CN105999282A - Composite nano-drug carrier with tumor inhibiting effect and preparation process - Google Patents
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Abstract
The invention discloses a composite nano-drug carrier with a tumor inhibiting effect and a preparation process, and belongs to the field of biological materials. The amphiphilic polymer PLA-block-PAAA and PLA-block-PEG are subjected to joint self-assembling, and the composite nano-drug carrier is obtained. Composite nano-particles can protect the oxidation resistance of vitamin C, and the advantages of polymer nano-particles in chemical drug delivery can be exerted on the basis that the functionality of the nano-carrier is maintained in a drug delivery system.
Description
Technical field
The invention belongs to technical field of biological material, be specifically related to a kind of composite Nano medicine containing poly-vitamin C segment and deliver
System and preparation technology thereof.
Technical background
Cancer is still the most scabrous problem so far.The treatment of cancer needs examination accurately and selection to control
Treatment method, such as radiotherapy, chemotherapy or operative treatment.Although radiotherapy and operative treatment can make tumor growth obtain in the short time
To suppression, but they need many complicated schedules.Furthermore there is relatively low utilization ratio of drug in chemotherapy, high cell toxicant pair is made
By the defect with non-specific grade, seriously limit they application in treatment of cancer.Therefore, be badly in need of development one active or
Passive target cancerous cell medicament carrier system.Nanometer biotechnology can be that a difficult problem for current chemotherapy provides a good solution party
Method, and can be the medicine for the treatment of of cancer and gene provides a controlled stable and release for targeting.But at present for
The research of nano-medicament carrier primarily focuses on its intelligent, targeting, and the research to nano-carrier itself with inhibition is non-
The fewest.Studies have reported that ascorbic acid has the effect of suppression tumor simultaneously, grind including on last Nov " Science "
Study carefully report, also demonstrate vitamin C and can contain the function of tumor growth in Mice Body.According to pharmacology's ascorbic acid
The understanding of mechanism of action can use it for disease treatment, such as using ascorbic acid as the adjuvant for the treatment of of cancer.
Summary of the invention
The present invention utilizes common self-assembling method, a kind of good biocompatibility of preparation, degradable, has tumor inhibition effect
Composite Nano pharmaceutical carrier.We are based primarily upon above 2 points, are keeping nano-carrier functional and protection vitamin C antioxidation
On the basis of property, design has synthesized the polymer nano-particle containing vitamin C unit, is allowed to be possible not only to play polymer nano
Rice corpuscles is delivering the advantage of chemical medicine, and itself also has certain effect suppressing tumor, makes traditional delivery
" car " of chemotherapeutics self also can play the effect of medicine, gives full play to the effect that pharmaceutical preparation is overall, strengthens therapeutic effect.
A kind of composite Nano medicine delivery carrier self with function of tumor inhibition that the present invention proposes, it is characterised in that
Amphipathic nature polyalcohol polylactic acid-embedding-poly-vitamin C acrylate (PLA-block-PAAA) and polylactic acid-embedding-Polyethylene Glycol
(PLA-block-PEG) the composite Nano pharmaceutical carrier prepared by the way of common self assembly.Chemotherapy is delivered in targeting
On the basis of medicine, self there is antitumor action, with the effect that chemotherapeutics has collaborative suppression tumor.
The structural formula of material polylactic acid-embedding-poly-vitamin C acrylate (PLA-block-PAAA):
10≤n≤200,5≤m≤100, n and m is integer.
The structural formula of material polylactic acid-embedding-Polyethylene Glycol (PLA-block-PEG):
40≤p≤200,10≤q≤200, p and q is integer, and R is the merit that can couple fluorescence molecule or target molecules
Neng Xing functional group, such as succinyl ester (NHS), amino (NH2), maleimide maleimide (MAL) and biotin
Etc. (Biotin) group.
Polylactic acid-embedding-poly-vitamin C acrylate (PLA-block-PAAA) and polylactic acid-embedding-Polyethylene Glycol (PLA-
Block-PEG) both molar ratios are 1:1～12:1.
