% mentioned to 12.6% by its drugloading rate, and the drug delivery system has reduction-sensitive, good biocompatibility and the ability for suppressing tumor cell proliferation.
Description
Technical field
The invention belongs to biological medicine and nanometer pharmaceutical technology field, and in particular to a kind of reduction sensitivity of high drug load
The preparation method and applications of drug delivery system.
Background technology
Camptothecine (Camptothecin, CPT) is a kind of botanical anticancer medicine, from the camplotheca acuminata of Central-South, the southwestern distribution of China
Middle extraction obtains.Camptothecine has the effect of preferable to intestines and stomach and incidence cancer etc., but has the side effect of hematuria to a few patients.
The active anticancer of 10-hydroxycamptothecine exceedes camptothecine, also there is obvious curative effects to liver cancer and incidence cancer, and side effect compared with
It is few.Camptothecin analogues are used widely as cancer therapy drug in worldwide for many years.But due to as camplotheca acuminata
The small-molecule drug water solubility of alkali etc. is poor, pharmacokinetics is low and accumulation is small in blood, the low and secondary work of bioavailability
With obvious, therefore, polymer science men seek improves small point with the good polymer of good biocompatibility and biodegradability
The shortcomings of sub- medicine.In recent years, amphipathic nature block polymer is self-assembled into micella packaging medicine and obtained extensively in the solution
General development and application, significantly improved compared with small molecule anticancer drug, after polymer micelle packaging medicine pharmacokinetics and
The drug accumulation on tumor tissues is improved, bioavilability is also significantly increased and significantly reduces poison pair of the medicine to body
Effect.Poly (ethyleneglycol)-b-poly (caprolactone) (PEG-b-PCL) amphipathic nature block polymer is made
For a typical example, high carrier medicine carrying efficiency and hypotoxicity are shown.In order to improve the drugloading rate of camptothecine, the present invention is set
Camptothecine is connected by meter by reducible degraded disulfide bond obtains dimer, significantly improves camptothecine in amphipathic nature block polymer
Drugloading rate in PEG-b-PCL, cutting is carried out to disulfide bond by dithiothreitol (DTT) (DTT) in extracellular simulated in vivo environment and released
Camptothecine is put to reach the effect of controlled release.Camptothecine is designed to dimer so that camptothecine drugloading rate improves nearly 10 times,
This delivers small molecule dewatering medicament in a manner of physically trapping for amphipathic nature polyalcohol and provides more possibility.
The content of the invention
Present invention solves the technical problem that it there is provided a kind of system of the drug delivery system of the reduction sensitivity of high drug load
Preparation Method, the drug delivery system compared with camptothecine transmission system, by 1% mentioned to 12.6% by its drugloading rate, and the medicine
Thing transmission system has reduction-sensitive, good biocompatibility and the ability for suppressing tumor cell proliferation, available for preparing
Cancer therapy drug with slow controlled release and targeting.
The present invention adopts the following technical scheme that a kind of high drug load reduces sensitive medicine to solve above-mentioned technical problem
The preparation method of transmission system, it is characterised in that detailed process is：By 2,2- dihydroxy ethyls disulphide by carbonic acid ester bond with
The camptothecine dimer (CPT-SS-CPT) of camptothecine bonding structure reduction-sensitive, secondly utilizes dialysis by camptothecine dimerization
Body is encapsulated into the reduction sensitivity that high drug load is made in amphipathic nature block polymer PEG-PCL (mPEG-b-PCL)
Drug delivery system, the structural formula of wherein camptothecine dimer is：
The camptothecine dimer has the disulfide bond group of reduction-sensitive, the disulfide bonds under reductive condition, mercapto
Base attack carbonic acid ester bond forms five-membered cyclic lactoneAnd then camptothecine discharges from prodrug, the amphipathic block
The number-average molecular weight of copolymer PEG-PCL is 6000-11000.
