CN105770900B - The application of carbonate polymer of the side chain containing double sulphur five-membered ring functional groups - Google Patents
The application of carbonate polymer of the side chain containing double sulphur five-membered ring functional groups Download PDFInfo
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- CN105770900B CN105770900B CN201510973700.3A CN201510973700A CN105770900B CN 105770900 B CN105770900 B CN 105770900B CN 201510973700 A CN201510973700 A CN 201510973700A CN 105770900 B CN105770900 B CN 105770900B
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- 229920000642 polymer Polymers 0.000 title claims abstract description 113
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 239000005864 Sulphur Substances 0.000 title claims abstract description 59
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 title claims abstract description 48
- 125000000524 functional group Chemical group 0.000 title claims abstract description 47
- 239000003814 drug Substances 0.000 claims abstract description 48
- 239000000178 monomer Substances 0.000 claims abstract description 40
- 229940079593 drug Drugs 0.000 claims abstract description 31
- -1 cyclic carbonate ester Chemical class 0.000 claims abstract description 18
- 239000000126 substance Substances 0.000 claims description 18
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- 238000000034 method Methods 0.000 abstract description 9
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- YFHICDDUDORKJB-UHFFFAOYSA-N trimethylene carbonate Chemical compound O=C1OCCCO1 YFHICDDUDORKJB-UHFFFAOYSA-N 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
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- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
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- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 1
- CHUGKEQJSLOLHL-UHFFFAOYSA-N 2,2-Bis(bromomethyl)propane-1,3-diol Chemical compound OCC(CO)(CBr)CBr CHUGKEQJSLOLHL-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
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- 125000000950 dibromo group Chemical group Br* 0.000 description 1
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- MAHNFPMIPQKPPI-UHFFFAOYSA-N disulfur Chemical compound S=S MAHNFPMIPQKPPI-UHFFFAOYSA-N 0.000 description 1
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- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- UWJJYHHHVWZFEP-UHFFFAOYSA-N pentane-1,1-diol Chemical compound CCCCC(O)O UWJJYHHHVWZFEP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—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
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Polyesters Or Polycarbonates (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of applications of carbonate polymer of side chain containing double sulphur five-membered ring functional groups.The polymer matrix is obtained in the cyclic carbonate ester monomer containing double sulphur five-membered ring functional groups by active controllable ring-opening polymerisation, and molecular weight is controllable, molecular weight distribution is relatively narrow, without protecting and being deprotected process；There is biodegradability using the polymer that cyclic carbonate ester monomer ring-opening polymerisation of the present invention obtains, it can be used for controlled drug delivery systems, long circulating in the nano-medicament carrier support of the sensitive reversible crosslink of reduction of the cancer target of preparation, but crosslinking is solved in the enrichment of cancer cell height and quickly into the cell, releases drug, efficiently specifically kills cancer cell.The carbonate polymer has application prospect in tissue engineering bracket and biochip coating etc. simultaneously.
Description
It is May 28, entitled " side in 2014 that the present invention, which is application No. is the 201410231049.8, applying date,
The divisional application of the patent of carbonate polymer and its application of the chain containing double sulphur five-membered ring functional groups ".
Technical field
The present invention relates to a kind of applications of biodegradable polymer material, and in particular to a kind of side chain contains double sulphur five-membered rings
The application of the carbonate polymer of functional group belongs to medical material field.
Background technology
Biodegradable polymer has very unique performance, such as they usually have good biocompatibility,
Energy degradation in vivo, catabolite can be absorbed by the body or be excreted by human normal physiological pathway, and be widely used
It is controlled in biomedical every field, such as operation suture thread, bone fixation instrument, bioengineered tissue timbering material and drug
Discharge carrier etc..Wherein, the biodegradable polymer of synthesis since its immunogenicity is relatively low, its performance contains such as degradation property and
Mechanical performance etc. can be controlled conveniently etc. and be particularly subject to pay close attention to.The biodegradable polymer of synthesis mainly has aliphatic
Polyester, makrolon, polyaminoacid, polyphosphate, polyanhydride, polyorthoester etc..Wherein, makrolon such as polytrimethylene ring
Carbonic ester（PTMC）With aliphatic polyester such as polyglycolide（PGA）, polylactide（PLA）, lactide-glycolide copolymer
（PLGA）, polycaprolactone（PCL）Etc. being most common biodegradable polymer, U.S.'s food Drug Administration has been obtained
（FDA）License.
But the structures such as existing biodegradable polymer such as PTMC, PCL, PLA and PLGA are relatively simple, shortage can
Functional group for modification, it tends to be difficult to which the medicament nano carrier of stable circulation or the surface modification coating of stabilization are provided.
The catabolite of makrolon is mainly carbon dioxide and neutral dihydric alcohol, does not generate acid degradation products.Its
Middle functional cyclic carbonate monomer can be with many cyclic ester monomers, such as GA, LA and ε-CL and other cyclic carbonates
Monomer is copolymerized, and obtains the biodegradable polymer of different performance.
In addition, in the prior art, in ring opening polymerisation process, the reactive group in cyclic carbonate ester monomer structure easily reacts,
Therefore it is required for when preparing functional cyclic carbonate polymer by monomer through protection and deprotection steps, this causes to prepare
Process is cumbersome.
Invention content
It is an object of the present invention to provide a kind of applications of carbonate polymer of side chain containing double sulphur five-membered ring functional groups.
In order to achieve the above objectives, the specific technical solution of the present invention is：
A kind of carbonate polymer of the side chain containing double sulphur five-membered ring functional groups is in preparing drug controlled release carrier
Using；Carbonate polymer of the side chain containing double sulphur five-membered ring functional groups, chemical structural formula are：
Wherein, the one kind of R1 in following group：
The one kind of k=20-250 in formula, R4 in following group：
The molecular weight of carbonate polymer of the side chain containing double sulphur five-membered ring functional groups is 3000~70000 Da.
In above-mentioned technical proposal, double sulphur are contained on carbonate polymer strand of the side chain containing double sulphur five-membered ring functional groups
The unit number of the cyclic carbonate ester monomer of five-membered ring functional group is 4~50.
Preferably, the R1 is。
The carbonate polymer that above-mentioned side chain contains double sulphur five-membered ring functional groups can be in the presence of initiator, in solvent
In, it is obtained by the cyclic carbonate monomer ring-opening polymerisation containing double sulphur five-membered ring functional groups, or by containing double sulphur five-membered ring functions
The cyclic carbonate monomer of group and other cyclic ester monomers, cyclic carbonate ester monomer ring-opening polymerisation obtain；Other described cyclic carbonate esters
Monomer includes Trimethylene Carbonate (TMC), other described cyclic ester monomers include caprolactone (ε-CL), lactide (LA) or
Glycolide (GA).