A kind of preparation method of the drug delivery system containing the composite Nano carrier self with function of tumor inhibition, its
Specifically comprise the following steps that
1. synthesizing polylactic acid-embedding-poly-vitamin C acrylate (PLA-block-PAAA) and polylactic acid-embedding-Polyethylene Glycol
(PLA-block-PEG)
1) polylactic acid-embedding-poly-vitamin C acrylate (PLA-block-PAAA) is obtained by Raolical polymerizable；
Protect ascorbic reactive enol formula hydroxyl with halogenation benzyl, prepare vitamin C acrylate monomer
(BnAA)；Metallic catalyst catalyzing ring-opening polymerization of lactide obtains polylactic acid homopolymer (PLA-Br), and PLA-Br leads to BnAA again
Cross radical polymerization and obtain polylactic acid-embedding-benzyl protection poly-vitamin C acrylate (PLA-block-PBnAA), lead to the most again
Cross catalytic hydrogenation and obtain polylactic acid-embedding-poly-vitamin C acrylate (PLA-block-PAAA).
2) using the PEG of double hydroxyl terminals as raw material, one end functionalization, the other end causes polymerization, obtains polylactic acid-embedding-poly-
Ethylene glycol (PLA-block-PEG).
Using the PEG of double hydroxyl terminals as raw material, Polyethylene Glycol one terminal hydroxy group is carried out the protection of tolysulfonyl, then carries out
Azide, modifies the functionalization functional group that can couple fluorescence molecule and target molecules the most again；One end retains hydroxyl and causes third
The ring-opening polymerisation of lactide, obtains polylactic acid-embedding-Polyethylene Glycol (PLA-block-PEG).
2. the drug delivery system of composite Nano medicine delivery carrier is prepared:
Under the conditions of lucifuge, by polylactic acid-embedding-poly-vitamin C acrylate (PLA-block-PAAA), polylactic acid-embedding-poly-
Ethylene glycol (PLA-block-PEG) and chemotherapeutics are dissolved in organic solvent, wherein the mass fraction concentration of preferred chemotherapeutics
Being 10%～100%, the concentration of whole polymeric material is 1.0mg/mL, uses self-assembling method altogether to obtain composite Nano medicine
Delivery materials.
Radical polymerization used is RAFT, ATRP or NMRP method.
The PEG molecular weight of double hydroxyl terminals used is 2000-5000.
It is succinyl ester that PEG one end used is used for coupling the functional functional group (R) of fluorescence molecule or target molecules
(NHS), maleimide maleimide (MAL), amino (NH2) and biotin (Biotin) etc..
Organic solvent used is chloroform, dimethyl sulfoxide, oxolane.
Self-assembling method in the preparation method of composite Nano delivery system used is emulsification mechanism, dialysis
Or microphase-separated method.
Advantage of the invention is that the composite nanoparticle of formation can protect vitamin C non-oxidizability, and make medicine pass
Send system on the basis of keeping nano-carrier functional, polymer nano-particle can be played and delivering the advantage of chemical medicine, and
And itself also there is certain effect suppressing tumor, make " car " of traditional delivery chemotherapeutics self also can play
The effect of medicine, gives full play to pharmaceutical preparation and works in coordination with the effect of suppression tumor, heighten the effect of a treatment.
Accompanying drawing explanation
The drug delivery system schematic diagram of the Fig. 1 composite Nano carrier containing the present invention；
Fig. 2 composite nanoparticle toxicity test result figure to NIH 3T3 cell；
Fig. 3 difference tumor cell line sensitivity tests design sketch to composite nanoparticle and ascorbic acid.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further described, but the present invention is not limited to following example.