Further preferably, the specific synthetic route of the camptothecine dimer is：
Specifically building-up process is：Intermediate 1 is made in camptothecine and the reaction of p-nitrophenyl chloro-formate, then by intermediate
1 is made camptothecine dimer with the reaction of 2,2- dihydroxy ethyls disulphide.
Further preferably, the specific synthesis step of the camptothecine dimer is：At ambient temperature, with camptothecine and right
Chloroformate nitrophenyl ester is reactant, using DMAP as catalyst, using dichloromethane as solvent, is protected in argon gas
Intermediate 1 is made in lower room temperature reaction 2h；At ambient temperature, using DMAP as catalyst, intermediate 1 and 2,2-
Dihydroxy ethyl disulphide reacts 48h, and crude by column chromatography purifies to obtain camptothecine dimer.
Further preferably, the specific building-up process of the amphipathic nature block polymer PEG-PCL is：With
MPEG is macromole evocating agent, and using stannous octoate as catalyst, amphipathic nature block polymer is made in the ring-opening polymerisation of caprolactone body
PEG-PCL.
The preparation method of the drug delivery system of the reduction sensitivity of high drug load of the present invention, it is characterised in that：With
Camptothecine dimer is drug model, using amphipathic nature block polymer PEG-PCL as carrier, passes through legal system of dialysing
Standby carrier micelle, its drugloading rate bring up to 12.6wt%.
Further preferably, the molecular cut off for involved bag filter during carrier micelle being prepared by dialysis is
14000。
The drug delivery system that the reduction of high drug load of the present invention is sensitive is being prepared with slow controlled release and targeting
Application in cancer therapy drug.
The present invention has the advantages that compared with prior art：
1st, the invention provides a kind of method for the drugloading rate that drug delivery system is improved using camptothecine dimer, the medicine
For thing transmission system compared with camptothecine transmission system, its drugloading rate brings up to 12.6% by 1%.
2nd, the present invention uses the good amphipathic nature block polymer PEG-PCL of biocompatibility as medicine
Carrier, can be self-assembly of stable carrier micelle in water, hydrophilic polyglycol as micella shell play stably micella,
The effect of micella blood circulation time is improved, when carrier micelle reaches tumour or pathological tissues, local reduction condition makes two
Sulfide linkage is broken, and so as to discharge cancer therapy drug, adds the utilization rate and targeting of medicine, in terms of the treatment of cancer,
With potential application value.
3rd, the drug delivery system provided by the invention based on camptothecine dimer is rational in infrastructure clearly, the encapsulating to medicine
Efficiency high, preparation process are simple.
Brief description of the drawings
Fig. 1 be embodiment it is 2-in-1 into camptothecine dimer proton nmr spectra spectrogram；
Fig. 2 is the cumulative release amount curve of carrier micelle in embodiment 5.
Embodiment
The above of the present invention is described in further details by the following examples, but this should not be interpreted as to this
The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair
Bright scope.
Embodiment 1
0.5g camptothecines (1.44mmol), 0.29g p-nitrophenyl chloro-formates are sequentially added in 100mL Shrek bottles
With 0.39g DMAP, the anhydrous CH of 25mL are dissolved in2Cl2In, 2h is reacted at room temperature under Ar gas shieldeds, with 25mL water washings 3 times, is had
Machine is mutually with anhydrous MgSO4Dry, be concentrated under reduced pressure to give the crude product of intermediate 1.
Embodiment 2
Gained crude product in embodiment 1 is dissolved in the anhydrous CH of 25mL2Cl2In, add 92.5mg ethyl disulfides
2.5mL THF and 7.5mL CH2Cl2Mixed solution, react at room temperature 48h under Ar gas shieldeds, filter, concentration, purified through column chromatography
(eluent：CH3OH/CH2Cl2) obtain target product camptothecine dimer about 0.23g, yield 35.5%.