The chemical structural formula of the cyclic carbonate monomer containing double sulphur five-membered ring functional groups is as follows：
, can be prepared by following steps：
(1) by a water and NaHS（NaSH·H2O）It is dissolved in N,N-dimethylformamide（DMF）In, dibromo is new
Pentanediol is slowly added dropwise with constant pressure funnel, is reacted under 50 DEG C of parts 48 hours, after reaction, reactant vacuum distillation removes
Then solvent DMF is diluted with distilled water, be extracted with ethyl acetate four times, and last organic phase rotates to obtain yellow, viscous chemical combination
Object A；
The chemical structural formula of the compound A is as follows：
(2) compound A is stored in tetrahydrofuran solution, is aoxidized 24 hours in air, obtain compound B, it is described
The chemical structural formula of compound B is as follows：
(3) in nitrogen atmosphere, compound B and ethyl chloroformate are dissolved in dried tetrahydrofuran, then use perseverance
Triethylamine is slowly added dropwise in pressure dropping funel, react 4 hours in ice-water bath, after reaction, filters, filtrate through spin concentration,
3-5 recrystallization is carried out with ether again, obtains yellow crystals, the i.e. cyclic carbonate monomer containing double sulphur five-membered ring functional groups.
Above-mentioned cyclic carbonate ester monomer in methylene chloride can be using polyethylene glycol as initiator, double（Double trimethyl silicon substrates）Amine
Zinc is catalyst ring-opening polymerisation, forms block polymer, and reaction equation is as follows：
The carbonate polymer that above-mentioned side chain contains double sulphur five-membered ring functional groups has biodegradable, can be prepared into
To nano-particle（20-250 nanometers of grain size）, and then anticancer drug can be loaded；Polymer nano-particle can be in catalytic amount
Reducing agent such as dithiothreitol dithio or glutathione the catalysis lower chemical crosslinking for forming stabilization, in vivo long circulating, but enter thin
A large amount of reducing substances are deposited and can quickly solve crosslinking at ambient in the cell after born of the same parents, release drug, efficiently kill cancer cell.
Meanwhile carbonate polymer of the above-mentioned side chain containing double sulphur five-membered ring functional groups is formed to be chemically crosslinked to obtain being crosslinked and be received
After meter Zai Ti, it can be coupled tumor cell specific targeted molecular such as rgd peptide, nucleic acid in the crosslinking nano carrier surface and be adapted to
Son, antibody, folic acid or lactose etc. can greatly increase intake of the Nano medication in cancer cell.
The carbonate polymer that above-mentioned side chain contains double sulphur five-membered ring functional groups has biodegradable, can prepare life
Object organization bracket, polymer is in the reducing substances of catalytic amount, such as dithiothreitol dithio or glutathione deposit at ambient, can
To promote to be prepared into fiber by electrostatic spinning after reversible polymer crosslinking, this fiber can be very good to glue after modification
Attached cell can greatly enhance the stability of fiber by crosslinking, keep it more stable in tissue site, it is unstable to avoid holder
Legibility from the drawbacks of.
Above-mentioned side chain contains the carbonate polymer of double sulphur five-membered ring functional groups as biochip coating, with biological group
Knit that holder is similar, forming stable chemistry under reducing agent such as dithiothreitol dithio or the glutathione catalysis of catalytic amount hands over
Connection, keeps biochip coating more stable in vivo, reduces non-specific adsorption, reduces the measurement noise of biological components content.
Due to the implementation of said program, compared with prior art, the present invention haing the following advantages：
1. the present invention utilizes the cyclic carbonate monomer containing double sulphur five-membered ring functional groups to pass through the controllable open loop of activity for the first time
Homopolymerization obtains the carbonic acid that molecular weight is controllable, molecular weight distribution is relatively narrow with the combined polymerization of other carbonate monomers, cyclic ester monomer
Ester polymer, since sulphur sulphur five-membered ring group does not influence the ring-opening polymerisation of cyclic carbonate ester monomer, polymerization process is without existing
Protection in technology and deprotection process, simplify operating procedure.
2. carbonate polymer of the side chain disclosed by the invention containing double sulphur five-membered ring functional groups has excellent biology can
Degradability can be used for controlled drug delivery systems, can prepare the nano-medicament carrier of the sensitive reversible crosslink of reduction of cancer target,
Long circulating in support releases drug, efficiently specifically kills cancer in the intracellular quick solution crosslinking of cancer cell height enrichment
Cell.
3. cyclic carbonate ester monomer disclosed by the invention prepare it is simple, by its can convenient ring-opening polymerisation obtain side chain and contain
The carbonate polymer of double sulphur five-membered ring functional groups；The polymer can further carry out self assembly for Drug controlled release body
System, organizational project and biochip coating have good application value in terms of biomaterial.
Description of the drawings
Fig. 1 is polymer P EG5k-P (CDC2.5k- in embodiment twoco- CL3.9k) nuclear magnetic spectrogram；
Fig. 2 is polymer P (CDC- in embodiment 13co-CL)(6.21k)-PEG(0.5k)-P(CDC-co-CL)
The nuclear magnetic spectrogram of (6.21k)；
Fig. 3 is polymer P EG5k- in embodiment 15b- PCDC2.8k nano particle diameter distribution maps；
Fig. 4 is polymer P EG5k- in embodiment 16b- PCDC2.8k cross-linking nanoparticles high dilution change of size
Figure；
Fig. 5 is polymer P EG5k- in embodiment 16b- PCDC2.8k cross-linking nanoparticles are in reducing substances gluathione
Change of size figure in the presence of peptide；
Fig. 6 is polymer P EG5k- in embodiment 16b- PCDC2.8k cross-linking nanoparticles are to Raw264.7 and MCF-7
The toxicity data figure of cell；
Fig. 7 is the polymer P EG5k- that adriamycin is loaded in embodiment 17b- PCDC2.8k cross-linking nanoparticles it is external
Releasing result；
Fig. 8 is the polymer P EG5k- that medicine is carried in embodiment 17b- PCDC2.8k cross-linking nanoparticles are to Raw264.7
With the toxicity data figure of MCF-7 cells；
Fig. 9 is polymer P EG5k-P (CDC3.2k- in embodiment 18co- TMBPEC3.5k) cross-linking nanoparticles grain
Diameter distribution map and electron projection microscope photograph figure；
Figure 10 is polymer P EG5k-P (CDC3.2k- in embodiment 18co- TMBPEC3.5k) cross-linking nanoparticles pair
The toxicity data figure of Raw264.7 cells；
Figure 11 is the polymer P EG5k-P (CDC3.2k- that adriamycin is contained in embodiment 19co- TMBPEC3.5k) it hands over
Join toxicity data figure of the nano-particle to Raw264.7 cells.
