CN105770900A - Application of carbonate polymer containing bi-sulfur five-member ring functional gene in side chain - Google Patents
Application of carbonate polymer containing bi-sulfur five-member ring functional gene in side chain Download PDFInfo
- Publication number
- CN105770900A CN105770900A CN201510973700.3A CN201510973700A CN105770900A CN 105770900 A CN105770900 A CN 105770900A CN 201510973700 A CN201510973700 A CN 201510973700A CN 105770900 A CN105770900 A CN 105770900A
- Authority
- CN
- China
- Prior art keywords
- polymer
- sulfur
- double
- membered ring
- functional groups
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 CCC1(C*)CNCC1 Chemical compound CCC1(C*)CNCC1 0.000 description 2
- ARNUGZYCAANCLP-UHFFFAOYSA-N C=C1OCC2(CSCC2)CO1 Chemical compound C=C1OCC2(CSCC2)CO1 ARNUGZYCAANCLP-UHFFFAOYSA-N 0.000 description 1
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 application of a carbonate polymer containing a bi-sulfur five-member ring functional gene in a side chain. The polymer is obtained through activity-controllable ring-opening polymerization based on a cyclic carbonate monomer containing the bi-sulfur five-member ring functional gene; the polymer is controllable in molecular wight, relatively narrow in molecular weight distribution and free from protection and deprotection processes; the polymer obtained from the cyclic carbonate monomer through ring-opening polymerization is biodegradable and is suitable for controlling a drug release system; a prepared tumor-targeted reduction-sensitive reversible cross-linking nano-drug carrier supports in vivo long circulation, but the nano-drug carrier can be rapidly de-cross-linked to release drugs in cells highly enriched with cancer cells, so that the cancer kills can be killed with high specificity. Meanwhile, the carbonate polymer has application prospect in such aspects as tissue engineering scaffolds, biochip coatings and the like.
Description
The divisional application of the patent that the present invention is application number is 201410231049.8, the applying date is May 28, denomination of invention in 2014 is " side chain carbonate polymer containing double; two sulfur five-membered ring functional groups and application thereof ".
Technical field
The present invention relates to the application of a kind of biodegradable polymer material, be specifically related to the application containing the carbonate polymer of double; two sulfur five-membered ring functional groups of a kind of side chain, belong to medical material field.
Background technology
Biodegradable polymer has very unique performance, such as they are generally of good biocompatibility, energy degradation in vivo, catabolite can be absorbed by the body or be excreted by human normal physiological pathway, and it is widely used in biomedical every field, such as operation suture thread, bone anchor tool, bioengineered tissue timbering material and drug controlled release carrier etc..Wherein, the biodegradable polymer of synthesis owing to its immunogenicity is relatively low, its performance all can conveniently obtain control etc. and be particularly subject to pay close attention to containing such as degradation property and mechanical performance etc..The biodegradable polymer of synthesis mainly has aliphatic polyester, Merlon, polyamino acid, poly phosphate, condensing model, poe etc..Wherein, Merlon such as polytrimethylene cyclic carbonate ester (PTMC) and aliphatic polyester such as PGA (PGA), polylactide (PLA), PLGA (PLGA), polycaprolactone (PCL) etc. are the most frequently used biodegradable polymer, have obtained the license of U.S. food Drug Administration (FDA).
But, such as the structure comparison such as PTMC, PCL, PLA and PLGA is single for existing biodegradable polymer, lacks the functional group that can be used for modifying, it tends to be difficult to provide the medicament nano carrier of stable circulation or stable finishing coating.
The catabolite of Merlon is mainly carbon dioxide and neutral dihydroxylic alcohols, does not produce acid degradation products.Wherein functional cyclic carbonate monomer with a lot of cyclic ester monomers, such as GA, LA and ε-CL etc., and other cyclic carbonate monomer copolymerization, can obtain the biodegradable polymer of different performance.
It addition, in prior art, in ring opening polymerisation process, the reactive group in cyclic carbonate ester monomer structure easily reacts, being therefore required for when being prepared functional cyclic carbonate polymer by monomer by protecting and deprotection steps, this causes that preparation process is loaded down with trivial details.
Summary of the invention
It is an object of the present invention to provide the application containing the carbonate polymer of double; two sulfur five-membered ring functional groups of a kind of side chain.
For reaching above-mentioned purpose, the technical scheme that the present invention is concrete is:
The application in preparing drug controlled release carrier of a kind of side chain carbonate polymer containing double; two sulfur five-membered ring functional groups；Described side chain is containing the carbonate polymer of double; two sulfur five-membered ring functional groups, and its chemical structural formula is:
Wherein, R1 one in following group:
K=20-250, the R4 one in following group in formula:
Described side chain is 3000～70000Da containing the molecular weight of the carbonate polymer of double; two sulfur five-membered ring functional groups.
In technique scheme, the unit number of the cyclic carbonate ester monomer that the side chain carbonate polymer strand containing double; two sulfur five-membered ring functional groups contains double; two sulfur five-membered ring functional groups is 4～50.
Preferably, described R1 is。
Above-mentioned side chain contains the carbonate polymer of double; two sulfur five-membered ring functional group can under initiator exists, in a solvent, obtained by the cyclic carbonate monomer ring-opening polymerisation containing double; two sulfur five-membered ring functional groups, or obtained by the cyclic carbonate monomer containing double; two sulfur five-membered ring functional groups and other cyclic ester monomers, cyclic carbonate ester monomer ring-opening polymerisation；Other cyclic carbonate ester monomers described include TMC (TMC), and other cyclic ester monomers described include caprolactone (ε-CL), lactide (LA) or Acetic acid, hydroxy-, bimol. cyclic ester (GA).
The described chemical structural formula containing the cyclic carbonate monomer of double; two sulfur five-membered ring functional groups is as follows:
, it can be prepared by following steps:
(1) by a water and NaHS (NaSH H2O) it is dissolved in N, in dinethylformamide (DMF), dibromoneopentyl glycol constant pressure funnel is slowly added dropwise, react 48 hours under 50 DEG C of parts, after reaction terminates, reactant decompression is distilled off solvent DMF, then with distilled water diluting, being extracted with ethyl acetate four times, the rotation steaming of last organic facies obtains yellow, viscous compound A；
The chemical structural formula of described compound A is as follows:
(2) being saved in tetrahydrofuran solution by compound A, oxidation 24 hours, obtain compound B in atmosphere, and the chemical structural formula of described compound B is as follows:
(3) in nitrogen atmosphere, compound B is dissolved in dried oxolane with ethyl chloroformate, then it is slowly added dropwise triethylamine with constant pressure funnel, ice-water bath reacts 4 hours, after reaction terminates, filters, the rotated concentration of filtrate, carry out 3-5 recrystallization with ether again, obtain yellow crystals, namely containing the cyclic carbonate monomer of double; two sulfur five-membered ring functional groups.
