CN105640922A - Preparation method of novel arsenic trioxide preparation with positive charges and liver targeting effect - Google Patents
Preparation method of novel arsenic trioxide preparation with positive charges and liver targeting effect Download PDFInfo
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Abstract
The invention provides a preparation method of a novel arsenic trioxide preparation with positive charges and a liver targeting effect, and belongs to the technical field of biological medicine. An As2O3 sodium hydroxide solution is used as an internal water phase, a lactic acid-glycolic acid chloroform solution is used as an oil phase, and the internal water phase is wrapped by the oil phase to form W/O primary emulsion; an emulsifier aqueous solution containing polyethylene glycol/lactobionic acid-chitosan is used as an external water phase; biodegradable and high-biocompatibility lactic acid-glycolic acid copolymer is used as a wrapping material. As2O3-PLGA/PLC NPs prepared through the double-emulsion-solvent volatilization method is uniform in nanometer particle size, good in dispersity and high in wrapping rate and medicine loading capacity, can be stably released in vitro, shows good anti-tumor performance in vivo and in vitro and shows a certain liver targeting function, As2O3 can directly target at liver cancer tumor parts and achieve controllable medicine release at the tumor parts, and the treatment effect is improved.
Description
Technical field
The invention belongs to biomedicine technical field, particularly relate to the technology of preparing of a kind of positively charged novel arsenic trioxide preparation with Liver targeting effect.
Background technology:
Arsenic trioxide (As2O3) it is the principle active component of Chinese medicine arsenicum, its injection is used for treating acute promyelocytic leukemia the earliest. Research finds, arsenic trioxide is not only evident in efficacy to acute promyelocytic leukemic, and solid tumor also has good inhibiting effect. But As2O3Half-life is shorter in vivo, can quickly be removed after administration; In addition the As of high dose2O3The toxic and side effects such as neural paralysis, liver failure can be brought, limit its application clinically.
Summary of the invention
It is an object of the invention to overcome cancer therapy drug As2O3In use without target function, and the defect that Half-life in vivo is shorter, thus preparing a kind of positively charged novel arsenic trioxide preparation with liver targeting function.
The step of the present invention is as follows:
1) by As2O3It is dissolved in sodium hydrate aqueous solution, makes As2O3Sodium hydroxide solution;
2) poly lactic coglycolic acid (PLGA) is dissolved in chloroform, makes the chloroformic solution of lactic-co-glycolic acid;
3) under magnetic stirring, by As2O3Sodium hydroxide solution join in the chloroformic solution of lactic-co-glycolic acid, then ice-bath ultrasonic emulsifying, form W/O colostrum;
4) Polyethylene Glycol/lactobionic acid-chitosan (PLC) is dissolved in emulsifier aqueous solution, makes the emulsifier aqueous solution containing Polyethylene Glycol/lactobionic acid-chitosan;
5) being mixed with the emulsifier aqueous solution containing Polyethylene Glycol/lactobionic acid-chitosan by W/O colostrum, ice-bath ultrasonic emulsifying forms W/O/W emulsion;
6) by after the emulsifier aqueous solution Homogeneous phase mixing of W/O/W emulsion and low concentration, evaporating organic solvent, centrifugal collecting precipitation, deionized water wash, lyophilization must carry As2O3Nanoparticle (As2O3-PLGA/PLCNPs)��
The present invention is with As2O3Sodium hydroxide solution be interior aqueous phase, with the chloroformic solution of lactic-co-glycolic acid for oil phase, first with aqueous phase in oil phase encapsulating, form W/O colostrum. Again with the emulsifier aqueous solution containing Polyethylene Glycol/lactobionic acid-chitosan for outer aqueous phase.Adopt the poly lactic coglycolic acid (PLGA) biodegradable, biocompatibility is good as encapsulating material, adopt double; two emulsification-evaporation method to prepare As2O3-PLGA/PLCNPs��
The inventive method preparation method is simple, the nanoparticle size uniformity prepared, morphology controllable, good dispersion, envelop rate, drug loading are high, in vitro can Stable Release, external in vivo all show good antitumor performance, embody certain liver targeting function, make As2O3Hepatic carcinoma position can be directly targeted and realize the controllable release of medicine at tumor locus, improving therapeutic effect.