Specific implementation mode
With reference to embodiment and attached drawing, the invention will be further described：
Cyclic carbonate monomer of the embodiment one containing double sulphur five-membered ring functional groups（CDC）Synthesis
1, a hydration NaHS（28.25 g, 381.7 mmol）It is dissolved in 400 mL n,N-Dimethylformamide（DMF）
In, 50 DEG C are heated to being completely dissolved, and dibromoneopentyl glycol is added dropwise（20 g, 76.4 mmol）, react 48 hours.Reactant
Vacuum distillation removes solvent DMF, then 200mL distilled water is used to dilute, and is extracted four times with 250 mL ethyl acetate, last organic phase
Revolving obtains yellow, viscous compound A, yield：70%；
2, it is dissolved in the tetrahydrofuran of 400 mL（THF）In compound A place in air 24 hours, intermolecular sulfydryl
It is oxidized to sulphur sulfide linkage, obtains compound B, yield；>98%；
3, under nitrogen protection, compound B（11.7 g, 70.5 mmol）It is dissolved in dried THF（150 mL）In, it stirs
It mixes to being completely dissolved.It is consequently cooled to 0 DEG C, ethyl chloroformate is added（15.65 mL, 119.8 mmol）, then it is added dropwise
Et3N（22.83 mL, 120.0 mmol）.After being added dropwise, the system the reaction was continued under the conditions of ice-water bath 4 h.Reaction knot
Shu Hou filters out the Et of generation3NHCl, filtrate finally carry out repeated recrystallize through spin concentration with ether, obtain yellow crystalline substance
Body, the i.e. cyclic carbonate monomer containing double sulphur five-membered ring functional groups（CDC）, yield：64%.
Carbonate polymer PEG5k-P (CDC2.5k- of the two liang of block side chains of embodiment containing double sulphur five-membered ring functional groups
Co-CL3.9k synthesis)
In a nitrogen environment, 0.28 g（1.46 mmol）CDC monomers and 0.4 g（3.51 mmol）Caprolactone（ε-CL）
It is dissolved in 3 mL dichloromethane, is added in sealing reactor, 0.5 g of polyethylene glycol of molecular weight 5000 is then added（0.1
mmol）It is double with the catalyst of 0.1 mol/L（Double trimethyl silicon substrates）The dichloromethane solution of amine zinc（0.1 mol/L）, then
Reactor is sealed, and is transferred out of glove box, is put into after being reacted 1 day in 40 DEG C of oil baths, is terminated and is reacted with glacial acetic acid, in ice ether
Precipitation eventually passes through filtering, vacuum drying obtains carbonate polymer of the product side chain containing double sulphur five-membered ring functional groups
PEG5k-P(CDC2.5k-co-CL3.9k)。
In formula, m=113.6, x=34.2, y=13.0, n=47.2.
Attached drawing 1 is the nuclear magnetic spectrum of above-mentioned polymer.1H NMR (400 MHz, CDCl3): 1.40 (m, -
COCH2CH2CH2CH2CH2-), 1.65 (m, -COCH2CH2CH2CH2CH2-), 2.30 (t, -COCH2CH2CH2CH2CH2-),
3.08 (s, -CCH2), 3.30 (m ,-OCH3), 4.03 (t ,-COCH2CH2CH2CH2CH2O-), 4.05 (s, -
CH2OCOCHCH2-), 4.07 (s, -OCH2CCH2O-), 4.31 (m, -CCH2)；The molecular weight that GPC is surveyed：14.0 kDa, point
Son amount distribution：1.56.
Carbonate polymer PEG5k- of the three liang of block side chains of embodiment containing double sulphur five-membered ring functional groupsb-PCDC2.8k
Synthesis
In a nitrogen environment, by 0.3 g（1.56 mmol）CDC monomers, 2 mL dichloromethane are added in sealing reactor,
Then 0.5 g of polyethylene glycol that molecular weight is 5000 is added（0. 1 mmol）It is double with the catalyst of 1 mL（Double trimethyl silicanes
Base）The dichloromethane solution of amine zinc（0.1 mol/L）, then reactor is sealed, is transferred out of glove box, is put into 40 DEG C of oil baths
It after middle reaction 1 day, is terminated and is reacted with glacial acetic acid, precipitated in ice ether, eventually pass through filtering, vacuum drying obtains product side chain
Carbonate polymer PEG5k- containing double sulphur five-membered ring functional groupsb-PCDC2.8k。
1H NMR (400 MHz, CDCl3): 3.08 (s, -CCH2), 3.30 (m ,-OCH3), 4.05 (s ,-
CH2OCOCHCH2-), 4.07 (s, -OCH2CCH2O-), 4.31 (m, -CCH2)。
In formula, m=113.6, n=14.6.
Carbonate polymer PEG5k-P (CDC3.8k- of the two block side chain of example IV containing double sulphur five-membered ring functional groupsco- CL14k) synthesis
In a nitrogen environment, 0.5 g（2.6 mmol）CDC monomers and 1.5 g（13.2 mmol）Caprolactone（ε-CL）It is molten
In 10 mL dichloromethane, it is added in sealing reactor, 0.5 g of polyethylene glycol of molecular weight 5000 is then added（0.1
mmol）It is double with the catalyst of 1 mL（Double trimethyl silicon substrates）The dichloromethane solution of amine zinc（0.1 mol/L）, then reaction
Device is sealed, and is transferred out of glove box, is put into after being reacted 1 day in 40 DEG C of oil baths, is terminated and is reacted with glacial acetic acid, sinks in ice ether
It forms sediment, eventually passes through filtering, vacuum drying obtains carbonate polymer PEG5k-P of the product side chain containing double sulphur five-membered ring functional groups
(CDC3.8k-co- CL14k), the molecular weight that GPC is surveyed：30.6 kDa, molecular weight distribution：1.34.
In formula, m=113.6, x=122.8, y=19.8, n=142.
Carbonate polymer PEG1.9k-P of the five liang of block side chains of embodiment containing double sulphur five-membered ring functional groups
(CDC3.9k-co- CL3.8k) synthesis
In a nitrogen environment, 0.4 g（2.1 mmol）CDC monomers and 0.4 g（3.51 mmol）Caprolactone（ε-CL）It is molten
In 3 mL dichloromethane, it is added in sealing reactor, 0.4 g of polyethylene glycol of molecular weight 1900 is then added（0.21
mmol）It is double with the catalyst of 1 mL（Double trimethyl silicon substrates）The dichloromethane solution of amine zinc（0.1 mol/L）, then reaction
Device is sealed, and is transferred out of glove box, is put into after being reacted 1 day in 40 DEG C of oil baths, is terminated and is reacted with glacial acetic acid, sinks in ice ether
It forms sediment, eventually passes through filtering, vacuum drying obtains carbonate polymer of the two block side chains containing double sulphur five-membered ring functional groups
PEG1.9k-P(CDC3.9k-co- CL3.8k), the molecular weight that GPC is surveyed：0.96 kDa, molecular weight distribution：1.35.
In formula, m=43.2, x=33.3, y=20.3, n=53.6.
