CN104398493A - Tumor active-targeting nano drug delivery system capable of reversing drug-resistance - Google Patents
Tumor active-targeting nano drug delivery system capable of reversing drug-resistance Download PDFInfo
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- CN104398493A CN104398493A CN201410750956.3A CN201410750956A CN104398493A CN 104398493 A CN104398493 A CN 104398493A CN 201410750956 A CN201410750956 A CN 201410750956A CN 104398493 A CN104398493 A CN 104398493A
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Abstract
The invention provides a tumor active-targeting nano drug delivery system capable of reversing drug-resistance. The drug delivery system is polylactic-co-glycolic acid (PLGA) nanoparticles mixed with lipid, and the nanoparticle core is PLGA. Drug-loaded nanoparticles are prepared as follows: inserting AA-polyethylene glycol-cholesterol linkers and triphenylphosphine-cholesterol linkers in the surface of PLGA; encapsulating DOX into the PLGA nanoparticles mixed with lipid to obtain the drug-loaded nanoparticles. The drug delivery system has the acid sensitivity, which enables the drug delivery system to proactively recognize tumor cells and position and release DOX into the mitochondria and cell nuclei of tumor cells, thereby enhancing the anti-tumor activity, reversing the drug-resistance of the tumor and providing a new strategy for improving the efficacy of DOX.
Description
Technical field
The present invention relates to a kind of prescription composition and application scheme of tumor-targeting nanoscale medicine delivery system of reversible tumor drug resistance, delivery system is novel lipid mixing Poly(D,L-lactide-co-glycolide (PLGA) nanoparticle of parcel amycin (DOX).
Background technology
Tumor is a class disease of serious threat human health.Amycin (DOX) is the first-line drug of chemotherapy of tumors, determined curative effect, cheap, but the feature of the toxic and side effects of amycin normal tissue and easy drug resistance limits its clinical practice.Therefore, take amycin as object of study, build the novel delivery system having cancer target and acid-sensitive characteristic concurrently, increase the content of amycin at tumor tissues, reduce its distribution in normal structure, and reversing drug resistance, obtain the novel tumor targeting drug delivery system of high-efficiency low-toxicity.
Nanoscale medicine delivery system is widely used in cancer target delivery system because of its passive target characteristic.Conventional nanoscale medicine delivery system comprises nanoparticle, polymer micelle etc.Poly(D,L-lactide-co-glycolide (PLGA) has non-immunogenicity, the characteristic such as biodegradable, is ratified to be used for intravenous injection by U.S. food and Drug Administration and European Drug Administration.PLGA can wrap up small molecule chemotherapeutic medicine, gene, albumen etc. and form nanoparticle, but the drug loading of PLGA nanoparticle is low, hydrophilic is poor, easily removed by immune system in blood circulation, and enter in cell and easily caught by lysosome, reduce transmission efficiency and the curative effect of medicine.Lipid mixing PLGA nanoparticle is study hotspot in recent years, by embedding the mixing lipid of functionalization on PLGA nanoparticle surface, makes nanoparticle have the several functions such as cancer target, long-acting stable, lysosome escape concurrently.
Tumor produces the first cause that multidrug resistance is chemotherapy failure.The Main Function target spot that chemotherapy represents drug adriamycin is nucleus, and when tumor cell produces drug resistance, amycin is pumped out extracellular and inactivation before arrival action target spot.Therefore, look for other action target spot, improving the valid density of amycin in born of the same parents is one of means of reversing drug resistance.Research finds that amycin can be distributed in mitochondrion, and generate by increasing reactive oxygen free radical, the approach such as lesion wire mitochondrial respiratory chain cause mitochondrial injury, cell death inducing.Therefore, Mitochondrially targeted adriamycin composite or delivery system reversible drug resistance is designed.Cation lipid compound (3-third carboxyl) triphenylphosphinebromide (TPP) has very high affinity to mitochondrion, if TPP is connected with carrier material and can obtains Mitochondrially targeted delivery system, thus the interior distribution of the born of the same parents changing DOX, and reversing drug resistance.
Summary of the invention
The object of this invention is to provide a kind of tumor-targeting nanoscale medicine delivery system of reversible tumor drug resistance.By the design of delivery system, the valid density at tumor cell of amycin can be improved, reduce the distribution of medicine in normal structure, reversing drug resistance, thus obtain efficient, low toxicity, reversing drug resistance delivery system, for antitumor drug exploitation provides new approaches.