Above-mentioned cyclic carbonate ester monomer can be initiator with Polyethylene Glycol in dichloromethane, double; two (double; two trimethyl silicon based) amine zinc is catalyst ring-opening polymerisation, forms block polymer, and its reaction equation is as follows:
The carbonate polymer that above-mentioned side chain contains double; two sulfur five-membered ring functional group has biodegradable, can prepare nanoparticle (particle diameter 20-250 nanometer), and then can load cancer therapy drug；Polymer nano-particle can form stable chemical crosslinking, in vivo long circulating under the reducing agent of catalytic amount such as dithiothreitol dithio or glutathion catalysis, but in cell, a large amount of reducing substanceses are deposited and can quickly be solved crosslinking at ambient after entrance cell, discharge medicine, efficiently kill cancerous cell.
Simultaneously, after the carbonate polymer formation chemical crosslinking containing double; two sulfur five-membered ring functional groups of the above-mentioned side chain obtains crosslinking nano carrier, can coupling tumor cell specific targeted molecular such as rgd peptide, nucleic acid aptamer, antibody, folic acid or lactose etc. at this crosslinking nano carrier surface, it is possible to be greatly increased Nano medication intake in cancerous cell.
The carbonate polymer that above-mentioned side chain contains double; two sulfur five-membered ring functional group has biodegradable, biological tissue's support can be prepared, polymer is at the reducing substances of catalytic amount, such as dithiothreitol dithio or glutathion are deposited at ambient, fiber is prepared into by electrostatic spinning after can promoting reversible polymer crosslinking, this fibrid can well adherent cell after modifying, the stability of fiber can be greatly enhanced through crosslinking, make it more stable at tissue site, it is to avoid support instability legibility from drawback.
Above-mentioned side chain contains the carbonate polymer of double; two sulfur five-membered ring functional group as biochip coating, similar with biological tissue support, it forms stable chemical crosslinking under the reducing agent such as dithiothreitol dithio or glutathion catalysis of catalytic amount, make biochip coating more stable in vivo, reduce non-specific adsorption, reduce the mensuration noise of biological components content.
Due to the enforcement of such scheme, the present invention compared with prior art, has the advantage that
1. the present invention utilize the cyclic carbonate monomer containing double; two sulfur five-membered ring functional groups to be all polymerized by active controlled open loop first or and other carbonate monomers, cyclic ester monomer combined polymerization obtain the carbonate polymer that molecular weight is controlled, molecular weight distribution is narrower; owing to sulfur sulfur five-membered ring group does not affect the ring-opening polymerisation of cyclic carbonate ester monomer; therefore polymerization process is without protection of the prior art and deprotection process, simplifies operating procedure.
2. the side chain disclosed by the invention carbonate polymer containing double; two sulfur five-membered ring functional groups has the biodegradability of excellence, can be used for controlled drug delivery systems, the nano-medicament carrier of the sensitive reversible crosslink of reduction of cancer target can be prepared, long circulating in support, crosslinking is quickly solved in the cell of cancerous cell height enrichment, discharge medicine, efficiently kill cancerous cell specifically.
3. cyclic carbonate ester monomer disclosed by the invention preparation is simple, it ring-opening polymerisation easily can obtain the side chain carbonate polymer containing double; two sulfur five-membered ring functional groups；This polymer can carry out self assembly further for controlled drug delivery systems, organizational project and biochip coating, in biomaterial, has good using value.
Accompanying drawing explanation
Fig. 1 is the nuclear magnetic spectrogram of polymer P EG5k-P (CDC2.5k-co-CL3.9k) in embodiment two；
Fig. 2 is the nuclear magnetic spectrogram of polymer P (CDC-co-CL) (6.21k)-PEG (0.5k)-P (CDC-co-CL) (6.21k) in embodiment 13；
Fig. 3 is polymer P EG5k-b-PCDC2.8k nano particle diameter scattergram in embodiment 15；
Fig. 4 is polymer P EG5k-b-PCDC2.8k cross-linking nanoparticles high dilution change of size figure in embodiment 16；
Fig. 5 is polymer P EG5k-b-PCDC2.8k cross-linking nanoparticles change of size figure under reducing substances glutathion exists in embodiment 16；
Fig. 6 is the polymer P EG5k-b-PCDC2.8k cross-linking nanoparticles toxicity data figure to Raw264.7 and MCF-7 cell in embodiment 16；
Fig. 7 is the release in vitro result of the polymer P EG5k-b-PCDC2.8k cross-linking nanoparticles being loaded with amycin in embodiment 17；
Fig. 8 is the polymer P EG5k-b-PCDC2.8k cross-linking nanoparticles of medicine carrying in the embodiment 17 toxicity data figure to Raw264.7 and MCF-7 cell；
Fig. 9 is polymer P EG5k-P (CDC3.2k-co-TMBPEC3.5k) cross-linking nanoparticles grain size distribution and electron projection microscope photograph figure in embodiment 18；
Figure 10 is polymer P EG5k-P (CDC3.2k-co-TMBPEC3.5k) cross-linking nanoparticles toxicity data figure to Raw264.7 cell in embodiment 18；
Figure 11 is polymer P EG5k-P (CDC3.2k-co-TMBPEC3.5k) cross-linking nanoparticles of the bag load amycin toxicity data figure to Raw264.7 cell in embodiment 19.
Detailed description of the invention
Below in conjunction with embodiment and accompanying drawing, the invention will be further described:
Embodiment one is containing the synthesis of the cyclic carbonate monomer (CDC) of double; two sulfur five-membered ring functional groups
1, a hydration NaHS (28.25g, 381.7mmol) is dissolved in 400mLN, and in dinethylformamide (DMF), 50 DEG C of heating, to being completely dissolved, are added dropwise over dibromoneopentyl glycol (20g, 76.4mmol), react 48 hours.Reactant decompression is distilled off solvent DMF, then use 200mL distilled water diluting, and with 250mL extraction into ethyl acetate four times, last organic facies is revolved steaming and obtained yellow, viscous compound A, productivity: 70%；
2, the compound A being dissolved in the oxolane (THF) of 400mL places 24 hours in atmosphere, and intermolecular sulfhydryl oxidase becomes sulfur sulfide linkage, obtains compound B, productivity；>98%；
3, under nitrogen protection, compound B(11.7g, 70.5mmol) it is dissolved in dried THF(150mL) in, stirring is to being completely dissolved.It is consequently cooled to 0 DEG C, adds ethyl chloroformate (15.65mL, 119.8mmol), be then added dropwise over Et3N(22.83mL, 120.0mmol).After dropwising, this system continues reaction 4h when ice-water bath.Reaction filters out the Et of generation after terminating3N HCl, the rotated concentration of filtrate, finally carry out repeatedly recrystallization with ether, obtain yellow crystals, namely containing the cyclic carbonate monomer (CDC) of double; two sulfur five-membered ring functional groups, productivity: 64%.