1H NMR(600MHz,CDCl3)δ8.39(s,1H),8.18(d,1H),7.93(d,1H),7.82(t,1H),7.66
(t, 1H),5.76(d,1H),5.41-5.18(m,1H),5.46-5.14(m,1H),4.00(d,1H),2.81(d,1H),2.23
(d,1H), 2.09(d,1H),0.97(t,1H).ESI-MS for C46H38N4O12S2[M+H+] and [M+Na+]calcd:
902.1928, found:903.2006 and 925.1786.
Embodiment 3
By the Sn (Oct) of 0.464g mPEG and 0.204g CL2 ‰2It is added in polymerization pipe, is placed in 38 DEG C of vacuum drying chambers
Middle drying, the tube sealing when vacuum is 1Pa, reaction, which is placed in 140 DEG C of oil baths, to be polymerize, polymerase 17 0h, by reactant THF
Dissolving, dialysis treatment in MW=14000 bag filters is transferred to, aqueous phase is freezed after deionized water dialysis 48h, produced amphipathic embedding
Section copolymer mPEG-b-PCL.
1H NMR(400MHz,CDCl3)δ4.05(t,1H),3.64(s,17H),3.37(s,1H),2.39-2.23(m,
1H), 1.71-1.57(m,2H),1.45-1.30(m,1H)。
Embodiment 4
100mg amphipathic nature block polymer mPEG-b-PCL and 20mg camptothecine dimers are taken to be placed in 10mL DMF, magnetic
Power stirring room temperature reaction 30min, is transferred in bag filter (MWCO 3500), dialyse 24h in distilled water, is changed once every 4h
Distilled water, dialysis are filtered to remove insoluble CPT-SS-CPT after terminating, and freeze.
Embodiment 5
The carrier micelle for weighing 5mg is dissolved in 3mL 0.1M pH=7.4 phosphate buffer solution, is transferred to bag filter
In (MWCO 3500), be subsequently placed in 20mL 10mM DTT phosphate buffer solution, in 37 DEG C dialysis, in the predetermined time
3mL cushioning liquid is taken, the burst size of camptothecine is determined with high performance liquid chromatography.
Embodiment above describes the general principle of the present invention, main features and advantages, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (7)
1. the preparation method of the sensitive drug delivery system of the reduction of a kind of high drug load, it is characterised in that detailed process is：Will
2,2- dihydroxy ethyl disulphide are bonded the camptothecine dimer of structure reduction-sensitive by carbonic acid ester bond with camptothecine, secondly
Camptothecine dimer is encapsulated into amphipathic nature block polymer PEG-PCL using dialysis high drug load is made
The sensitive drug delivery system of reduction, the structural formula of wherein camptothecine dimer is：
The camptothecine dimer has the disulfide bond group of reduction-sensitive, the disulfide bonds under reductive condition, and sulfydryl enters
Attack carbonic acid ester bond and form five-membered cyclic lactoneAnd then camptothecine discharges from prodrug, the amphiphilic block
The number-average molecular weight of thing PEG-PCL is 6000-11000.
2. the preparation method of the sensitive drug delivery system of the reduction of high drug load according to claim 1, its feature exist
It is in the specific synthetic route of the camptothecine dimer：
Specifically building-up process is：By camptothecine and p-nitrophenyl chloro-formate reaction be made intermediate 1, then by intermediate 1 with
Camptothecine dimer is made in the reaction of 2,2- dihydroxy ethyls disulphide.
3. the preparation method of the sensitive drug delivery system of the reduction of high drug load according to claim 1, its feature exist
It is in the specific synthesis step of the camptothecine dimer：At ambient temperature, with camptothecine and p-nitrophenyl chloro-formate
For reactant, using DMAP as catalyst, using dichloromethane as solvent, room temperature reaction 2h is made under argon gas protection
Intermediate 1；At ambient temperature, using DMAP as catalyst, intermediate 1 and 2,2- dihydroxy ethyl disulphide are anti-
48h is answered, crude by column chromatography purifies to obtain camptothecine dimer.
4. the preparation method of the sensitive drug delivery system of the reduction of high drug load according to claim 1, its feature exist
It is in the specific building-up process of the amphipathic nature block polymer PEG-PCL：Using mPEG as macromole evocating agent,
Using stannous octoate as catalyst, amphipathic nature block polymer PEG-PCL is made in the ring-opening polymerisation of caprolactone body.