The synthesis of carbonate homopolymer Alk-PCDC2.8k of six side chain of embodiment containing double sulphur five-membered ring functional groups
In a nitrogen environment, 0.3 g（1.6 mmol）CDC monomers are dissolved in 1 mL dichloromethane, and sealing reactor is added
In, the catalyst that refined propilolic alcohol 1 mmol/L and 1 mL is then added is double（Double trimethyl silicon substrates）The dichloromethane of amine zinc
Solution（0.1 mol/L）, then reactor is sealed, is transferred out of glove box, is put into after being reacted 1 day in 40 DEG C of oil baths, uses ice
Acetic acid terminates reaction, is precipitated in ice ether, eventually passes through filtering, vacuum drying obtains product side chain and contains double sulphur five-membered ring functions
The carbonate homopolymer Alk-PCDC2.8k of group.
Carbonate polymer iPr-P (CDC0.8k-of the embodiment heptalateral chain containing double sulphur five-membered ring functional groupsco-
CL92k synthesis)
In a nitrogen environment, 0.1 g（0.52 mmol）CDC monomers and 10 g（87.7 mmol）Caprolactone monomer（CL）
ε-the CL being dissolved in 10 mL dichloromethane are added in sealing reactor, 6 mg of isopropanol are then added（0.1 mmol）And 1mL
Catalyst it is double（Double trimethyl silicon substrates）The dichloromethane solution of amine zinc（0.1 mol/L）, then reactor is sealed, is shifted
Go out glove box, be put into after being reacted 2 days in 40 DEG C of oil baths, is terminated and reacted with glacial acetic acid, precipitated, eventually passed through in ice ether
Filter, vacuum drying obtain carbonate polymer iPr-P of the product side chain containing double sulphur five-membered ring functional groups（CDC-co-CL）
（0.8k-92k）, the molecular weight of GPC surveys：102.3 kDa, molecular weight distribution：1.36.
In formula, x=4.2, y=80.7, n=84.9.
Carbonate polymer PEG5k-PCDC1.0k- of the eight three block side chain of embodiment containing double sulphur five-membered ring functional groups
The synthesis of PCL3.2k
In a nitrogen environment, 0.12 g（1.5 mmol）CDC monomers are dissolved in 2 mL dichloromethane, and sealing reactor is added
In, 0.5 g of polyethylene glycol of molecular weight 5000 is then added（0.31 mmol）It is double with the catalyst of 1mL（Double trimethyl silicanes
Base）The dichloromethane solution of amine zinc（0.1 mol/L）, then reactor is sealed, is transferred out of glove box, is put into 40 DEG C of oil baths
After middle reaction 1 day, then caprolactone is added under glove box nitrogen protection（ε-CL）0.35 g（0.31 mmol）, the reaction was continued one
It after it, is terminated and is reacted with glacial acetic acid, precipitated in ice ether, eventually pass through filtering, vacuum drying obtains product three block side chain
Carbonate polymer PEG5k-PCDC1.0k-PCL3.2k containing double sulphur five-membered ring functional groups.
1H NMR (400 MHz, CDCl3): 1.40 (m, -COCH2CH2CH2CH2CH2-), 1.65 (m, -
COCH2CH2CH2CH2CH2-), 2.30 (t, -COCH2CH2CH2CH2CH2-), 3.08 (s, -CCH2), 3.30 (m ,-
OCH3), 4.03 (t ,-COCH2CH2CH2CH2CH2O-), 4.05 (s, -CH2OCOCHCH2-), 4.07(s, -
OCH2CCH2O-), 4.31 (m, -CCH2)；The molecular weight that GPC is surveyed：10.4 kDa, molecular weight distribution：1.45.
Carbonate polymer PEG5k-P (CDC3.2k- of the nine liang of block side chains of embodiment containing double sulphur five-membered ring functional groupsco- TMBPEC3.5k) synthesis
In a nitrogen environment, 0.4 g（2.1 mmol）CDC monomers and 0.4 g（1.2 mmol）2,4,6- trimethoxies
Base benzene dimethoxym ethane pentaerythrite carbonate monomer（TMBPEC）It is dissolved in 5 mL dichloromethane, sealing is added
In reactor, 0.5 g of polyethylene glycol of molecular weight 5000 is then added（0.1 mmol）It is double with the catalyst of 1mL（Double front threes
Base silicon substrate）The dichloromethane solution of amine zinc（0.1 mol/L）, then reactor is sealed, is transferred out of glove box, is put into 40 DEG C
It after being reacted 1 day in oil bath, is terminated and is reacted with glacial acetic acid, precipitated in ice ether, eventually pass through that filtering, to obtain two embedding for vacuum drying
Carbonate polymer PEG5k-P (CDC3.2k- of the section side chain containing double sulphur five-membered ring functional groupsco-TMBPEC3.5k).GPC is surveyed
Molecular weight：12.4 kDa, molecular weight distribution：1.47.
In formula, m=113.6, x=16.7, y=10.2, n=26.9.
Carbonate polymer PEG1.9k-PCL1.8k- of the ten three block side chain of embodiment containing double sulphur five-membered ring functional groups
The synthesis of PCDC0.7k
In a nitrogen environment, 0.2 g（1.76 mmol）Caprolactone（ε-CL）It is dissolved in 2 mL dichloromethane, sealing is added
In reactor, 0.19 gram of the polyethylene glycol of molecular weight 1900 is then added（0.1 mmol）It is double with the catalyst of 1mL（Double trimethyls
Silicon substrate）The dichloromethane solution of amine zinc（0.1 mol/L）, then reactor is sealed, is transferred out of glove box, is put into 40 DEG C of oil
After being reacted 1 day in bath, then 80 mg of CDC monomers is added under glove box nitrogen protection（0.42 mmol）, after the reaction was continued one day,
It is terminated and is reacted with glacial acetic acid, precipitated in ice ether, eventually pass through filtering, vacuum drying obtains three block side chain and contains double five yuan of sulphur
The carbonate polymer PEG1.9k-PCL1.8k-PCDC0.7k of ring function group.
1H NMR (400 MHz, CDCl3): 1.40 (m, -COCH2CH2CH2CH2CH2-), 1.65 (m, -
COCH2CH2CH2CH2CH2-), 2.30 (t, -COCH2CH2CH2CH2CH2-), 3.08 (s, -CCH2), 3.30 (m ,-
OCH3), 4.03 (t ,-COCH2CH2CH2CH2CH2O-), 4.05 (s, -CH2OCOCHCH2-), 4.07 (s, -
OCH2CCH2O-), 4.31 (m, -CCH2)；The molecular weight that GPC is surveyed：0.64 kDa, molecular weight distribution：1.32.