Two liang of block side chains of embodiment are containing the synthesis of the carbonate polymer PEG5k-P (CDC2.5k-co-CL3.9k) of double; two sulfur five-membered ring functional groups
In a nitrogen environment, 0.28g(1.46mmol) CDC monomer and 0.4g(3.51mmol) caprolactone (ε-CL) be dissolved in 3mL dichloromethane, add in sealed reactor, it is subsequently adding the Polyethylene Glycol 0.5g(0.1mmol of molecular weight 5000) and the dichloromethane solution (0.1mol/L) of double, two (double, two trimethyl silicon based) the amine zinc of catalyst of 0.1mol/L, then reactor good seal, migrate out glove box, put into after 40 DEG C of oil baths are reacted 1 day, reaction is terminated with glacial acetic acid, ice ether precipitates, eventually pass through filtration, vacuum drying obtains the product side chain carbonate polymer PEG5k-P (CDC2.5k-co-CL3.9k) containing double, two sulfur five-membered ring functional groups.
In formula, m=113.6, x=34.2, y=13.0, n=47.2.
Accompanying drawing 1 is the nuclear magnetic spectrum of above-mentioned polymer.1HNMR(400MHz,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 surveys: 14.0kDa, molecular weight distribution: 1.56.
Three liang of block side chains of embodiment are containing the synthesis of the carbonate polymer PEG5k-b-PCDC2.8k of double; two sulfur five-membered ring functional groups
In a nitrogen environment, by 0.3g(1.56mmol) CDC monomer, 2mL dichloromethane adds in sealed reactor, it is subsequently adding the Polyethylene Glycol 0.5g(0.1mmol that molecular weight is 5000) and the dichloromethane solution (0.1mol/L) of double, two (double, two trimethyl silicon based) the amine zinc of catalyst of 1mL, then reactor good seal, migrate out glove box, put into after 40 DEG C of oil baths are reacted 1 day, reaction is terminated with glacial acetic acid, ice ether precipitates, eventually pass through filtration, vacuum drying obtains the product side chain carbonate polymer PEG5k-b-PCDC2.8k containing double, two sulfur five-membered ring functional groups.
1HNMR(400MHz,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.
Four liang of block side chains of embodiment are containing the synthesis of the carbonate polymer PEG5k-P (CDC3.8k-co-CL14k) of double; two sulfur five-membered ring functional groups
nullIn a nitrogen environment，0.5g(2.6mmol) CDC monomer and 1.5g(13.2mmol) caprolactone (ε-CL) be dissolved in 10mL dichloromethane，Add in sealed reactor，It is subsequently adding the Polyethylene Glycol 0.5g(0.1mmol of molecular weight 5000) and the dichloromethane solution (0.1mol/L) of double; two (double; two trimethyl silicon based) the amine zinc of catalyst of 1mL，Then reactor good seal，Migrate out glove box，Put into after 40 DEG C of oil baths are reacted 1 day，Reaction is terminated with glacial acetic acid，Ice ether precipitates，Eventually pass through filtration、Vacuum drying obtains the product side chain carbonate polymer PEG5k-P (CDC3.8k-co-CL14k) containing double; two sulfur five-membered ring functional groups，The molecular weight that GPC surveys: 30.6kDa，Molecular weight distribution: 1.34.
In formula, m=113.6, x=122.8, y=19.8, n=142.
Five liang of block side chains of embodiment are containing the synthesis of the carbonate polymer PEG1.9k-P (CDC3.9k-co-CL3.8k) of double; two sulfur five-membered ring functional groups
nullIn a nitrogen environment，0.4g(2.1mmol) CDC monomer and 0.4g(3.51mmol) caprolactone (ε-CL) be dissolved in 3mL dichloromethane，Add in sealed reactor，It is subsequently adding the Polyethylene Glycol 0.4g(0.21mmol of molecular weight 1900) and the dichloromethane solution (0.1mol/L) of double; two (double; two trimethyl silicon based) the amine zinc of catalyst of 1mL，Then reactor good seal，Migrate out glove box，Put into after 40 DEG C of oil baths are reacted 1 day，Reaction is terminated with glacial acetic acid，Ice ether precipitates，Eventually pass through filtration、Vacuum drying obtains the two block side chains carbonate polymer PEG1.9k-P (CDC3.9k-co-CL3.8k) containing double; two sulfur five-membered ring functional groups，The molecular weight that GPC surveys: 0.96kDa，Molecular weight distribution: 1.35.
In formula, m=43.2, x=33.3, y=20.3, n=53.6.
Embodiment six side chain is containing the synthesis of the carbonate homopolymer Alk-PCDC2.8k of double; two sulfur five-membered ring functional groups
In a nitrogen environment, 0.3g(1.6mmol) CDC monomer is dissolved in 1mL dichloromethane, add in sealed reactor, it is subsequently adding the dichloromethane solution (0.1mol/L) of double; two (double; two trimethyl silicon based) amine zinc of catalyst of refining propilolic alcohol 1mmol/L and 1mL, then reactor good seal, migrate out glove box, put into after 40 DEG C of oil baths are reacted 1 day, reaction is terminated with glacial acetic acid, ice ether precipitates, eventually passes through filtration, vacuum drying obtains the product side chain carbonate homopolymer Alk-PCDC2.8k containing double; two sulfur five-membered ring functional groups.
Embodiment heptalateral chain is containing the synthesis of the carbonate polymer iPr-P (CDC0.8k-co-CL92k) of double; two sulfur five-membered ring functional groups
nullIn a nitrogen environment，0.1g(0.52mmol) CDC monomer and 10g(87.7mmol) caprolactone monomer (CL) be dissolved in the ε-CL in 10mL dichloromethane，Add in sealed reactor，It is subsequently adding isopropanol 6mg(0.1mmol) and the dichloromethane solution (0.1mol/L) of double; two (double; two trimethyl silicon based) the amine zinc of catalyst of 1mL，Then reactor good seal，Migrate out glove box，Put into after 40 DEG C of oil baths are reacted 2 days，Reaction is terminated with glacial acetic acid，Ice ether precipitates，Eventually pass through filtration、Vacuum drying obtains the product side chain carbonate polymer iPr-P(CDC-co-CL containing double; two sulfur five-membered ring functional groups) (0.8k-92k)，The molecular weight that GPC surveys: 102.3kDa，Molecular weight distribution: 1.36.
In formula, x=4.2, y=80.7, n=84.9.