5. the preparation method of the sensitive drug delivery system of the reduction of high drug load according to claim 1, its feature exist
In：Using camptothecine dimer as drug model, using amphipathic nature block polymer PEG-PCL as carrier, by saturating
Analysis method prepares carrier micelle, and its drugloading rate brings up to 12.6wt%.
6. the preparation method of the sensitive drug delivery system of the reduction of high drug load according to claim 5, its feature exist
In：The molecular cut off that involved bag filter during carrier micelle is prepared by dialysis is 14000.
7. the drug delivery system of the reduction sensitivity according to high drug load made from the method described in any one in claim 1-6
Unite and preparing with the application in slow controlled release and targeting antitumor medicine.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109293683A (en) * | 2018-09-05 | 2019-02-01 | 河南师范大学 | A kind of drug delivery system of reduction response type camptothecine dimer and the reduction sensitivity based on the camptothecine dimer |
| CN111053911A (en) * | 2019-12-20 | 2020-04-24 | 西南大学 | Reduction response type cross-linking agent and preparation and application of cross-linked hydroxyl drug molecule thereof |
| CN112656950A (en) * | 2021-01-25 | 2021-04-16 | 浙江大学 | Camptothecin-polycaprolactone coupled prodrug, preparation method and application thereof |
| CN112891556A (en) * | 2021-02-01 | 2021-06-04 | 浙江大学医学院附属第一医院 | Oral nanogel of monoclonal antibody medicines and preparation method 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 |
| WO2022190626A1 (en) * | 2021-03-12 | 2022-09-15 | 国立大学法人東北大学 | Sn-38 derivative, nano-particles containing said derivative, medicine, and method for producing said nano-particles |
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| US20130266508A1 (en) * | 2012-04-09 | 2013-10-10 | Atomic Energy Council-Institute Of Nuclear Energy Research | Thermosensitive hydrogel for coating radioisotope and chemotherapeutic agent to treat cancer and method for preparing the same |
| CN107375238A (en) * | 2016-05-16 | 2017-11-24 | 刘东飞 | A kind of superelevation medicine-carried nano particles and preparation method thereof |
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Patent Citations (3)
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| CN101961494A (en) * | 2010-09-26 | 2011-02-02 | 苏州同科生物材料有限公司 | Star polymer nano-medicament carrier preparation used for intracellular medicament delivery and preparation method thereof |
| US20130266508A1 (en) * | 2012-04-09 | 2013-10-10 | Atomic Energy Council-Institute Of Nuclear Energy Research | Thermosensitive hydrogel for coating radioisotope and chemotherapeutic agent to treat cancer and method for preparing the same |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109293683A (en) * | 2018-09-05 | 2019-02-01 | 河南师范大学 | A kind of drug delivery system of reduction response type camptothecine dimer and the reduction sensitivity based on the camptothecine dimer |
| CN111053911A (en) * | 2019-12-20 | 2020-04-24 | 西南大学 | Reduction response type cross-linking agent and preparation and application of cross-linked hydroxyl drug molecule thereof |
| CN112656950A (en) * | 2021-01-25 | 2021-04-16 | 浙江大学 | Camptothecin-polycaprolactone coupled prodrug, preparation method and application thereof |
| CN112656950B (en) * | 2021-01-25 | 2023-10-13 | 浙江大学 | Camptothecin-polycaprolactone coupled prodrug, preparation method and application thereof |
| CN112891556A (en) * | 2021-02-01 | 2021-06-04 | 浙江大学医学院附属第一医院 | Oral nanogel of monoclonal antibody medicines and preparation method thereof |
| WO2022190626A1 (en) * | 2021-03-12 | 2022-09-15 | 国立大学法人東北大学 | Sn-38 derivative, nano-particles containing said derivative, medicine, and method for producing said nano-particles |
| 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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