Carbonate polymer PEG5k-P (CDC5k- of the 10 block side chain of embodiment containing double sulphur five-membered ring functional groupsco- TMC20k) synthesis
In a nitrogen environment, 0.1 g（0.52 mmol）CDC monomers and 0.4 g（3.85 mmol）Trimethylene carbonic acid
Ester（TMC）It is dissolved in 3 mL dichloromethane, is added in sealing reactor, 0.1 g of polyethylene glycol of molecular weight 5000 is then added
（0.02 mmol）It is double with the catalyst of 0.1 mol/L（Double trimethyl silicon substrates）The dichloromethane solution of amine zinc（0.1 mol/L）,
Then reactor is sealed, is transferred out of glove box, be put into after being reacted 1 day in 40 DEG C of oil baths, terminated and reacted with glacial acetic acid, in ice
It is precipitated in ether, eventually passes through filtering, vacuum drying obtains carbonic ester of the two block side chains containing double sulphur five-membered ring functional groups and gathers
Close object PEG5k-P (CDC4.9k-co-TMC19.0k).
1H NMR (400 MHz, CDCl3): 2.08 (t, -COCH2 CH 2 CH2O-), 3.08 (s, -CCH2),
3.30 (m ,-OCH3), 3.65（T ,-OCH 2 CH2O-）, 4.28 (t ,-COCH2CH2 CH 2 O-), 4.31 (m, -CCH2)；
The molecular weight that GPC is surveyed：34.5 kDa, molecular weight distribution：1.48.
In formula, m=113.6, x=25.5, y=186.3, n=211.8.
Carbonate polymer PEG5k-PLA7.8k- of the 12 three block side chain of embodiment containing double sulphur five-membered ring functional groups
The synthesis of PCDC1.7k
In a nitrogen environment, 0.45 g（3.13 mmol）Lactide（LA）It is dissolved in 3 mL dichloromethane, it is anti-that sealing is added
It answers in device, 0.25 g of polyethylene glycol of molecular weight 5000 is then added（0.05 mmol）It is double with the catalyst of 1 mL（Double three
Methylsilyl）The dichloromethane solution of amine zinc（0.1 mol/L）, then reactor is sealed, is transferred out of glove box, is put into 40
After being reacted 1 day in DEG C oil bath, then 100 mg of CDC monomers is added under glove box nitrogen protection（0.52 mmol）, the reaction was continued one
It after it, is terminated and is reacted with glacial acetic acid, precipitated in ice ether, eventually pass through filtering, vacuum drying obtains three block side chain containing double
The carbonate polymer PEG5k-PLA7.8k-PCDC1.7k of sulphur five-membered ring functional group.
1H NMR (400 MHz, CDCl3): 1.59 (m, -COCH（CH 3 ) O-), 3.08 (s, -CCH2),
3.30 (m ,-OCH3), 3.65 (m ,-OCH 2 CH2O-), 4.07 (s ,-OCH 2 CCH2O-), 5.07 (m, -COCH（CH3)；
The molecular weight that GPC is surveyed：16.8 kDa, molecular weight distribution：1.47.
In formula, m=113.6, x=122.2, y=8.9, n=131.1.
Carbonate polymer P (CDC- of the 13 three block side chain of embodiment containing double sulphur five-membered ring functional groupsco-CL)
(6.21k)-PEG(0.5k)-P(CDC-co- CL) (6.21k) synthesis
In a nitrogen environment, 1.5 g（13.2 mmol）ε-CL and 0.0625 g（0.325 mmol）CDC monomers are dissolved in 8
It in mL dichloromethane, is added in sealing reactor, the rear PEG500 that 0.05 g is added（0.01 mmol）It is double with the catalyst of 1 mL
（Double trimethyl silicon substrates）The dichloromethane solution of amine zinc（0.1 mol/L）, after reacting one day, terminated and reacted with glacial acetic acid, in ice
It is precipitated in ether, eventually passes through filtering, vacuum drying obtains carbonic ester of the three block side chain containing double sulphur five-membered ring functional groups and gathers
Close object P (CDC-co-CL) (6.21k)-PEG (0.5k)-P (CDC-co-CL)(6.21k)。
Attached drawing 2 is the nuclear magnetic spectrum of above-mentioned polymer：1H NMR (400 MHz, CDCl3): 1.40 (m, -
COCH2CH2CH2CH2CH2-), 1.65 (m, -COCH2CH2CH2CH2CH2-), 2.30 (t, -COCH2CH2CH2CH2CH2-),
3.08 (s, -CCH2), 4.03 (t, -COCH2CH2CH2CH2CH2O-), 4.05 (s, -CH2OCOCHCH2-), 4.07
(s, -OCH2CCH2O-), 4.31 (m, -CCH2)；The molecular weight that GPC is surveyed：14.6 kDa, molecular weight distribution：1.38.
In formula, m=11.4, x=6.3, y=43.9, n=51.2.
Carbonate polymer PEG1.9k- of the 14 liang of block side chains of embodiment containing double sulphur five-membered ring functional groupsb-
The synthesis of PCDC0.8k
In a nitrogen environment, by 0.08 g（0.42 mmol）CDC monomers, 2 mL dichloromethane are added in sealing reactor,
Then 1.9 g of polyethylene glycol that molecular weight is 1900 is added（1 mmol）It is double with the catalyst of 1 mL（Double trimethyl silicon substrates）
The dichloromethane solution of amine zinc（0.1 mol/L）, then reactor is sealed, is transferred out of glove box, is put into 40 DEG C of oil baths
It after reaction 1 day, is terminated and is reacted with glacial acetic acid, precipitated in ice ether, eventually pass through filtering, vacuum drying obtains product side chain and contains
The carbonate polymer PEG1.9k- of double sulphur five-membered ring functional groupsb-PCDC0.8k。
1H NMR (400 MHz, CDCl3): 3.08 (s, -CCH2), 3.30 (m ,-OCH3), 4.05 (s ,-
CH2OCOCHCH2-), 4.07 (s, -OCH2CCH2O-), 4.31 (m, -CCH2)。
In formula, m=43.2, n=4.2.
It can be seen from the above result that by a series of characterization to polymer, the ring-opening polymerisation and combined polymerization of CDC are controllable
, and its molecular weight is consistent with design, and the molecular weight distribution of polymer is relatively narrow.
15 polymer nano-particle PEG5k- of embodimentbThe preparation of-PCDC2.8k
Polymer nanoparticle is prepared using dialysis.Polymer P EG5k-b- PCDC2.8k is dissolved in N, N- dimethyl formyls
Amine（2 mg/mL）In, take 200 μ L to be added drop-wise to 800 μ L phosphate buffer solutions（10 mM, pH 7.4, PB）In, it is packed into dialysis
Bag（MWCO 3500）Middle dialysed overnight, changes five water, and dialysis medium is PB（10 mM, pH 7.4）.Finally obtained polymer
A concentration of 0.2 mg/mL of nanoparticle.By dynamic light scattering particle size analyzer（DLS）The nanoparticle of the formation of survey is 173 nm,
And particle diameter distribution is very narrow, sees attached drawing 3.