Embodiment eight or three block side chain is containing the synthesis of the carbonate polymer PEG5k-PCDC1.0k-PCL3.2k of double; two sulfur five-membered ring functional groups
nullIn a nitrogen environment，0.12g(1.5mmol) CDC monomer is dissolved in 2mL dichloromethane，Add in sealed reactor，It is subsequently adding the Polyethylene Glycol 0.5g(0.31mmol of molecular weight 5000) and the dichloromethane solution (0.1mol/L) of double; two (double; two trimethyl silicon based) the amine zinc of catalyst of 1mL，Then reactor good seal，Migrate out glove box，Put into after 40 DEG C of oil baths are reacted 1 day，Caprolactone (ε-CL) 0.35g(0.31mmol is added again) under glove box nitrogen protection，After continuing reaction one day，Reaction is terminated with glacial acetic acid，Ice ether precipitates，Eventually pass through filtration、Vacuum drying obtains the product three block side chain carbonate polymer PEG5k-PCDC1.0k-PCL3.2k containing double; two sulfur five-membered ring functional groups.
1HNMR(400MHz,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 surveys: 10.4kDa, molecular weight distribution: 1.45.
Nine liang of block side chains of embodiment are containing the synthesis of the carbonate polymer PEG5k-P (CDC3.2k-co-TMBPEC3.5k) of double; two sulfur five-membered ring functional groups
nullIn a nitrogen environment，0.4g(2.1mmol) CDC monomer and 0.4g(1.2mmol) 2,4,6-trimethoxy-benzene dimethoxym ethane tetramethylolmethane carbonate monomer (TMBPEC) is dissolved in 5mL dichloromethane，Add in sealed reactor，It is subsequently adding the Polyethylene Glycol 0.5g(0.1mmol of molecular weight 5000) and the dichloromethane solution (0.1mol/L) of double; two (double; two trimethyl silicon based) the amine zinc of catalyst of 1mL，Then reactor good seal，Migrate out glove box，Put into after 40 DEG C of oil baths are reacted 1 day，Reaction is terminated with glacial acetic acid，Ice ether precipitates，Eventually pass through filtration、Vacuum drying obtains the two block side chains carbonate polymer PEG5k-P (CDC3.2k-co-TMBPEC3.5k) containing double; two sulfur five-membered ring functional groups.The molecular weight that GPC surveys: 12.4kDa, molecular weight distribution: 1.47.
In formula, m=113.6, x=16.7, y=10.2, n=26.9.
Embodiment 13 block side chain is containing the synthesis of the carbonate polymer PEG1.9k-PCL1.8k-PCDC0.7k of double; two sulfur five-membered ring functional groups
nullIn a nitrogen environment，0.2g(1.76mmol) caprolactone (ε-CL) is dissolved in 2mL dichloromethane，Add in sealed reactor，It is subsequently adding the Polyethylene Glycol 0.19 gram (0.1mmol) of molecular weight 1900 and the dichloromethane solution (0.1mol/L) of double; two (double; two trimethyl silicon based) amine zinc of catalyst of 1mL，Then reactor good seal，Migrate out glove box，Put into after 40 DEG C of oil baths are reacted 1 day，CDC monomer 80mg(0.42mmol is added again) under glove box nitrogen protection，After continuing reaction one day，Reaction is terminated with glacial acetic acid，Ice ether precipitates，Eventually pass through filtration、Vacuum drying obtains the three block side chains carbonate polymer PEG1.9k-PCL1.8k-PCDC0.7k containing double; two sulfur five-membered ring functional groups.
1HNMR(400MHz,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 surveys: 0.64kDa, molecular weight distribution: 1.32.
Embodiment 10 block side chain is containing the synthesis of the carbonate polymer PEG5k-P (CDC5k-co-TMC20k) of double; two sulfur five-membered ring functional groups
nullIn a nitrogen environment，0.1g(0.52mmol) CDC monomer and 0.4g(3.85mmol) trimethylene carbonate (TMC) be dissolved in 3mL dichloromethane，Add in sealed reactor，It is subsequently adding the Polyethylene Glycol 0.1g(0.02mmol of molecular weight 5000) and the dichloromethane solution (0.1mol/L) of double; two (double; two trimethyl silicon based) the amine zinc of catalyst of 0.1mol/L，Then reactor good seal，Migrate out glove box，Put into after 40 DEG C of oil baths are reacted 1 day，Reaction is terminated with glacial acetic acid，Ice ether precipitates，Eventually pass through filtration、Vacuum drying obtains the two block side chains carbonate polymer PEG5k-P (CDC4.9k-co-TMC19.0k) containing double; two sulfur five-membered ring functional groups.
1HNMR(400MHz,CDCl3):2.08(t,-COCH2CH2CH2O-),3.08(s,-CCH2), 3.30 (m ,-OCH3), 3.65(t ,-OCH2CH2O-), 4.28 (t ,-COCH2CH2CH2O-),4.31(m,-CCH2)；The molecular weight that GPC surveys: 34.5kDa, molecular weight distribution: 1.48.
In formula, m=113.6, x=25.5, y=186.3, n=211.8.
Embodiment 12 block side chain is containing the synthesis of the carbonate polymer PEG5k-PLA7.8k-PCDC1.7k of double; two sulfur five-membered ring functional groups
nullIn a nitrogen environment，0.45g(3.13mmol) lactide (LA) is dissolved in 3mL dichloromethane，Add in sealed reactor，It is subsequently adding the Polyethylene Glycol 0.25g(0.05mmol of molecular weight 5000) and the dichloromethane solution (0.1mol/L) of double; two (double; two trimethyl silicon based) the amine zinc of catalyst of 1mL，Then reactor good seal，Migrate out glove box，Put into after 40 DEG C of oil baths are reacted 1 day，CDC monomer 100mg(0.52mmol is added again) under glove box nitrogen protection，After continuing reaction one day，Reaction is terminated with glacial acetic acid，Ice ether precipitates，Eventually pass through filtration、Vacuum drying obtains the three block side chains carbonate polymer PEG5k-PLA7.8k-PCDC1.7k containing double; two sulfur five-membered ring functional groups.
1HNMR(400MHz,CDCl3): 1.59 (m ,-COCH(CH3)O-),3.08(s,-CCH2), 3.30 (m ,-OCH3), 3.65 (m ,-OCH2CH2O-), 4.07 (s ,-OCH2CCH2O-), 5.07 (m ,-COCH(CH3)；The molecular weight that GPC surveys: 16.8kDa, molecular weight distribution: 1.47.
In formula, m=113.6, x=122.2, y=8.9, n=131.1.
The synthesis of embodiment 13 block side chain carbonate polymer P (CDC-co-CL) (6.21k)-PEG (the 0.5k)-P (CDC-co-CL) (6.21k) containing double; two sulfur five-membered ring functional groups
In a nitrogen environment, 1.5g(13.2mmol) ε-CL and 0.0625g(0.325mmol) CDC monomer is dissolved in 8mL dichloromethane, add in sealed reactor, the rear PEG500(0.01mmol adding 0.05g) and the dichloromethane solution (0.1mol/L) of catalyst pair (double, two trimethyl silicon based) amine zinc of 1mL, after reacting one day, reaction is terminated with glacial acetic acid, ice ether precipitates, eventually pass through filtration, vacuum drying obtains three block side chains carbonate polymer P (CDC-co-CL) (6.21k)-PEG (the 0.5k)-P (CDC-co-CL) (6.21k) containing double, two sulfur five-membered ring functional groups.