Further, in step 1) of the present invention, described As2O3Sodium hydroxide solution in As2O3Content is 60mg/mL.
In order to improve envelop rate and drug loading, the step 2 of drug-carrying nanometer particle) in, described poly lactic coglycolic acid (PLGA) content is 30mg/mL.
In order to improve envelop rate and the drug loading of drug-carrying nanometer particle, in step 3), described As2O3Sodium hydroxide solution and the mixed volume ratio of chloroformic solution of lactic-co-glycolic acid be 1: 20.
In step 3), during described ultrasonic emulsification, ultrasonic power is 300W, and ultrasonic time is 90s, to promote to form uniform W/O colostric fluid.
In order to make Polyethylene Glycol/lactobionic acid-chitosan successfully be coated on the surface of nanoparticle, preparing the drug-carrying nanometer particle with positive charge, in step 4), emulsifying agent used is poloxamer; In described emulsifier aqueous solution, the concentration of Polyethylene Glycol/lactobionic acid-chitosan is 1mg/mL.
In step 5), during ultrasonic emulsification, ultrasonic power is 500W, and ultrasonic time is 180s, to form finely dispersed W/O/W double emulsion.
For further stably dispersing W/O/W emulsion, in step 6), the emulsifier aqueous solution of described low concentration is concentration is the poloxamer aqueous solution of 0.9% (w/v).
Additionally, in step 4), described Polyethylene Glycol/lactobionic acid-chitosan synthesizes by the following method: be dissolved in by 1g chitosan in the 6mL acetic acid that mass fraction is 2%, add the 20mLTEMED HCL buffer solution that pH is 4.7, it is then respectively adding 3.83mgEDC and 2.30mgNHS, 0.16mg Polyethylene Glycol and 1.43mg lactobionic acid is added after 30min, when the pH value of reaction system is 4-6, stirring reaction under 35 DEG C of conditions, obtain crude product, crude product is placed in bag filter after dialysis, freeze-dried, obtain Polyethylene Glycol/lactobionic acid-chitosan. Polyethylene Glycol and lactobionic acid can one-step method be modified on chitosan by this synthetic method, it is thus achieved that dual-function chitosan derivant.
Accompanying drawing explanation
Fig. 1 is the synthesis schematic diagram of PLC.
Fig. 2 is double; two emulsification-evaporation method synthesis As2O3The schematic diagram of-PLGA/PLCNPs.
Fig. 3 is PLGA, PLC, As2O3The infrared spectrogram of-PLGA/PLCNPs.
Fig. 4 is As2O3The TEM figure of-PLGA/PLCNPs.
Fig. 5 is the enlarged drawing of Fig. 4.
Fig. 6 is the AFS As recorded2O3Standard curve.
Fig. 7 is medicine As2O3From As2O3External elution profiles in-PLGA/PLCNPs.
Fig. 8 is As2O3Inhibitory action design sketch to SMMC-7721 hepatoma carcinoma cell.
Fig. 9 is As2O3-the PLGA/PLCNPs inhibitory action design sketch to SMMC-7721 hepatoma carcinoma cell.
Figure 10 is As2O3-PLGA/PLCNPs sky the ball inhibitory action design sketch to SMMC-7721 hepatoma carcinoma cell.
Figure 11 is for accepting mouse tumor change in volume curve (X �� SD, n=5) figure after different pharmaceutical is treated.
Figure 12 is oncological pathology detection (HE dyeing) photo after intravenous injection normal saline.
Figure 13 is intravenous injection As2O3Rear oncological pathology detection (HE dyeing) photo.
Figure 14 is intravenous injection As2O3Oncological pathology detection (HE dyeing) photo after-PLGA/PLCNPs.
Figure 15 is kidney organ's pathology detection (HE dyeing) photo after intravenous injection normal saline.
Figure 16 is intravenous injection As2O3Rear kidney organ's pathology detection (HE dyeing) photo.
Figure 17 is intravenous injection As2O3Kidney organ's pathology detection (HE dyeing) photo after-PLGA/PLCNPs.