Technical scheme of the present invention is: a kind of tumor-targeting nanoscale medicine delivery system of reversible tumor drug resistance, it is characterized in that delivery system is lipid mixing PLGA nanoparticle, the core of nanoparticle is Poly(D,L-lactide-co-glycolide (PLGA), surface embeds methoxy benzamide-PEG-CHOL junctional complex (AA-PEG-hyd-CHEMS) and triphenylphosphine-cholesterol junctional complex, wherein
(1) to the preparation method of methoxy benzamide-PEG-CHOL junctional complex (AA-PEG-hyd-CHEMS) be:
Taking aminocaproic acid is dissolved in anhydrous methylene chloride; Separately taking anisoyl chloride is dissolved in anhydrous methylene chloride, and slowly join in above-mentioned reactant liquor, stirring reaction is stopped reaction after 12 hours, vacuum rotating evaporate to dryness reactant liquor; With appropriate acetic acid ethyl dissolution reactant, add the hydrochloric acid solution washing of 0.5M, collect organic facies, add anhydrous sodium sulfate drying, cross and filter sodium sulfate, evaporate to dryness organic facies, silica gel chromatography column purification obtains methoxy benzamide base caproic acid; N, N-dicyclohexylcarbodiimide and 4-dimethylamino pyridine (DCC/DMAP) are dissolved in dichloromethane, add methoxy benzamide base caproic acid, activate after 6 hours and add end through amido modified Polyethylene Glycol (NH
2-PEG-NH
2), add appropriate triethylamine, continuation reaction stopped reaction after 12 hours, filters, evaporate to dryness reactant liquor simultaneously.In reactant, add proper amount of methanol, dialysis, lyophilizing obtains AA-PEG-NH
2; Separately take appropriate acetylbenzoic acid, be dissolved in dichloromethane, add DCC/DMAP, reactant liquor adds AA-PEG-NH after activating 6 hours
2, add appropriate triethylamine simultaneously, after reaction terminates, filter, evaporate to dryness reactant liquor, by proper amount of methanol again lysate, dialysis, lyophilizing, obtains AA-PEG-to acetylbenzoic acid;
Taking cholesterol is dissolved in dichloromethane, adds succinic anhydride, DMAP, triethylamine successively, and stirring at room temperature is reacted; After reaction terminates, silica gel chromatography column purification obtains cholesterol-monomester succinate (Chol-suc); Chol-suc, DCC, DMAP are dissolved in dichloromethane, activate and add tert-butyl carbazate (BOC-NH-NH after 6 hours
2) and triethylamine, reaction terminates rear silica gel chromatography column purification and obtains cholesterol-succinic acid-NHNHBOC; Above-mentioned product is dissolved in dichloromethane, adds trifluoroacetic acid, normal-temperature reaction 2 hours, add aqueous phase and wash away trifluoroacetic acid, then use dichloromethane extraction reactant liquor after reaction terminates, collect organic facies, dry, evaporate to dryness obtains cholesterol-succinhydrazide (Chol-NHNH
2);
Take AA-PEG-to acetylbenzoic acid and Chol-NH-NH
2be dissolved in dichloromethane, add a small amount of trifluoroacetic acid, stirring reaction, after reaction terminates, evaporate to dryness reactant liquor, uses a small amount of dissolve with methanol, and lyophilizing of dialysing obtains having the end-product of acid-sensitive characteristic to methoxy benzamide-PEG-CHOL junctional complex (AA-PEG-hyd-CHEMS);
(2) preparation method of triphenylphosphine-cholesterol junctional complex (TPP-CHEMS) is:
Be dissolved in dichloromethane by (3-third carboxyl) triphenylphosphinebromide and DCC/DMAP, activate and add hexamethylene diamine after 6 hours, react stopped reaction after 24 hours, filter, evaporate to dryness reactant liquor, purification by silica gel column chromatography obtains intermediate; Separately getting cholesterol-monomester succinate is dissolved in dichloromethane, add after DCC/DMAP activates 6 hours and add above-mentioned intermediate, react stopped reaction after 24 hours, filter, evaporate to dryness reactant liquor, purification by silica gel column chromatography obtains triphenylphosphine-cholesterol succinate (TPP-CHEMS);
(3) preparation method of lipid mixing PLGA nanoparticle is:
Take a certain amount of PLGA, TPP-CHEMS and AA-PEG-hyd-CHEMS is dissolved in (V in dichloromethane
1), separately doxorubicin hydrochloride is dissolved in (V in distilled water
2, V
1>=V
2), mixing aforesaid liquid, ultrasonic, then add polyvinyl alcohol (PVA, the V of 3%
3, V
3>=V
1), ultrasonic, transfer in beaker, stirring at room temperature 3h, centrifugal (15000rpm, 15min), the precipitation distilled water flushing obtained three times, again disperses with distilled water, obtains nanoparticle.