Accompanying drawing 2 is the nuclear magnetic spectrum of above-mentioned polymer:1HNMR(400MHz,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 surveys: 14.6kDa, molecular weight distribution: 1.38.
In formula, m=11.4, x=6.3, y=43.9, n=51.2.
14 liang of block side chains of embodiment are containing the synthesis of the carbonate polymer PEG1.9k-b-PCDC0.8k of double; two sulfur five-membered ring functional groups
In a nitrogen environment, by 0.08g(0.42mmol) CDC monomer, 2mL dichloromethane adds in sealed reactor, it is subsequently adding the Polyethylene Glycol 1.9g(1mmol that molecular weight is 1900) and the dichloromethane solution (0.1mol/L) of double, two (double, two trimethyl silicon based) the amine zinc of catalyst of 1mL, then reactor good seal, migrate out glove box, put into after 40 DEG C of oil baths are reacted 1 day, reaction is terminated with glacial acetic acid, ice ether precipitates, eventually pass through filtration, vacuum drying obtains the product side chain carbonate polymer PEG1.9k-b-PCDC0.8k containing double, two sulfur five-membered ring functional groups.
1HNMR(400MHz,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.
By result above it can be seen that by the sign to a series of polymer, the ring-opening polymerisation of CDC and combined polymerization are controlled, and its molecular weight is consistent with design, and the molecular weight distribution of polymer is narrower.
The preparation of embodiment 15 polymer nano-particle PEG5k-b-PCDC2.8k
Dialysis is adopted to prepare polymer nanoparticle.Polymer P EG5k-b-PCDC2.8k is dissolved in DMF (2mg/mL), takes 200 μ L and is added drop-wise to 800 μ L phosphate buffered solution (10mM, pH7.4, PB) in, load dialysed overnight in bag filter (MWCO3500), changing five water, dialysis medium is PB(10mM, pH7.4).The concentration of the polymer nanoparticle finally given is 0.2mg/mL.The nanoparticle formed surveyed by dynamic light scattering particle size analyser (DLS) is 173nm, and particle size distribution is very narrow, sees accompanying drawing 3.
The crosslinking of embodiment 16 polymer nano-particle PEG5k-b-PCDC2.8k, solution crosslinking, cytotoxicity
The crosslinking of nanoparticle is undertaken by the dithiothreitol dithio (DTT) adding catalytic amount.Polymer nanoparticle aqueous solution is led to nitrogen 10 minutes, air is caught up with only as far as possible.Then to nanoparticle solution (1mL, 0.25mg/mL, 3.21 × 10 in closed reactor-5Mmol) add in 10 μ L be dissolved in dithiothreitol dithio (DTT) in secondary water (0.007mg, 4.67 × 10-5Mmol, thioctic acid functional group molal quantity 10%), airtight room temperature stirring reaction 1 day.Measuring particle and be of a size of 150 nanometers, compare less about 15% with the particle diameter not having crosslinking, the Nanoparticle Size before crosslinking is 173 ran.Nanoparticle after crosslinking its particle diameter and particle size distribution after concentration dilution 100 times have almost no change；Stable in physiological conditions, it can thus be seen that double; two sulfur-crosslinked stability that can largely improve nanoparticle, see accompanying drawing 4.
Disulfide bond can be easy to rupture under reducing agent such as glutathion (GSH) acts on.Under nitrogen protection and 37 DEG C of conditions, after logical for crosslinking nano grain solution nitrogen 10 minutes, add reducing substances glutathion and make its ultimate density in polymer nano-particle solution be 10mM.Dynamic light scattering particle size analyser is utilized to follow the tracks of the situation of change of nanoparticle subsolution crosslinking particle diameter, see accompanying drawing 5, can be seen that, after adding 10mM reducing substances glutathion (GSH), As time goes on cross-linking nanoparticles particle diameter is progressively destroyed, and illustrates that in polymer, double; two sulfur rings can rupture under a large amount of reducing substances exist.Cytoplasm there is also the GSH of high concentration, the nano-medicament carrier stable circulation therefore prepared, but can quickly be dissociated after cell endocytic, discharge medicine.
Adopt mtt assay that the cytotoxicity of cross-linking nanoparticles is tested.The cell used is MCF-7(human breast cancer cell) cell and Raw264.7(mouse macrophage) cell.With 1 × 104HeLa cell or Raw264.7 cell are inoculated in 96 orifice plates, every hole 100 μ L by individual/mL, and after being cultured to cell attachment, experimental group adds the culture fluid of the polymer nanoparticle containing variable concentrations, separately set cell blank control wells and culture medium blank well, parallel 4 multiple holes.96 orifice plates are taken out after incubator is cultivated 24 hours, add MTT(5.0mg/mL) 10 μ L, after continuing cultivation 4 hours, every hole adds crystallization that 150 μ LDMSO dissolvings generate, by microplate reader in 492nm place its absorbance of survey (A), return to zero with culture medium blank well, calculate cell survival rate.
A in formulaTFor the absorbance at test group 490nm place, ACAbsorbance for blank group 492nm place.Polymer concentration respectively 0.1,0.2,0.3,0.4,0.5mg/mL.Accompanying drawing 6 is the cytotoxicity result of nanoparticle, as can be seen from the figure, when the concentration of polymer nanoparticle increases to 0.5mg/mL from 0.1mg/mL, the survival rate of Raw264.7 cell and MCF-7 cell remains above 85%, illustrates that PEG5k-b-PCDC2.8k polymer nanoparticle has good biocompatibility.
The medicine carrying of embodiment 17 crosslinking nano grain PEG5k-b-PCDC2.8k, release in vitro and cytotoxicity
Using amycin as medicine.Owing to anticancer drugs, doxorubicin is sensitive fluorescent material, whole operation carries out when lucifuge.First removing the hydrochlorate of amycin, its operation is: 1.2mg (0.002mmol) amycin is dissolved in the DMSO of 225 μ L, adds triethylamine 0.58mL (m=0.419mg, 0.004mmol) and stirs 12 hours, siphons away the supernatant.The DMSO solution concentration of amycin is 5.0mg/mL.Nanometer polymer nanoparticle PEG5k-b-PCDC2.8k is dissolved in N,N-dimethylformamide (DMF).The dimethyl sulfoxide solution of amycin and the DMF solution of polymer nano-particle PEG5k-b-PCDC2.8k are compared with polymer quality by predetermined medicine and mixs homogeneously, slowly it is added thereto to the secondary water (15s/d) of 4 times of its volumes under stirring, after dripping off, a water is dialysed.