Detailed description of the invention
One, preparation As2O3-PLGA/PLCNPs:
1, synthesizing polyethylene glycol/lactobionic acid-chitosan PEG/LA-CS (be called for short: PLC):
Weigh 1g chitosan (CS) and be dissolved in 6mL acetic acid (2%), add 20mLTEMED HCL buffer solution (pH=4.7) dilution, stirring 20min, it is then respectively adding 3.83mgEDC and 2.30mgNHS, 0.16mg Polyethylene Glycol (mPEG) and 1.43mg lactobionic acid (LA) is added after 30min, stirring reaction 36h at 35 DEG C, strictly controls pH4-6 in course of reaction, course of reaction is as shown in Figure 1. Crude product is placed in bag filter and dialyses 4 days, and lyophilization can obtain Polyethylene Glycol/lactobionic acid-chitosan (PLC).
2, preparation As2O3-PLGA/PLCNPs:
As shown in Figure 2:
(1) by As2O3It is dissolved in the sodium hydrate aqueous solution that sodium hydroxide mass percent is 4%, is made into As2O3Content is the As of 60mg/mL2O3Sodium hydroxide solution, as interior aqueous phase.
(2) poly lactic coglycolic acid (PLGA) is dissolved in chloroform, makes the PLGA chloroformic solution that PLGA concentration is 30mg/mL, as oil phase.
(3) under magnetic stirring, interior aqueous phase is joined in PLGA chloroformic solution, then ice-bath ultrasonic emulsifying (ultrasound condition: 300W, 90s), form W/O colostrum.
(4) being dissolved in the poloxamer aqueous solution of 9% (outer aqueous phase) by Polyethylene Glycol/lactobionic acid-chitosan (PLC), in obtained solution, PLC concentration is the PLC emulsifier aqueous solution of 1mg/mL.
(5) W/O colostrum is mixed with PLC emulsifier aqueous solution, ice-bath ultrasonic emulsifying (ultrasound condition: 500W, 180s), form W/O/W emulsion.
(6) by after W/O/W emulsion and 0.9% (w/v) poloxamer aqueous solution Homogeneous phase mixing, evaporating organic solvent, centrifugal collecting precipitation, deionized water wash, lyophilization obtains As2O3-PLGA/PLCNPs��
Two, As2O3The sign of-PLGA/PLCNPs and character:
1, Infrared Characterization
Fig. 3 is PLGA, PLC, As2O3The infrared spectrogram of-PLGA/PLCNPs, at As2O3In-PLGA/PLCNPs spectrogram, 1760cm-1Place occurs in that the characteristic absorption peak of C=O in PLGA (carboxyl), 2997cm-1Place is the stretching vibration peak of C-H, 2947cm in methyl-1Place is the stretching vibration peak of C-H in methylene, and 1180cm-1There is the stretching vibration of C-O in place, it was shown that the existence of-COO-in nanoparticle; Additionally, 3544cm-1The broad peak that place occurs is the stretching vibration of O-H and the fused peaks of N-H stretching vibration absworption peak in PLC, it can be said that bright As2O3-PLGA/PLCNPs is successfully prepared.
2, nanometer appearance and current potential
Fig. 4 is As2O3The TEM of-PLGA/PLCNPs, it can be seen that the nanoparticle prepared is regular spherical, size uniformity, smooth surface atresia. By dynamic light scattering (DLS), nanoparticle size and dispersibility are measured. The As of preparation2O3-PLGA/PLCNPs particle diameter is less, at ~ 200nm, is evenly distributed, and the coefficient of dispersion (PDI) is 0.197 �� 0.008.
After being amplified by Fig. 4, from Fig. 5 it is apparent that nanoparticle surface is wrapped up by one layer of PLC thin film, result is consistent with infrared spectrum.As after testing2O3-PLGA/PLCNPs surface positively charged (+28.9 �� 0.3) mV, has confirmed PLC surface parcel further.
3, envelop rate and drug loading
As2O3Standard curve use atomic fluorescence spectrometer (AFS) be measured, draw As2O3Standard curve, as shown in Figure 6. The linear equation of gained standard curve is: Y=8.87821X+35.3255, R2=0.997461. Wherein Y represents fluorescence intensity, and X represents As2O3Mass concentration (ng/mL). It is computed, As2O3-PLGA/PLCNPs envelop rate is 91.68% �� 1.42%, and drug loading is 72.0 �� 1.24%.