16 polymer nano-particle PEG5k- of embodimentbThe crosslinking of-PCDC2.8k, solution crosslinking, cytotoxicity
The crosslinking of nanoparticle is by the dithiothreitol dithio for adding catalytic amount（DTT）It carries out.Polymer nanoparticle aqueous solution is led to
Nitrogen 10 minutes, as possible catches up with air only.Then the nanoparticle solution into closed reactor（1 mL, 0.25 mg/mL,
3.21×10-5 mmol）10 μ L of middle addition are dissolved in the dithiothreitol dithio in secondary water（DTT）（0.007 mg, 4.67 ×
10-5 Mmol, 10 % of lipoic acid functional group molal quantity）, closed room temperature is stirred to react 1 day.The size for measuring particle is 150 nanometers,
Less about 15% is compared with no crosslinked grain size, the Nanoparticle Size before being crosslinked is 173 rans.Receiving after crosslinking
Rice corpuscles has almost no change in 100 times of its later grain sizes of concentration dilution and particle diameter distribution；Stablize in physiological conditions, thus may be used
To find out, double sulfur-crosslinked stability that can largely improve nanoparticle are shown in attached drawing 4.
Disulfide bond can be easy in reducing agent such as glutathione（GSH）The lower fracture of effect.In nitrogen protection and 37 DEG C of items
Under part, crosslinking nano grain solution is led into nitrogen after ten minutes, reducing substances glutathione, which is added, makes it in polymer nanoparticle
Ultimate density in sub- solution is 10 mM.The change of grain size is crosslinked using dynamic light scattering particle size analyzer tracking nanoparticle subsolution
Change situation, sees attached drawing 5, it can be seen that add 10 mM reducing substances glutathione（GSH）Afterwards, cross-linking nanoparticles grain size with
The passage for the time is gradually destroyed, and illustrates that double sulphur rings can be broken in the presence of a large amount of reducing substances in polymer.In cytoplasm
In there is also the GSH of high concentration, therefore the nano-medicament carrier stable circulation prepared, but can quickly be dissociated after cell endocytic,
Discharge drug.
The cytotoxicity of cross-linking nanoparticles is tested using mtt assay.Using to cell be MCF-7（Human milk gland
Cancer cell）Cell and Raw 264.7（Mouse macrophage）Cell.With 1 × 104A/mL is thin by HeLa cells or Raw 264.7
Born of the same parents are inoculated in 96 orifice plates, per 100 μ L of hole, culture to cell it is adherent after, the polymer nanocomposite containing various concentration is added in experimental group
The culture solution of grain, separately sets cell blank control wells and culture medium blank well, parallel 4 multiple holes.After being cultivated 24 hours in incubator
96 orifice plates are taken out, MTT is added（5.0 mg/mL）150 μ L DMSO dissolving lifes are added in 10 μ L per hole after continuing culture 4 hours
At crystallization son, its absorbance value is surveyed at 492 nm with microplate reader（A）, returned to zero with culture medium blank well, calculate cell survival
Rate.
A in formulaTFor the absorbance at 490 nm of test group, ACFor the absorbance at 492 nm of blank control group.Polymer is dense
Degree is respectively 0.1,0.2,0.3,0.4,0.5 mg/mL.Attached drawing 6 is the cytotoxicity result of nanoparticle, it can be seen from the figure that
When the concentration of polymer nanoparticle increases to 0.5 mg/mL from 0.1 mg/mL, Raw264.7 cells and MCF-7 cells are deposited
Motility rate remains above 85%, illustrates PEG5k-b- PCDC2.8k polymer nanoparticles have good biocompatibility.
17 crosslinking nano grain PEG5k- of embodimentbLoad medicine, release in vitro and the cytotoxicity of-PCDC2.8k
Using adriamycin as drug.Since anticancer drugs, doxorubicin is sensitive fluorescent substance, whole operation is being protected from light condition
Lower progress.The hydrochloride of adriamycin is removed first, and operation is：1.2 mg (0.002 mmol) adriamycin is dissolved in 225 μ L
DMSO in, add 0.58 mL of triethylamine (m=0.419 mg, 0.004 mmol) stir 12 hours, siphon away supernatant liquor.
A concentration of 5.0 mg/mL of DMSO solution of adriamycin.By nanometer polymer nanoparticle PEG5k-b- PCDC2.8k is dissolved in N, N-
Dimethylformamide（DMF）In.By the dimethyl sulfoxide solution of adriamycin and polymer nano-particle PEG5k-b- PCDC2.8k's
DMF solution is uniformly mixed by scheduled drug with polymer quality ratio, stirs the two of 4 times of its volumes of lower slow addition thereto
Secondary water（15 s/d）, dialyse to a water after dripping off.
The cross-linking method that embodiment 15 is also pressed in the crosslinking of medicine-carried nano particles carries out.100 μ L crosslinkings are carried into adriamycin
Polymer nano-particle solution is freeze-dried, and is then dissolved in 3.0 mL DMSO, is tested using fluorescence spectrophotometer spectrometer, knot
Close the standard curve computational envelope rate of adriamycin.
Drugloading rate（DLC）And encapsulation rate（DLE）It is calculated according to following formula：
Drugloading rate（wt.%）=（Drug weight/polymer weight）×100 %
Encapsulation rate（%）=（Load the total input amount of drug weight/drug）×100 %
Table 1 is above-mentioned result of calculation, it can be seen that polymer P EG5k-b- PCDC2.8k nano-particles are to small molecule anti-cancer
Drug adriamycin has efficient embedding effect.
The result of drugloading rate, encapsulation rate in the polymer nano-particle of the crosslinking load adriamycin of table 1
The release experiment of adriamycin is shaken in 37 DEG C of constant-temperature tables（200 rpm）It carries out.Drug release is with two groups
What Duplicate Samples were compared, every group has two Duplicate Samples：First group, the polymer nano-particle that crosslinking carries adriamycin is being added
10 mM glutathione（GSH）Simulate the release in intracellular reducing environment PB (10 mM, pH 7.4)；Second group, crosslinking
Carry release of the polymer nano-particle of adriamycin in PB (10 mM, pH 7.4)；Drug-carrying polymer nanoparticle concentration
For 25 mg/L, 0.5 mL is taken to be put into release bag filter（MWCO: 12,000-14,000）In, phase is added in each test tube
25 mL of dialysis solvent answered takes out 5.0 mL bag filter external agencies and is used as test, while to examination in predetermined time interval
5.0 mL respective medias are added in pipe.Drug concentration in solution is measured using EDINBURGH FLS920 luminoscopes.Attached drawing 7 is
The relationship of adriamycin cumulative release amount and time, it can be seen from the figure that the reducing substances paddy Guang of simulation tumour cell is added
Sweet peptide（GSH）Afterwards, release, which is signifi-cantly more rapidly than, does not add GSH components, illustrates that the cross-linking nanoparticles for carrying medicine are restored in 10 mM
In the presence of substance GSH, drug can be effectively discharged.