The crosslinking of medicine-carried nano particles is also undertaken by the cross-linking method of embodiment 15.By the polymer nano-particle solution lyophilization of 100 μ L crosslinking load amycin, it is then dissolved in 3.0mLDMSO, utilizes fluorescence spectrophotometer spectrogrph to test, in conjunction with the standard curve computational envelope rate of amycin.
Drug loading (DLC) and envelop rate (DLE) calculate according to below equation:
Drug loading (wt.%)=(drug weight/polymer weight) × 100%
Envelop rate (%)=(loading the total input amount of drug weight/medicine) × 100%
Table 1 is above-mentioned result of calculation, it can be seen that small molecule anticancer drug amycin is had efficient embedding effect by polymer P EG5k-b-PCDC2.8k nanoparticle.
The result of drug loading, envelop rate in the polymer nano-particle of table 1 crosslinking load amycin
The release experiment of amycin is to shake (200rpm) in 37 DEG C of constant-temperature tables to carry out.Drug release contrasts with two groups of Duplicate Samples, often group is respectively arranged with two Duplicate Samples: first group, the polymer nano-particle of crosslinking load amycin is in the release added in 10mM glutathion (GSH) analog cell in reducing environment PB (10mM, pH7.4)；Second group, the release in PB (10mM, pH7.4) of the polymer nano-particle of crosslinking load amycin；Drug-carrying polymer nanoparticle concentration is 25mg/L, take 0.5mL and put into release bag filter (MWCO:12,000-14,000) in, each test tube adds corresponding dialysis solvent 25mL, at predetermined interval, take out 5.0mL bag filter external agency and be used as test, in test tube, add 5.0mL respective media simultaneously.EDINBURGHFLS920 luminoscope is used to measure drug concentration in solution.Accompanying drawing 7 is the relation of amycin cumulative release amount and time, as can be seen from the figure, after adding the reducing substances glutathion (GSH) of simulation tumor cell, its release is signifi-cantly more rapidly than and does not add GSH component, illustrate that the cross-linking nanoparticles of medicine carrying is under the existence of 10mM reducing substances GSH, can effectively discharge medicine.
The PEG5k-b-PCDC2.8k cross-linking nanoparticles mtt assay of load DOX tests it to Raw264.7 cell (mouse macrophage), MCF-7(human breast cancer cell) toxicity of cell etc., the uncrosslinked nanoparticle of medicine carrying and free drug are as comparison.For Raw264.7 cell, by Raw264.7 cell with 1 × 104Individual/mL is inoculated in 96 orifice plates, every hole 100 μ L, after being cultured to cell attachment, experimental group is separately added into the load amycin cross-linking nanoparticles solution containing 0.01,0.1,1,5,10,50 and 100 μ g/mL, the fresh medium of the load uncrosslinked nano-particle solution of amycin and free amycin, separately setting cell blank control wells and culture medium blank well, every hole sets 4 multiple holes.96 orifice plates are taken out after incubator is cultivated 48 hours, add MTT(5.0mg/mL) 10 μ L, after continuing cultivation 4h, every hole adds crystallization that 150 μ LDMSO dissolvings generate, by microplate reader in 492nm place its absorbance of survey (A), return to zero with culture medium blank well, calculate cell survival rate.
Accompanying drawing 8 is the polymer P EG5k-b-PCDC2.8k cross-linking nanoparticles of the above-mentioned medicine carrying toxicity data figure to Raw264.7 and MCF-7 cell；As can be seen from the results, the half lethal concentration of Raw264.7 cell is 4.89 μ g/mL by the cross-linking nanoparticles of load amycin, the half lethal concentration of MCF-7 cell is 2.31 μ g/mL by the cross-linking nanoparticles of load amycin, so the PEG5k-b-PCDC2.8k cross-linking nanoparticles of load DOX effective can discharge medicine and kill cancerous cell in cell.
The preparation of embodiment 18 polymer nanoparticle PEG5k-P (CDC3.2k-co-TMBPEC3.5k), crosslinking, solution crosslinking and cytotoxicity
Nanoparticle adopts dialysis to prepare.Polymer P EG5k-P (CDC3.2k-co-TMBPEC3.5k) is dissolved in N, in dinethylformamide (5mg/mL), take 200 μ L and be added drop-wise to 800 μ L phosphate buffered solution (10mM, pH7.4, PB), in, load dialysed overnight in bag filter (MWCO3500), change five water, dialysis medium is PB(10mM, pH7.4).The polymer nanoparticle finally given is micellar structure, and its concentration is 0.2mg/mL.Accompanying drawing 9 is polymer P EG5k-P (CDC3.2k-co-TMBPEC3.5k) cross-linking nanoparticles grain size distribution and electron projection microscope photograph figure；It can be seen that the nano-micelle formed surveyed by dynamic light scattering particle size analyser (DLS) is 60nm, and particle size distribution is very narrow；By transmission electron microscope it can be seen that the nanoparticle of crosslinking is spherical, and being uniformly dispersed, size is surveyed with DLS and is matched.
The crosslinking of nanoparticle is undertaken by the dithiothreitol dithio (DTT) adding catalytic amount.Polymer nanoparticle aqueous solution is led to nitrogen 10 minutes, air is caught up with only as far as possible.Then to nanoparticle solution (1mL, 0.25mg/mL, 3.21 × 10 in closed reactor-5Mmol) add in 10 μ L be dissolved in dithiothreitol dithio (DTT) in secondary water (0.007mg, 4.67 × 10-5Mmol, sulfur sulfur five-membered ring molal quantity 10%), airtight room temperature stirring reaction 1 day.Measure particle and be of a size of 55 nanometers, compare minimizing about 8% with the particle diameter not having crosslinking.This is because nanoparticle after crosslinking is relative to not have more consolidation in the nanoparticle core that cross-links.Nanoparticle after crosslinking its particle diameter and particle size distribution after concentration dilution 100 times have almost no change；Stable in physiological conditions, it can thus be seen that double; two sulfur-crosslinked stability that can largely improve nanoparticle.
Disulfide bond can be easy under reducing agent such as glutathion effect to rupture.Under nitrogen protection and 37 DEG C of conditions, after logical for crosslinking nano grain solution nitrogen 10 minutes, add glutathion (GSH) and make its ultimate density in polymer nano-particle solution be 10mM.Dynamic light scattering particle size analyser is utilized to follow the tracks of the situation of change of nanoparticle subsolution crosslinking particle diameter.After adding 10mM reducing substances glutathion (GSH), As time goes on cross-linking nanoparticles particle diameter is progressively destroyed, and illustrates that in polymer, double; two sulfur rings can rupture under a large amount of reducing substances exist.Cytoplasm there is also the GSH of high concentration, the nano-medicament carrier stable circulation therefore prepared, but can quickly be dissociated after cell endocytic, discharge medicine.