(1)As2O3-PLGA/PLCNPs is external controls release
Fig. 7 is As2O3At As2O3External elution profiles in-PLGA/PLCNPs, it can be seen that As2O3-PLGA/PLCNPs can sustained release drugs 15 days in vitro, the accumulative release rate of medicine reaches 72.83%, it may be achieved the control release of medicine.
Three, As2O3The anti-liver tumor performance of-PLGA/PLCNPs:
In order to assess As2O3The anti-liver tumor performance of-PLGA/PLCNPs, in having investigated nanoparticle body respectively, extracorporeal anti-tumor function.
1, extracorporeal anti-tumor performance
Adopt As2O3��As2O3-PLGA/PLCNPs and As2O3-PLGA/PLCNPs sky ball inhibitory action to SMMC-7721 hepatoma carcinoma cell respectively, result is as shown in Figure 8,9, 10.
As seen from Figure 8: As2O3The growth of SMMC-7721 cell can be suppressed, prolongation in time and the increase of drug level, it is suppressed that effect strengthens, the 503nhibiting concentration (IC of medicine after effect 72h50) it is 0.96 �� 0.033 �� gAs2O3/ml��
It can be seen in figure 9 that As2O3SMMC-7721 cell is had obvious inhibitory action by-PLGA/PLCNPs, prolongation in time and the increase of drug level, it is suppressed that effect strengthens, the 503nhibiting concentration (IC of medicine after effect 72h50) it is 0.47 �� 0.017 �� gAs2O3/ mL, lower than As2O3The IC of solution50, illustrate that the growth of hepatoma carcinoma cell is had higher inhibitory action by nanoparticle.
As seen from Figure 10: when, after PLGA/PLCNPs sky ball with cell co-culture 72h, cell survival rate is higher than 85%, and the no cytotoxicity effect of carrier own is described.
2, anti-tumor in vivo performance
With the subcutaneous animal tumor model of setting up in HEPG-2 cell infusion male Bale/c nude mice axillary region, investigate As2O3-PLGA/PLCNPs anti-tumor in vivo performance. Figure 11 is for accepting mouse tumor change in volume curve after different pharmaceutical is treated, after a test period terminates, and As2O3It is 1.602 �� 0.524mm that-PLGA/PLCNPs organizes mouse tumor volume3, far below normal saline (NS) model group (2.262 �� 0.546mm3), tumor control rate is reached 34.19%.
In addition, the tumor tissue that after death obtains of place is detected by histopathology after whole treatment cycle terminates and evaluates the drug delivery system impact on tumor inhibition effect further by we.
Figure 12,13,14 respectively accept (A:NS after different pharmaceutical is treated; B:As2O3;C:As2O3-PLGA/PLCNPs) oncological pathology detection (HE dyeing) photo.
Blank group tumor cell atypia is obvious, shows as cell big, and endochylema is abundanter, polygon, and nucleus dye big, deep, karyokinesis picture are clear to. Tumor cell Dispersed precipitate, tumor cell necrosis slightly accounts for tumor tissues about 2/4, and most necrosis are coagulation necrosis, i.e. tumor cell necrosis, hypochromatosis, but cell outline retains, and interstitial has a small amount of blood vessel, without substantially hemorrhage. Tumor tissues and downright bad part intersection a small amount of cell infiltration as seen. As2O3And As2O3-PLGA/PLCNPs treatment group tumors cellular prion protein is substantially with blank group, but the arrangement of edge part tumor cell is in streak, but As2O3-PLGA/PLCNPs treatment group tumors degree of necrosis is lighter than blank group and As2O3Matched group, illustrates through As2O3After-PLGA/PLCNPs treatment, tumor growth rate is slack-off, and grade malignancy reduces.These show that tumor cell is served good inhibiting effect by treatment group.