Carry the PEG5k- of DOXb- PCDC2.8k cross-linking nanoparticles test it to Raw264.7 cells with mtt assay（Mouse is huge
Phagocyte）,MCF-7（Human breast cancer cell）The toxicity of cell etc. carries the uncrosslinked nanoparticle of medicine and free drug as a contrast.With
For Raw264.7 cells, by Raw264.7 cells with 1 × 104A/mL is inoculated in 96 orifice plates, per 100 μ L of hole, cultivates to thin
After born of the same parents are adherent, experimental group is separately added into the load adriamycin crosslinking nano grain containing 0.01,0.1,1,5,10,50 and 100 μ g/mL
Sub- solution carries the fresh medium of the uncrosslinked nano-particle solution of adriamycin and free adriamycin, separately sets cell blank control wells
With culture medium blank well, 4 multiple holes are set per hole.96 orifice plates are taken out after being cultivated 48 hours in incubator, and MTT is added（5.0 mg/
mL）10 μ L continue that crystallization that 150 μ L DMSO dissolvings generate is added per hole after cultivating 4 h, with microplate reader at 492 nm
Survey its absorbance value（A）, returned to zero with culture medium blank well, calculate cell survival rate.
Attached drawing 8 is the polymer P EG5k- of above-mentioned load medicineb- PCDC2.8k cross-linking nanoparticles are to Raw264.7 and MCF-7
The toxicity data figure of cell；From the results, it was seen that carrying semilethal of the cross-linking nanoparticles to Raw264.7 cells of adriamycin
A concentration of 4.89 μ g/mL, the cross-linking nanoparticles for carrying adriamycin are 2.31 μ g/mL, institute to the half lethal concentration of MCF-7 cells
To carry the PEG5k- of DOXb- PCDC2.8k cross-linking nanoparticles can effectively discharge drug in the cell and kill cancer cell.
18 polymer nanoparticle PEG5k-P (CDC3.2k- of embodimentco- TMBPEC3.5k) preparation, crosslinking, solution hand over
Connection and cytotoxicity
Nano-particle is prepared using dialysis.Polymer P EG5k-P (CDC3.2k-co- TMBPEC3.5k) it is dissolved in N, N-
Dimethylformamide（5 mg/mL）In, take 200 μ L to be added drop-wise to 800 μ L phosphate buffer solutions（10 mM, pH 7.4, PB）
In, it is packed into bag filter（MWCO 3500）Middle dialysed overnight, changes five water, and dialysis medium is PB（10 mM, pH 7.4）.Final
The polymer nanoparticle arrived is micellar structure, a concentration of 0.2 mg/mL.Attached drawing 9 is polymer P EG5k-P (CDC3.2k-co-
TMBPEC3.5k) cross-linking nanoparticles grain size distribution and electron projection microscope photograph figure；As can be seen that by dynamic light scattering
Particle Size Analyzer（DLS）The nano-micelle of the formation of survey is 60 nm, and particle diameter distribution is very narrow；It can by transmission electron microscope
To find out, crosslinked nano-particle is spherical, and is uniformly dispersed, and size is surveyed with DLS and matched.
The crosslinking of nanoparticle is by the dithiothreitol dithio for adding catalytic amount（DTT）It carries out.Polymer nanoparticle aqueous solution is led to
Nitrogen 10 minutes, as possible catches up with air only.Then the nanoparticle solution into closed reactor（1 mL, 0.25 mg/mL,
3.21×10-5 mmol）10 μ L of middle addition are dissolved in the dithiothreitol dithio in secondary water（DTT）（0.007 mg, 4.67 ×
10-5 Mmol, 10 % of sulphur sulphur five-membered ring molal quantity）, closed room temperature is stirred to react 1 day.The size for measuring particle is 55 nanometers, and
There is no crosslinked grain size compared to reduction about 8%.This is because the nano-particle after crosslinking is relative to no crosslinked nano-particle
More consolidation in core.Nano-particle after crosslinking has almost no change in 100 times of its later grain sizes of concentration dilution and particle diameter distribution；?
Stablize under physiological condition, it can thus be seen that double sulfur-crosslinked stability that can largely improve nanoparticle.
Disulfide bond can be easy to be broken under reducing agent such as glutathione effect.Under the conditions of nitrogen protection and 37 DEG C,
Crosslinking nano grain solution is led into nitrogen after ten minutes, glutathione is added（GSH）Make it in polymer nano-particle solution
Ultimate density is 10 mM.The situation of change of grain size is crosslinked using dynamic light scattering particle size analyzer tracking nanoparticle subsolution.Add
10 mM reducing substances glutathione（GSH）Afterwards, cross-linking nanoparticles grain size is gradually destroyed over time, explanation
Double sulphur rings can be broken in the presence of a large amount of reducing substances in polymer.There is also the GSH of high concentration in cytoplasm, therefore prepare
Nano-medicament carrier stable circulation, but can quickly be dissociated after cell endocytic, release drug
The cytotoxicity of crosslinking nano grain is tested using mtt assay.Using to cell be HepG2（Human liver cancer is thin
Born of the same parents）Cell and Raw 264.7（Mouse macrophage）Cell.With 1 × 104A/mL is by MCF-7（Human liver cancer cell）Cell or
Raw 264.7（Mouse macrophage）Cell inoculation is in 96 orifice plates, per 100 μ L of hole, culture to cell it is adherent after, experimental group adds
Enter the culture solution of the polymer nanoparticle containing various concentration, separately sets cell blank control wells and culture medium blank well, parallel 4
Multiple holes.96 orifice plates are taken out after being cultivated 24 hours in incubator, and MTT is added（5.0 mg/mL）10 μ L, after continuing culture 4 hours
Crystallization that 150 μ L DMSO dissolvings generate is added per hole, its absorbance value is surveyed at 492 nm with microplate reader（A）, with culture
Base blank well returns to zero, and calculates cell survival rate.
A in formulaTFor the absorbance at 490 nm of test group, ACFor the absorbance at 492 nm of blank control group.Polymer is dense
Degree is respectively 0.3,0.6,0.9,1.2,1.5 mg/mL.Attached drawing 10 is nanoparticle cytotoxicity result, it can be seen from the figure that
When the concentration of polymer nanoparticle increases to 1.5 mg/mL from 0.3 mg/mL, HepG2 and MCF-7 cells after being incubated 24 hours
Survival rate remain above 85%, illustrate PEG5k-P (CDC3.2k-co- TMBPEC3.5k) polymer nanoparticle have good life
Object compatibility.