Embodiment 1
1) under nitrogen protection, in 10 milliliters of reaction bulbs, compound initiator PLA-Br (1.12mmol) is added successively,
Azodiisobutyronitrile (0.014mmol), vitamin C monomer (2.16mmol) and toluene (1mL), reaction system is placed in 60 DEG C of oil baths
After middle stirring 14h.Reaction system chloroform dissolves, and precipitates and is repeated 3 times, obtain polymer after concentration in absolute methanol
PLA120-block-PAAA30；
2) lactide ring-opening polymerisation, straight are caused using the PEG4000 of double hydroxyl terminals as raw material, one end NHSization, the other end
Schlenk bottle except adding L-type lactide (9.0mmol), the initiator HO-PEG-that recrystallization processed after water deoxygenation
Maleimide (0.085mmol), octoate catalyst stannous (1.05mmol) and toluene 2.0mL.Whole reaction system is placed in 85
DEG C oil bath starts reaction, stops after reaction 4h, react with liquid nitrogen Quick stop.Reaction system chloroform dissolves, in nothing
Pelleting centrifugation 3 times in water methanol, are vacuum dried 5h, obtain white powder polymer P LA200-block-PEG80。
2. composite Nano delivery system is prepared:
Under the conditions of lucifuge, by oxaliplatin (10%), polymer P LA120-block-PAAA30(1.68 μm ol) and polymer
PLA200-block-PEG80(0.14 μm ol) is dissolved in 4mL oxolane.4mL deionized water it is slowly added dropwise after being completely dissolved.Continuously
After stir about 2h, rotary evaporation removes organic solvent, obtains carrying the solution of the composite nanoparticle of oxaliplatin.
Embodiment 2
1. synthetic polymer PLA-block-PAAA and PLA-block-PEG
1) in round bottom Schlenk bottle add initiator PLA-Br (0.085mmol), vitamin C monomer (2.16mmol),
Part PMDETA (0.11mmol), copper bromide (0.0043mmol) and dry toluene 2.0mL, room temperature lower seal stirring and dissolving mistake
Night.Freeze cycle three times, adds cuprous bromide (0.085mmol) under nitrogen protection, proceeds freeze cycle 3 times.75℃
Oil bath is reacted 40h, reacts with liquid nitrogen Quick stop.Reaction system chloroform dissolves, and removes with the pillar of neutral alumina
Copper, precipitates in absolute methanol after concentration and is repeated 3 times, obtain polymer P LA80-block-PAAA10；
2) ethylene glycol polymerization is caused using the PEG2000 of double hydroxyl terminals as raw material, one end amination, the other end, straight
Schlenk bottle except add after water deoxygenation ethylene glycol (10.5mmol), initiator HO-PEG-Maleimide (0.0525mmol) and
Toluene 3.0mL.Whole reaction system is placed in 90 DEG C of oil baths and starts reaction, stop after reaction 8h, anti-with liquid nitrogen Quick stop
Should.Reaction system chloroform dissolves, and pelleting centrifugation 3 times in absolute methanol are vacuum dried 5h, obtains white powder and gathers
Compound PLA300-block-PEG40。
2. composite Nano delivery system is prepared:
Under the conditions of lucifuge, by amycin (50%), polymer P LA80-block-PAAA10(0.98 μm ol) and polymer
PLA300-block-PEG40(0.14 μm ol) is dissolved in 4mL chloroform.4mL deionized water it is slowly added dropwise after being completely dissolved.Continuously
After stir about 2h, transfer to nanometer system, in the dialysis bag that molecular cut off (MWCO) is 3500, be placed in the pH 7.4 of 0.15M
Phosphate buffer in carry out dialysis, obtain carrying the solution of composite nanoparticle of amycin.