The present invention designs a kind of novel nano delivery system, and this delivery system is lipid mixing PLGA nanoparticle, and nanoparticle structure comprises PLGA, AA-PEG-CHOL junctional complex (AA-PEG-hyd-CHEMS) and TPP-CHEMS.This nanoparticle has active targeting characteristic, sigma receptor high expression tumour cell can be increased to the picked-up of amycin, after entering cells of resistant tumors, in lysosome, the surperficial AA-PEG-hyd-CHEMS with acid-sensitive characteristic of nanoparticle is hydrolyzed, nanoparticle surface charge is reversed, surface exposes the TPP-CHEMS with mitochondrion positioning function, thus delivery system is delivered to mitochondrion and nucleus, and it is active that release amycin plays reversing drug resistance.
Accompanying drawing explanation
Fig. 1 is the Zeta potential of lipid mixing PLGA nanoparticle in different pH medium.n＝3，
**p<0.01，vs pH7.4。
Fig. 2 is DOX, lipid mixing PLGA nanoparticle (LNPs-1) of load DOX and the PLGA nanoparticle (NNPs) of load DOX to the Cytotoxic evaluation of A549 cell (A) and HepG2 cell (B).N=6,
*p<0.01,
*the dosage DOX such as p<0.05, vs; The dosage LNPs-1 such as ##p<0.01, #p<0.05, vs.
Fig. 3 is that the PLGA nanoparticle (NNPs) of DOX, lipid mixing PLGA nanoparticle (LNPs-1) of load DOX and load DOX is to the cytotoxicity of mdr cell MDA-MB-231/ADR cell.N=6,
*p<0.01,
*the dosage DOX such as p<0.05, vs; The dosage LNPs-1 such as ##p<0.01, #p<0.05, vs.
Fig. 4 is that the picked-up of lipid mixing PLGA nanoparticle (D) in MDA-MB-231/ADR cell of DOX (C) and load DOX locates schematic diagram with sub-.
Fig. 5 be DOX, load DOX lipid mixing PLGA nanoparticle (LNPs-1) to the inhibitory action of tumor bearing nude mice (transplant mdr cell MDA-MB-231/ADR) tumor growth.
Detailed description of the invention
The preparation of amycin cancer target delivery system and antitumor activity
1 object: the anti-tumor activity evaluating load DOX lipid mixing PLGA nanoparticle.
2 research methoies:
2.1 envelop rates and drug loading measure
Be dissolved in by nanoparticle in DMSO, destroy nanoparticle structure, HPLC-MS/MS method detects envelop rate and drug loading.
Drug loading=(medication amount of wrapping up in delivery system/medicine carrying delivery system weight) × 100%
Envelop rate=(actual drug loading/dosage) × 100%
2.2 acid-sensitive evaluating characteristics
Take lipid mixing PLGA nanoparticle, the Zeta potential of laser particle analyzer analysis lipid mixing PLGA nanoparticle in different pH (pH 5.0, pH 6.5 and pH 7.4) medium.
2.3 Cytotoxic evaluation
Cultivate typeⅡ pneumocyte, hepatoma Hep G 2 cells, adriamycin-resistant breast carcinoma MDA-MB-231/ADR cell respectively.Trophophase cell of taking the logarithm is inoculated in 96 orifice plates, and density is 1 × 10
4the PLGA nanoparticle of amycin, load amycin lipid mixing PLGA nanoparticle, load amycin is added respectively after cultivating 24h, culture fluid not containing serum is set to blank group, add 20 μ L MTT after 48h to continue to hatch 4h, discard culture fluid, with 150 μ LDMSO dissolve purple crystallizations, microplate reader reads OD value under 490nm, draw cell survival rate curve chart, by formulae discovery cell survival rate.
Cell survival rate (%)=(test group OD value/blank group OD value) × 100%
2.4 medicines sub-location in tumor cell is evaluated
The MDA-MB-231/ADR cell of growth of taking the logarithm is seeded to and is loaded with in the Tissue Culture Plate of microscope slide, add amycin after 24h, be loaded with the lipid mixing PLGA nanoparticle of amycin, after continuing to hatch 4h, removing culture fluid, adds nucleus dyestuff DAPI dyeing 10min, PBS rinses 3 times, mitochondrial dye MitoTracker green dyes 30min, removing dyestuff, and PBS rinses 3 times, paraformaldehyde is fixed, the Asia location of confocal laser scanning microscope medicine in cells of resistant tumors.