The load adriamycin of 19 crosslinking nano grain PEG5k-P (CDC3.2k-co-TMBPEC3.5k) of embodiment is released in vitro
It puts and cytotoxicity
PEG5k-P(CDC3.2k-co- TMBPEC3.5k) crosslinking nano grain load adriamycin, release in vitro method with implement
Example 17.Using mtt assay, to its shape, the crosslinking drug-carrying nanometer particle tests the isocellular toxicity of Raw264.7 and HepG2,
The uncrosslinked nanoparticle and free drug of load medicine are as a contrast.By taking Raw264.7 as an example, by Raw264.7 with 1 × 104A/mL connects
Kind in 96 orifice plates, per 100 μ L of hole, culture to cell it is adherent after, experimental group is separately added into containing 0.01,0.1,1,5,10,50 and
The load adriamycin crosslinking nano grain solution of 100 μ g/mL carries the fresh of the uncrosslinked nanoparticle solution of adriamycin and free adriamycin
Culture solution separately sets cell blank control wells and culture medium blank well, and 4 multiple holes are set per hole.It is taken after being cultivated 48 hours in incubator
Go out 96 orifice plates, the MTT of 10 μ L is added（5.0 mg/mL）, continue the DMSO dissolving lifes of 150 μ L of every hole addition after 4 h of culture
At crystallization son, its absorbance value is surveyed at 492 nm with microplate reader（A）, returned to zero with culture medium blank well, calculate cell survival
As a result rate is shown in attached drawing 11, the crosslinking nano grain for carrying adriamycin is 12.8 μ g/mL, phase to the half lethal concentration of Raw264.7 cells
It for the adriamycin that dissociates, only increases less than ten times, so carrying the PEG5k-P (CDC3.2k- of medicineco- TMBPEC3.5k) crosslinking
Nanoparticle can effectively discharge drug in the cell and kill cancer cell, and corresponding empty crosslinking nano grain to HepG2 and
Raw264.7 cells have good biocompatibility.
The drug-carrying polymer nanoparticle cRGD-PEG5k-P (CDC3.2k- of the cancer target of embodiment 20 cRGD modificationsco- TMBPEC3.5k) preparation and cytotoxicity
According to method synthesis Mal-PEG6k-P (CDC3.8k- in embodiment nineco- TMBPEC3.5k) polymer, and according to
Method described in embodiment 15 prepares the nanoparticle for loading DOX, and prepares crosslinking according to method described in example 16 and carry medicine
Nanoparticle.It uses cRGD-SH small peptides to prepare the nano-particle that surface is coupled cRGD by Michael addition reaction later, can be disliked
Property glioma cell specificity endocytosis achieve the effect that chemotherapy to more effectively killing tumour cell.According to embodiment
The experimental method of 19 cytotoxicities, herein we select malignant glioma（U87MG cells）Cell does MTT toxicity tests,
This is because this cell surface has the integral protein over-expressed to cRGD, by cell toxicity test result it is found that nanometer
CRGD- PEG6k-P (CDC3.8k- in particleco- TMBPEC3.5k) when entire polymer weight ratio is 20%, it has been incubated 48
Hour, and siphon away sample after 4 hours medicine-carried nano particles are added, continue to be incubated 44 hours, drug half lethal dose relative to
There is no the medicine-carried nano particles of cRGD to reduce six times, thus result is it is found that the medicine-carried nano particles of surface modification cRGD can be with
The receptor special with cell surface is combined and endocytosis enters cell, relative to the nano-particle not targeted, active targeting
It is very strong, tumour cell can be effectively killed, is had wide practical use in medicine-carried nano particles are to the targeted therapy of tumour.
What the load modified nano gold stick surfaces medicine PEG5k-PLGA7.8k-PCDC1.7k of embodiment 21 and NIR were triggered
Drug release
The preparation of the nanometer gold bar of triblock polymer PEG5k-PLGA7.8k-PCDC1.7k nanoparticles modification
With vigorous stirring, the polymer solution being dissolved in DMSO（2 mL, 5mg/mL）It is added drop-wise to point of nanometer gold bar
In dispersion liquid（5 mL, 0.1mg/mL）Stirring 4 hours, centrifugation remove the polymer not connected, are dispersed again in phosphoric acid twice
In buffer solution, the polymer yield of the upper golden stick of modification is detected by TGA, by with individual polymer phase ratio, polymer
The yield of the golden stick of modification is 80%（Theory feeds intake by 100 percent）.The load medicine of polymer-modified nanometer gold bar.Above-mentioned
In obtained polymer-modified nanometer gold bar solution, 10%, 20% is added dropwise dropwise, 30% drug being dissolved in DMSO stirs
It is incubated at room temperature 12 h after half an hour, and free small-molecule drug is removed by dialysing 12 hours, dialysis medium is pH
For 7.4 phosphate buffer solution, by fluoroscopic examination, it is 70 ~ 90% to the package efficiency of drug later, it follows that polymerization
The nanometer gold bar of object modification can efficiently wrap up small molecule dewatering medicament.
The drug release of the polymer-modified nanometer gold bar of NIR triggerings.Polymer-modified nanometer gold bar is dispersed in 10
In mL phosphate buffer solutions, it is 0.2 W/ ㎝ to use intensity every other hour2, wavelength is 5 min of Infrared irradiation of 808 nm,
It takes 500 μ L solution to come out in specific time interval, centrifuges, survey the fluorescence of supernatant, thus analyze the small molecule released
Medicament contg.By fluoroscopic examination it is found that the drug release of the polymer-modified nanometer gold bar after illumination is 92%, much
It is faster than the control group of not illumination（Release is only 18%）, it follows that such polymer-modified nanometer gold bar material can be applied
In the drug release of near-infrared triggering.
Claims (3)
1. application of carbonate polymer of the side chain containing double sulphur five-membered ring functional groups in preparing drug controlled release carrier；Institute
The chemical structural formula for stating carbonate polymer of the side chain containing double sulphur five-membered ring functional groups is：
Wherein, the one kind of R1 in following group：
The one kind of k=20-250 in formula, R4 in following group：
The molecular weight of carbonate polymer of the side chain containing double sulphur five-membered ring functional groups is 3000~70000 Da.
2. according to claim 1 carbonate polymer of the side chain containing double sulphur five-membered ring functional groups prepare drug control release
Put the application in carrier, it is characterised in that：On carbonate polymer strand of the side chain containing double sulphur five-membered ring functional groups
The unit number of cyclic carbonate ester monomer containing double sulphur five-membered ring functional groups is 4~50.
3. according to claim 1 carbonate polymer of the side chain containing double sulphur five-membered ring functional groups prepare drug control release
Put the application in carrier, it is characterised in that：The R1 is, k=20-250 in formula, R4 be selected from
One kind in lower group：
。
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| CN102245214A (en) * | 2008-10-10 | 2011-11-16 | 仿生耳研究所 | Biodegradable polymer - bioactive moiety conjugates |
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| CN102245214A (en) * | 2008-10-10 | 2011-11-16 | 仿生耳研究所 | Biodegradable polymer - bioactive moiety conjugates |
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