Embodiment 3
1. synthetic polymer PLA-block-PAAA and PLA-block-PEG
1) in round bottom Schlenk bottle add initiator PLA-Br (0.110mmol), vitamin C monomer (1.86mmol),
Chain transfer agents 4-cyanopentanoic acid dithiobenzoic acid (0.10mmol) and dioxane 3.0mL, the stirring of room temperature lower seal is to molten
Liquid is clarified.Freeze cycle three times.60 DEG C of oil baths are reacted 24h, reacts with liquid nitrogen Quick stop.Reaction system chloroform is molten
Solve, precipitate in absolute methanol and be repeated 3 times, obtain polymer P LA180-block-PAAA80；
2) ethylene glycol polymerization, straight are caused using the PEG5000 of double hydroxyl terminals as raw material, one end biotinylation, the other end
Schlenk bottle except adding ethylene glycol (10.5mmol), initiator HO-PEG-Maleimide (0.0525mmol) after water deoxygenation
With toluene 3.0mL.Whole reaction system is placed in 100 DEG C of oil baths and starts reaction, stop after reaction 4h, use liquid nitrogen Quick stop
Reaction.Reaction system chloroform dissolves, and pelleting centrifugation 3 times in absolute methanol are vacuum dried 5h, obtain white powder
Polymer P LA250-block-PEG120。
2. composite Nano delivery system is prepared:
Under the conditions of lucifuge, by docetaxel (100%), polymer P LA180-block-PAAA80(0.14 μm ol) and polymerization
Thing PLA250-block-PEG120(0.14 μm ol) is dissolved in 4mL dimethyl sulfoxide.4mL deionized water it is slowly added dropwise after being completely dissolved.
Centrifugal except organic reagent with the ultra-filtration centrifuge tube that MCWO is 1000, obtain carrying the solution of the composite nanoparticle of docetaxel.
Data set:
1) composite nanoparticle has good biocompatibility
Test condition: polymer micelle concentration: 0.1,0.2,0.4,0.6,0.8,1.0,1.2,1.5mg/mL；Test is thin
Born of the same parents: mouse embryo fibroblasts (NIH 3T3)；Testing time: 24,48,72h；Test kit: MTS reagent box；Test instrunment:
Microplate reader, 490nm.
2) composite nanoparticle self has certain tumor inhibition effect
Test condition: polymer micelle concentration: 800,400,200,100,50,25,12.5,6.75,3.38,1.56,
0.84、0.42μg/mL；Test cell: brain glioblastoma cell (C6), human breast cancer cell (MCF-7), human lung carcinoma cell
(H1299), human lung carcinoma cell (95C), people's ovary adenocarcinoma cells (Sk-ov-3), human cervical carcinoma cell (Hela), human oral cancer are thin
Born of the same parents (ACC), human liver cancer cell (Huh-7), human liver cancer cell (HepG2)；Testing time: 48h；Test kit: MTS reagent box；Survey
Test instrument: microplate reader, 490nm.
Table 1 Molecular Characteristics of PLA-block-PEG
Table 2 Molecular Characteristics of PLA-block-PAAA
Table 1:
aMI represents with maleylation end group PEG as macromole evocating agent；
b DPratioRepresent the hydrophobic patch number of repeat unit of block polymer PLA-block-PEG；
cNumber-average molecular weight is calculated by nucleus magnetic hydrogen spectrum；
dNumber-average molecular weight and Mw/MnI.e. PDI is obtained by GPC；
Table 2:
aMI represents with lactic acid homopolymer PLA-Br as macromole evocating agent；
b DPratioRepresent the hydrophobic patch of block polymer PLA-block-PBnAA and the number of repeat unit of hydrophilic segment
Ratio, as 120/30 represent hydrophobic patch repetitive be 120, hydrophilic segment repetitive is the block polymer of 30；
cNumber-average molecular weight is calculated by nucleus magnetic hydrogen spectrum；
dNumber-average molecular weight and Mw/MnI.e. PDI is obtained by GPC；
e DPratioThe calculated final amphipathic nature polyalcohol PLA-block-PAAA of hydrogenation ratio is passed through after representing hydrogenation
The hydrophobic ratio with hydrophilic segment number of repeat unit.
Claims (10)
1. a composite Nano medicine delivery carrier self with function of tumor inhibition, it is characterised in that amphipathic nature polyalcohol gathers
Lactic acid-embedding-poly-vitamin C acrylate (PLA-block-PAAA) and polylactic acid-embedding-Polyethylene Glycol (PLA-block-PEG)
The composite Nano pharmaceutical carrier obtained by the way of common self assembly；
The structural formula of material polylactic acid-embedding-poly-vitamin C acrylate (PLA-block-PAAA):
10≤n≤200,5≤m≤100, n and m is integer；
The structural formula of material polylactic acid-embedding-Polyethylene Glycol (PLA-block-PEG):
40≤p≤200,10≤q≤200, p and q is integer, and R is can couple fluorescence molecule or target molecules functional
Functional group.