The anti-tumor in vivo activity rating of 2.5 medicines
20 Balb/c male nude mouses (4 week age) are divided into 4 groups at random, often organize 4.Collect MDA-MB-231/ADR cell, be suspended in culture fluid, cell density is 3 × 10
7/ ml, every mouse back subcutaneous injection 0.2ml.Treat that gross tumor volume is 20mm
3time start administration, take normal saline as negative control, DOX is positive control, and dosage is 10 μm of ol/kg, carry DOX lipid mixing PLGA nanoparticle (LNPs-1) be two dosage groups, be respectively 2,10 μm of ol DOX/kg.Within every 5 days, be administered once, altogether administration 3 times.After administration, every three days record body weight and tumor size, gross tumor volume=(length of tumor × width
2)/2.
3 experimental results:
3.1 envelop rates and drug loading
Envelop rate and the drug loading of lipid mixing PLGA nanoparticle are as shown in table 1.The delivery system of result prompting this patent design has higher drug loading and encapsulation efficiency.
The drug loading of table 1 delivery system and envelop rate
| Drug loading (%) | Envelop rate (%) | |
| Lipid mixing PLGA nanoparticle | 5.6±1.2 | 85±4 |
3.2 acid-sensitive evaluating characteristics
The Zeta potential of lipid mixing PLGA nanoparticle presents significant change with pH change, when pH is 5.0, nanoparticle surface potential transfers positive electricity to, prompting is under this pH, the acid-sensitive materials A A-PEG-CHEMS hydrolysis on nanoparticle surface, make TPP-CHEMS be exposed to nanoparticle surface, nanoparticle has electropositive because of cationic lipid material TPP, thus shows Mitochondrially targeted characteristic.
3.3 anti tumor activity in vitro
MTT result shows, for the A549 cell of sigma receptor high expressed, the cytotoxicity of the lipid nanoparticle that surface is modified through sigma receptors ligand AA is apparently higher than not modified lipid nanoparticle, and for the HepG2 cell of the low expression of sigma receptor, the cytotoxicity of two kinds of nanoparticles there was no significant difference; Compared with free amycin, the cytotoxicity of lipid mixing PLGA nanoparticle (LNPs-1) of load DOX obviously increases; When hatching altogether with mdr cell MDA-MB-231/ADR, the PLGA nanoparticle of DOX and load DOX is all without obvious cytotoxicity, and lipid mixing PLGA nanoparticle still has certain cytotoxicity.The above results shows, lipid mixing PLGA nanoparticle enters tumor cell by sigma is receptor-mediated, obviously can increase the cytotoxicity of amycin, also have good cytotoxicity for cells of resistant tumors, prompting novel lipid mixing PLGA nanoparticle has active targeting anti-tumor activity and reversing drug resistance effect simultaneously.
3.4 intracellular targeting distributions
Laser co-focusing result shows, and when hatching altogether with cells of resistant tumors MDA-MB-231/ADR, free amycin is almost pumped extracellular by mdr cell completely, causes cytotoxicity to be lost; And after MDA-MB-231/ADR cell hatches with lipid mixing PLGA nanoparticle, can be observed DOX location is released in mitochondrion, inducible resistance apoptosis of tumor cells, thus reverse both drug resistance.
3.5 anti-tumor in vivo are active
To dissociate DOX compared to same dosage, carry the growth that DOX lipid mixing PLGA nanoparticle significantly can suppress drug-resistant tumor.
4 conclusions:
The anti-tumor experiment result of inside and outside shows, compared with free amycin, the lipid mixing PLGA nanoparticle of load DOX significantly increases the enrichment of amycin in tumor cell, effective raising amycin is to the cytotoxicity of tumor cell, and reversing tumor cells resistance, present good anti-tumor in vivo active, there is certain DEVELOPMENT PROSPECT.