Adopt mtt assay that the cytotoxicity of crosslinking nano grain is tested.The cell used is HepG2(human liver cancer cell) cell and Raw264.7(mouse macrophage) cell.With 1 × 104Individual/mL is by MCF-7(human liver cancer cell) cell or Raw264.7(mouse macrophage) cell is inoculated in 96 orifice plates, every hole 100 μ L, after being cultured to cell attachment, experimental group adds the culture fluid of the polymer nanoparticle containing variable concentrations, separately set cell blank control wells and culture medium blank well, parallel 4 multiple holes.96 orifice plates are taken out after incubator is cultivated 24 hours, add MTT(5.0mg/mL) 10 μ L, after continuing cultivation 4 hours, every hole adds crystallization that 150 μ LDMSO dissolvings generate, by microplate reader in 492nm place its absorbance of survey (A), return to zero with culture medium blank well, calculate cell survival rate.
A in formulaTFor the absorbance at test group 490nm place, ACAbsorbance for blank group 492nm place.Polymer concentration respectively 0.3,0.6,0.9,1.2,1.5mg/mL.Accompanying drawing 10 is nanoparticle cytotoxicity result, as can be seen from the figure, when the concentration of polymer nanoparticle increases to 1.5mg/mL from 0.3mg/mL, after hatching 24 hours, the survival rate of HepG2 and MCF-7 cell remains above 85%, illustrates that PEG5k-P (CDC3.2k-co-TMBPEC3.5k) polymer nanoparticle has good biocompatibility.
The load amycin of embodiment 19 crosslinking nano grain PEG5k-P (CDC3.2k-co-TMBPEC3.5k), release in vitro and cytotoxicity
PEG5k-P (CDC3.2k-co-TMBPEC3.5k) crosslinking nano grain loads amycin, release in vitro method with embodiment 17.Adopting mtt assay that the isocellular toxicity of Raw264.7 and HepG2 is tested by this crosslinking drug-carrying nanometer particle of its shape, the uncrosslinked nanoparticle of medicine carrying and free drug are as comparison.For Raw264.7, by Raw264.7 with 1 × 104Individual/mL is inoculated in 96 orifice plates, every hole 100 μ L, after being cultured to cell attachment, experimental group is separately added into the load amycin crosslinking nano grain solution containing 0.01,0.1,1,5,10,50 and 100 μ g/mL, the fresh medium of load amycin uncrosslinked nanoparticle solution and free amycin, separately setting cell blank control wells and culture medium blank well, every hole sets 4 multiple holes.null96 orifice plates are taken out after incubator is cultivated 48 hours，Add the MTT(5.0mg/mL of 10 μ L)，Continue every hole after cultivating 4h and add crystallization that the DMSO dissolving of 150 μ L generates，By microplate reader in 492nm place its absorbance of survey (A)，Return to zero with culture medium blank well，Calculate cell survival rate，Result is shown in accompanying drawing 11，The half lethal concentration of Raw264.7 cell is 12.8 μ g/mL by the crosslinking nano grain of load amycin，Relative to free amycin，Only increase less than ten times，So the PEG5k-P of medicine carrying (CDC3.2k-co-TMBPEC3.5k) crosslinking nano grain effectively can discharge medicine in cell and kill cancerous cell，And HepG2 and Raw264.7 cell is had good biocompatibility by the empty crosslinking nano grain of correspondence.
The preparation of drug-carrying polymer nanoparticle cRGD-PEG5k-P (CDC3.2k-co-TMBPEC3.5k) of the cancer target that embodiment 20 cRGD modifies and cytotoxicity
According to method synthesis Mal-PEG6k-P (CDC3.8k-co-TMBPEC3.5k) polymer in embodiment nine, and method preparation described in embodiment 15 loads the nanoparticle of DOX, and method preparation cross-links drug-carrying nanometer particle described in example 16.Prepared the nanoparticle of surface coupling cRGD afterwards by Michael addition reaction with cRGD-SH small peptide, it by Malignant glioma cells specificity endocytosis, thus more effectively killing tumor cell, can reach chemotherapeutical effect.nullAccording to the Cytotoxic experimental technique of embodiment 19，We select malignant glioma (U87MG cell) cell to do MTT toxicity test herein，This is because this cell surface has the integral protein to cRGD overexpression，By cell toxicity test result，In nanoparticle, cRGD-PEG6k-P (CDC3.8k-co-TMBPEC3.5k) is when whole polymer weight ratio is 20%，48 hours are hatched，And siphon away sample after adding medicine-carried nano particles 4 hours，Continue to hatch 44 hours，Its medicine half lethal dose decreases six times relative to the medicine-carried nano particles not having cRGD，Thus result is known，The medicine-carried nano particles of finishing cRGD can be special with cell surface receptor be combined and endocytosis enter cell，Relative to the nanoparticle not having targeting，Its active targeting is very strong，Can effectively kill tumor cell，The medicine-carried nano particles targeted therapy to tumor has wide practical use.
The drug release that embodiment 21 medicine carrying PEG5k-PLGA7.8k-PCDC1.7k modified nano gold rod surface and NIR trigger
The preparation of the nanometer gold bar that triblock polymer PEG5k-PLGA7.8k-PCDC1.7k nanoparticle is modified
With vigorous stirring, it is dissolved in the polymer solution (2mL in DMSO, 5mg/mL) it is added drop-wise in the dispersion liquid of nanometer gold bar (5mL, 0.1mg/mL) stir 4 hours, the polymer that centrifugal twice removing does not connect, is dispersed again in phosphate buffer solution, is detected the polymer yield modifying upper gold rod by TGA, by with independent polymer phase ratio, the productivity of polymer-modified gold rod is that 80%(theory feeds intake by one of percentage hundred).The medicine carrying of polymer-modified nanometer gold bar.In polymer-modified nanometer gold bar solution obtained above, dropwise drip 10%, 20%, the medicine being dissolved in DMSO of 30%, 12h is at room temperature hatched in stirring after half an hour, and removes free small-molecule drug by dialysing 12 hours, dialysis medium is pH is the phosphate buffer solution of 7.4, by fluoroscopic examination, the parcel efficiency of medicine is 70 ~ 90% by it afterwards, it follows that polymer-modified nanometer gold bar can wrap up little molecule dewatering medicament efficiently.
The drug release of the polymer-modified nanometer gold bar that NIR triggers.Polymer-modified nanometer gold bar is dispersed in 10mL phosphate buffer solution, is 0.2W/ by intensity every other hour2, wavelength is the Infrared irradiation 5min of 808nm, takes 500 μ L solution out in specific interval, centrifugal, surveys the fluorescence of supernatant, thus analyzes the small-molecule drug content discharged.By fluoroscopic examination, the drug release of the polymer-modified nanometer gold bar after illumination is 92%, this type of polymer-modified nanometer gold bar material it is significantly faster than the matched group (release is only 18%) not having illumination, it follows that can be applicable to the drug release that near-infrared triggers.