2. according to a kind of composite Nano medicine delivery carrier self with function of tumor inhibition described in claim 1, its feature
Being, R is succinyl ester (NHS), amino (NH2), maleimide maleimide (MAL) or biotin (Biotin)
Group.
3. according to a kind of composite Nano medicine delivery carrier self with function of tumor inhibition described in claim 1, its feature
It is, polylactic acid-embedding-poly-vitamin C acrylate (PLA-block-PAAA) and polylactic acid-embedding-Polyethylene Glycol (PLA-
Block-PEG) both molar ratios are 1:1～12:1.
4. the medicine containing the composite Nano medicine delivery carrier self with function of tumor inhibition described in claim 1 is passed
Send the preparation method of system, it is characterised in that comprise the following steps:
1. synthesizing polylactic acid-embedding-poly-vitamin C acrylate (PLA-block-PAAA) and polylactic acid-embedding-Polyethylene Glycol
(PLA-block-PEG)；
1) polylactic acid-embedding-poly-vitamin C acrylate (PLA-block-PAAA) is obtained by Raolical polymerizable；
2) cause the ring-opening polymerisation of lactide using the PEG of double hydroxyl terminals as raw material, one end functionalization, the other end, obtain poly-breast
Acid-embedding-Polyethylene Glycol (PLA-block-PEG)；
2. prepare and clad the drug delivery system closing Nano medication delivery carrier:
Under the conditions of lucifuge, by polylactic acid-embedding-poly-vitamin C acrylate (PLA-block-PAAA), polylactic acid-embedding-poly-second two
Alcohol (PLA-block-PEG) and chemotherapeutics are dissolved in organic solvent, use self-assembling method altogether to obtain drug delivery system.
5. according to the method for claim 4, it is characterised in that polylactic acid-embedding-poly-vitamin C acrylate (PLA-block-
PAAA) preparation: protect ascorbic reactive enol formula hydroxyl with halogenation benzyl, prepare vitamin C acrylate monomer
(BnAA)；Metallic catalyst catalyzing ring-opening polymerization of lactide obtains polylactic acid homopolymer (PLA-Br), and PLA-Br leads to BnAA again
Cross radical polymerization and obtain polylactic acid-embedding-benzyl protection poly-vitamin C acrylate (PLA-block-PBnAA), lead to the most again
Cross catalytic hydrogenation and obtain polylactic acid-embedding-poly-vitamin C acrylate (PLA-block-PAAA)；
The preparation of polylactic acid-embedding-Polyethylene Glycol (PLA-block-PEG): using the PEG of double hydroxyl terminals as raw material, to poly-second two
Alcohol one terminal hydroxy group carries out the protection of tolysulfonyl, then carries out Azide, modifies and can couple fluorescence molecule and target
The functionalization functional group of molecule；One end retains hydroxyl and causes the ring-opening polymerisation of lactide, obtains polylactic acid-embedding-Polyethylene Glycol
(PLA-block-PEG)。
6. according to the method for claim 4, it is characterised in that the drug delivery system of Nano medication delivery carrier is closed in preparation cladding
Time, the mass fraction concentration of chemotherapeutics is 10%～100%；The concentration of whole polymeric material is 1.0mg/mL.
7. according to the method for claim 4, it is characterised in that radical polymerization be RAFT, ATRP or NMRP method.
8. according to the method for claim 4, it is characterised in that the PEG molecular weight of double hydroxyl terminals used is 2000-5000.
9. according to the method for claim 4, it is characterised in that organic solvent used is chloroform, dimethyl sulfoxide or four
Hydrogen furan.
10. according to the method for claim 4, it is characterised in that the self assembly side in the preparation method of composite Nano delivery system
Method is emulsification mechanism, dialysis or microphase-separated method.
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| CN113321812A (en) * | 2021-05-31 | 2021-08-31 | 华中科技大学 | Polylactic acid-hydroxyethyl starch-folic acid macromolecular compound, drug delivery system, preparation method and application thereof |
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