Claims (1)
1. the tumor-targeting nanoscale medicine delivery system of a reversible tumor drug resistance, it is characterized in that delivery system is lipid mixing PLGA nanoparticle, the core of nanoparticle is Poly(D,L-lactide-co-glycolide (PLGA), surface embeds methoxy benzamide-PEG-CHOL junctional complex (AA-PEG-hyd-CHEMS) and triphenylphosphine-cholesterol junctional complex, wherein
(1) to the preparation method of methoxy benzamide-PEG-CHOL junctional complex (AA-PEG-hyd-CHEMS) be:
Taking aminocaproic acid is dissolved in anhydrous methylene chloride; Separately taking anisoyl chloride is dissolved in anhydrous methylene chloride, and slowly join in above-mentioned reactant liquor, stirring reaction is stopped reaction after 12 hours, vacuum rotating evaporate to dryness reactant liquor; With appropriate acetic acid ethyl dissolution reactant, add the hydrochloric acid solution washing of 0.5M, collect organic facies, add anhydrous sodium sulfate drying, cross and filter sodium sulfate, evaporate to dryness organic facies, silica gel chromatography column purification obtains methoxy benzamide base caproic acid; N, N-dicyclohexylcarbodiimide and 4-dimethylamino pyridine (DCC/DMAP) are dissolved in dichloromethane, add methoxy benzamide base caproic acid, activate after 6 hours and add end through amido modified Polyethylene Glycol (NH
2-PEG-NH
2), add appropriate triethylamine, continuation reaction stopped reaction after 12 hours, filters, evaporate to dryness reactant liquor simultaneously.In reactant, add proper amount of methanol, dialysis, lyophilizing obtains AA-PEG-NH2; Separately take appropriate acetylbenzoic acid, be dissolved in dichloromethane, add DCC/DMAP, reactant liquor adds AA-PEG-NH after activating 6 hours
2, add appropriate triethylamine simultaneously, after reaction terminates, filter, evaporate to dryness reactant liquor, by proper amount of methanol again lysate, dialysis, lyophilizing, obtains AA-PEG-to acetylbenzoic acid;
Taking cholesterol is dissolved in dichloromethane, adds succinic anhydride, DMAP, triethylamine successively, and stirring at room temperature is reacted; After reaction terminates, silica gel chromatography column purification obtains cholesterol-monomester succinate (Chol-suc); Chol-suc, DCC, DMAP are dissolved in dichloromethane, activate and add tert-butyl carbazate (BOC-NH-NH after 6 hours
2) and triethylamine, reaction terminates rear silica gel chromatography column purification and obtains cholesterol-succinic acid-NHNHBOC; Above-mentioned product is dissolved in dichloromethane, adds trifluoroacetic acid, normal-temperature reaction 2 hours, add aqueous phase and wash away trifluoroacetic acid, then use dichloromethane extraction reactant liquor after reaction terminates, collect organic facies, dry, evaporate to dryness obtains cholesterol-succinhydrazide (Chol-NHNH
2);
Take AA-PEG-to acetylbenzoic acid and Chol-NH-NH
2be dissolved in dichloromethane, add a small amount of trifluoroacetic acid, stirring reaction, after reaction terminates, evaporate to dryness reactant liquor, uses a small amount of dissolve with methanol, and lyophilizing of dialysing obtains having the end-product of acid-sensitive characteristic to methoxy benzamide-PEG-CHOL junctional complex (AA-PEG-hyd-CHEMS);
(2) preparation method of triphenylphosphine-cholesterol junctional complex (TPP-CHEMS) is:
Be dissolved in dichloromethane by (3-third carboxyl) triphenylphosphinebromide and DCC/DMAP, activate and add hexamethylene diamine after 6 hours, react stopped reaction after 24 hours, filter, evaporate to dryness reactant liquor, purification by silica gel column chromatography obtains intermediate; Separately getting cholesterol-monomester succinate is dissolved in dichloromethane, add after DCC/DMAP activates 6 hours and add above-mentioned intermediate, react stopped reaction after 24 hours, filter, evaporate to dryness reactant liquor, purification by silica gel column chromatography obtains triphenylphosphine-cholesterol succinate (TPP-CHEMS);
(3) preparation method of lipid mixing PLGA nanoparticle is:
Take a certain amount of PLGA, TPP-CHEMS and AA-PEG-hyd-CHEMS is dissolved in (V in dichloromethane
1), separately doxorubicin hydrochloride is dissolved in (V in distilled water
2, V
1>=V
2), mixing aforesaid liquid, ultrasonic, then add polyvinyl alcohol (PVA, the V of 3%
3, V
3>=V
1), ultrasonic, transfer in beaker, stirring at room temperature 3h, centrifugal (15000rpm, 15min), the precipitation distilled water flushing obtained three times, again disperses with distilled water, obtains nanoparticle.
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| CN116370436A (en) * | 2023-03-15 | 2023-07-04 | 暨南大学 | Application of emodin polymer lipid hybrid nanoparticles |
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