In order to verify As further2O3The liver tumor Targeting Performance of-PLGA/PLCNPs, after experiment mice is put to death, the pathological tissue of kidney organ is analyzed, shown in experimental result such as Figure 15,16,17. In blank group: kidney is by cortex, medullary substance and renal papillae composition, and each portion structure is clear, glomerule is without atrophy or increase, and balloon cavity is clear, renal cells intermediate edema degeneration, main manifestations is that cell increases, endochylema loosens light dye, and cell outline owes clear, and chamber edge is irregular. Have no cast in tube chamber, have the granular thing of disengaging. For As2O3And As2O3-PLGA/PLCNPs treatment group, the morphological change of nephridial tissue structure and degenerating cell such as blank group, but As2O3Group mesonephric tubule epithelial cell severe edema's degeneration, and As2O3-PLGA/PLCNPs organizes mesonephric tubule epithelial cell Mild edema degeneration. Thus can illustrate, As2O3Tumor cell of liver is had certain targeting by-PLGA/PLCNPs, reduces the accumulation at renal tissue, reduces the medicine toxic and side effects to kidney.
In sum, As2O3Liver tumor position is had certain targeting by-PLGA/PLCNPs, can be effectively improved therapeutic effect, and reduce the toxic and side effects to other tissue.
Claims (9)
1. the preparation method of the positively charged arsenic trioxide preparation with Liver targeting effect, it is characterised in that comprise the following steps:
1) by As2O3It is dissolved in sodium hydrate aqueous solution, makes As2O3Sodium hydroxide solution;
2) poly lactic coglycolic acid is dissolved in chloroform, makes the chloroformic solution of lactic-co-glycolic acid;
3) under magnetic stirring, by As2O3Sodium hydroxide solution join in the chloroformic solution of lactic-co-glycolic acid, then ice-bath ultrasonic emulsifying, form W/O colostrum;
4) Polyethylene Glycol/lactobionic acid-chitosan is dissolved in emulsifier aqueous solution, makes the emulsifier aqueous solution containing Polyethylene Glycol/lactobionic acid-chitosan;
5) being mixed with the emulsifier aqueous solution containing Polyethylene Glycol/lactobionic acid-chitosan by W/O colostrum, ice-bath ultrasonic emulsifying forms W/O/W emulsion;
6) by after the emulsifier aqueous solution Homogeneous phase mixing of W/O/W emulsion and low concentration, evaporating organic solvent, centrifugal collecting precipitation, deionized water wash, lyophilization obtains As2O3-PLGA/PLCNPs��
2. preparation method according to claim 1, it is characterised in that: in step 1), described As2O3Sodium hydroxide solution in As2O3Content is 60mg/mL.
3. preparation method according to claim 1, it is characterised in that: step 2) in, described poly lactic coglycolic acid content is 30mg/mL.
4. preparation method according to claim 1, it is characterised in that in step 3), described As2O3Sodium hydroxide solution and the mixed volume ratio of chloroformic solution of lactic-co-glycolic acid be 1: 20.
5. preparation method according to claim 1 or 4, it is characterised in that in step 3), during described ultrasonic emulsification, ultrasonic power is 300W, and ultrasonic time is 90s.
6. preparation method according to claim 1, it is characterised in that in step 4), emulsifying agent used is poloxamer; In described emulsifier aqueous solution, the concentration of Polyethylene Glycol/lactobionic acid-chitosan is 1mg/mL.
7. preparation method according to claim 1, it is characterised in that in step 5), during ultrasonic emulsification, ultrasonic power is 500W, and ultrasonic time is 180s.
8. preparation method according to claim 1, it is characterised in that in step 6), the emulsifier aqueous solution of described low concentration is concentration is the poloxamer aqueous solution of 0.9% (w/v).
9. preparation method according to claim 1, it is characterized in that in step 4), described Polyethylene Glycol/lactobionic acid-chitosan synthesizes by the following method: be dissolved in by 1g chitosan in the 6mL acetic acid that mass percent is 2%, add the 20mLTEMED HCL buffer solution that pH is 4.7, it is then respectively adding 3.83mgEDC and 2.30mgNHS, 0.16mg Polyethylene Glycol and 1.43mg lactobionic acid is added after 30min, when the pH value of reaction system is 4-6, stirring reaction under 35 DEG C of conditions, obtain crude product, crude product is placed in bag filter after dialysis, freeze-dried, obtain Polyethylene Glycol/lactobionic acid-chitosan.
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