Claims (3)
1. the side chain carbonate polymer containing double; two sulfur five-membered ring functional groups application in preparing drug controlled release carrier；Described side chain containing the chemical structural formula of the carbonate polymer of double; two sulfur five-membered ring functional groups is:
Wherein, R1 one in following group:
K=20-250, the R4 one in following group in formula:
Described side chain is 3000～70000Da containing the molecular weight of the carbonate polymer of double; two sulfur five-membered ring functional groups.
2. the side chain carbonate polymer containing double; two sulfur five-membered ring functional groups application in preparing drug controlled release carrier according to claim 1, it is characterised in that: the unit number of the cyclic carbonate ester monomer containing double; two sulfur five-membered ring functional groups on the described side chain carbonate polymer strand containing double; two sulfur five-membered ring functional groups is 4～50.
3. the side chain carbonate polymer containing double; two sulfur five-membered ring functional groups application in preparing drug controlled release carrier according to claim 1, it is characterised in that: described R1 is, k=20-250, the R4 one in following group in formula:
。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510973700.3A CN105770900B (en) | 2014-05-28 | 2014-05-28 | The application of carbonate polymer of the side chain containing double sulphur five-membered ring functional groups |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510973700.3A CN105770900B (en) | 2014-05-28 | 2014-05-28 | The application of carbonate polymer of the side chain containing double sulphur five-membered ring functional groups |
| CN201410231049.8A CN104031248B (en) | 2014-05-28 | 2014-05-28 | Side chain contains carbonate polymer and the application thereof of double sulphur five-membered ring functional groups |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410231049.8A Division CN104031248B (en) | 2014-05-28 | 2014-05-28 | Side chain contains carbonate polymer and the application thereof of double sulphur five-membered ring functional groups |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105770900A true CN105770900A (en) | 2016-07-20 |
| CN105770900B CN105770900B (en) | 2018-11-02 |
Family
ID=56390357
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510973700.3A Active CN105770900B (en) | 2014-05-28 | 2014-05-28 | The application of carbonate polymer of the side chain containing double sulphur five-membered ring functional groups |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105770900B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106581691A (en) * | 2016-12-04 | 2017-04-26 | 苏州大学 | Reduction-responding polyethylene glycol-polycarbonate targeting maytansine prodrug micelle and preparation method and application thereof |
| CN108451907A (en) * | 2018-02-09 | 2018-08-28 | 苏州大学 | Multifunctional polymer vesica is preparing the application in treating Huppert's disease drug |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102046679A (en) * | 2008-05-09 | 2011-05-04 | 科腾聚合物美国有限责任公司 | Improved method for making sulfonated block copolymers, method for making membranes from such block copolymers and membrane structures |
| CN102245214A (en) * | 2008-10-10 | 2011-11-16 | 仿生耳研究所 | Biodegradable polymer - bioactive moiety conjugates |
-
2014
- 2014-05-28 CN CN201510973700.3A patent/CN105770900B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102046679A (en) * | 2008-05-09 | 2011-05-04 | 科腾聚合物美国有限责任公司 | Improved method for making sulfonated block copolymers, method for making membranes from such block copolymers and membrane structures |
| CN102245214A (en) * | 2008-10-10 | 2011-11-16 | 仿生耳研究所 | Biodegradable polymer - bioactive moiety conjugates |
Non-Patent Citations (1)
| Title |
|---|
| WEI CHEN ET AL.: "Advanced drug and gene delivery systems based on functional biodegradable polycarbonates and copolymers", 《JOURNAL OF CONTROLLED RELEASE》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106581691A (en) * | 2016-12-04 | 2017-04-26 | 苏州大学 | Reduction-responding polyethylene glycol-polycarbonate targeting maytansine prodrug micelle and preparation method and application thereof |
| CN110339368A (en) * | 2016-12-04 | 2019-10-18 | 苏州大学 | The preparation method of the targeting polyethylene glycol carbonic ester maytansine prodrug micelle of reduction response |
| CN110339368B (en) * | 2016-12-04 | 2022-08-16 | 苏州大学 | Preparation method of reduction-responsive targeting polyethylene glycol-polycarbonate maytansine prodrug micelle |
| CN108451907A (en) * | 2018-02-09 | 2018-08-28 | 苏州大学 | Multifunctional polymer vesica is preparing the application in treating Huppert's disease drug |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105770900B (en) | 2018-11-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104031248B (en) | Side chain contains carbonate polymer and the application thereof of double sulphur five-membered ring functional groups | |
| CN104231193B (en) | A kind of layer crosslinking nano grain of pH and redox sensitive and its preparation method and application | |
| KR102144749B1 (en) | Biodegradable amphiphilic polymer, polymer vesicle produced therefrom, and use in the manufacture of therapeutic agents for lung cancer | |
| JP6677914B2 (en) | Specific targeted biodegradable amphiphilic polymers for ovarian cancer, polymer vesicles prepared therefrom and uses thereof | |
| CN104610538B (en) | A kind of side chain contains biodegradable polymer and its application of double iodine functional groups | |
| CN105968372B (en) | A kind of autofluorescence nanogel and the preparation method and application thereof | |
| CN107266384B (en) | N- carboxyl inner-acid anhydride monomer and polyaminoacid based on 2- aminohexadecanoic acid and preparation method thereof | |
| CN105860057A (en) | Hydrophobic functional micromolecule-hydrophilic polyamino acid based biodegradable polymer and preparation method and application thereof | |
| CN104004001B (en) | Contain cyclic carbonate monomer of two sulphur five-ring functional group and preparation method thereof | |
| CN105770900A (en) | Application of carbonate polymer containing bi-sulfur five-member ring functional gene in side chain | |
| CN105879048A (en) | Preparation method of functional biodegradable nano particle based on polyamino acid | |
| WO2018137658A1 (en) | Cp-irgd polypeptide, idpp nanoparticle, drug-loading compound, preparation method therefor and use thereof | |
| CN111281858B (en) | Application of carbonyl iron sulfur cluster compound nano particles in preparation of medicine | |
| CN105997867B (en) | The preparation method of functional drug composition | |
| CN108727597A (en) | Polyphosphate-polycaprolactone nano-medicament carrier and its application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20160725 Address after: Suzhou City, Jiangsu Province, Suzhou Industrial Park 215123 Xinghu Street No. 218 Nano Technology Park building C25 Applicant after: Borui Pharmaceutical (Suzhou) Limited by Share Ltd Address before: Suzhou City, Jiangsu province 215137 Xiangcheng District Ji Road No. 8 Applicant before: Soochow University |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |