CN104689330A - Antitumor drug PEGylation and applications of antitumor drug PEGylation in reversal of tumor multidrug resistance - Google Patents
Antitumor drug PEGylation and applications of antitumor drug PEGylation in reversal of tumor multidrug resistance Download PDFInfo
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Abstract
The present invention discloses antitumor drug PEGylation and applications of the antitumor drug PEGylation in reversal of tumor multidrug resistance. The PEGylated antitumor drug is prepared by conjugating activated PEG onto an antitumor drug, and can be used for preparing the drug for reversal of tumor multidrug resistance. According to the present invention, the antitumor drugs (particularly water insoluble drugs) containing amino, carboxyl, hydroxyl and other modifiable groups are PEGylated so as to increase the water solubility, such that excellent characteristics of micelle self-assembly forming, production of invisible nanoparticles or active targeting tumor nanoparticles, drug release behavior regulation, system toxicity reducing, biological half-life improving, EPR effect production, tumor passive/active targeting production, tumor multidrug resistance reversal and the like are provided, and good clinical application prospects are provided.
Description
Technical field
The invention belongs to anti-tumor medicine technical field, be specifically related to a kind of antitumor drug PEGization and the application on reverse multiple drug resistance of tumor thereof.
Background technology
Malignant tumor is one of disease of serious harm human health.International anti-cancer alliance declares, the summation of the death toll that the number of the death because of cancer every year causes considerably beyond these three kinds of diseases of malaria, acquired immune deficiency syndrome (AIDS) and tuberculosis.To the year two thousand twenty, the whole world may increase cancer patient 1,500 ten thousand people every year newly.Current China tumor incidence is about 2,00/,100,000, the annual new cancer cases of China about more than 2,200,000, and reach more than 6,000,000 controlling patient every year, medical expense, more than 1,500 hundred million, dies from cancer occurrence numbers every year more than 1,600,000.Oneself becomes one of global health strategy emphasis to control cancer.
At present, anti-cancer therapies mainly comprises surgical operation therapy, radiation and chemotherapy clinically, and wherein chemotherapy is the main means for the treatment of of cancer.But the generation of tumor cell multidrug resistance (multidrug resistance, MDR) is the main cause of current cancer chemotherapy failure.Therefore, focus and difficult point that tumor multi-medicine drug-resistant has become field of cancer is overcome.
The generation of tumor multidrug-resistance has number of mechanisms, mainly comprises: the overexpression of the P-glycoprotein of multidrug resistance gene (MDR1 gene) and coding thereof; The activity of glutathion and relevant enzyme increases; Expression of MRP increase etc.Medicine for the reverse multiple drug resistance of tumor of above mechanism has a lot, mainly comprises: cyclosporin A and derivant thereof, Progesterone, quinine etc.But it is unstable in vivo, tumor-targeting is poor and toxic and side effects is excessive.Therefore, the medicament research and development of the efficient reverse multiple drug resistance of tumor of low toxicity remains the focus that people pay close attention to.
Rapamycin (RAPA) is white crystalline solid, atomic water-soluble, is soluble in the organic solvents such as methanol, ethanol, chloroform.Rapamycin has the effects such as antitumor, antifungal and immunosuppressant.
Paclitaxel (PTX) all has good effect to kinds of tumors, but its water solublity is low, toxic and side effects is strong, and these all strongly limit its application clinically, and long-time use easily produces drug resistance phenomenon.
Amycin (DOX) is the antitumor drug that Clinical practice is maximum so far, but it has obvious accumulative cardiac toxicity, stopped treatment of sometimes having to, and is also easy to produce drug resistance simultaneously, causes chemotherapy failure.
Polyethylene Glycol (PEG) is the polymer substance that pH is neutral, nontoxic, have excellent hydrophilic and biocompatibility, and the only a few ratified by FDA can as one of polymer of injection drug in body.
Summary of the invention
The object of the present invention is to provide a kind of antitumor drug PEGization and the application on reverse multiple drug resistance of tumor thereof; The present invention by containing amino, carboxyl and hydroxyl etc. can the antitumor drug (particularly poorly water soluble drugs) of modification group after PEGization; water solublity can be improved; have and self assembly can form micelle, make invisible nano particle or active targeting tumor nanoparticle; the release behavior of regulating medicine; mitigation system toxicity, raising biological half-life, produces EPR effect and tumor is passive, active targeting; and the good characteristic such as reverse multiple drug resistance of tumor, there is good potential applicability in clinical practice.
The object of the invention is to be achieved through the following technical solutions:
First aspect, the present invention relates to a kind of PEGization antitumor drug, and described PEGization antitumor drug obtains by the PEG of activation being coupled to preparation on antitumor drug.
Preferably, the number-average molecular weight of described PEG is 0.1K ~ 1000K.
Preferably, described PEGization antitumor drug can connect target head.
Preferred, described target head comprises folic acid, biotin, RGD, antibody or aptamer.
Second aspect, the present invention relates to the purposes of a kind of above-mentioned PEGization antitumor drug in the medicine preparing reverse multiple drug resistance of tumor.
Preferably, the antitumor drug in described PEGization antitumor drug comprises the antitumor drug of cell toxicant class.
Preferred, the antitumor drug of described cell toxicant class is the medicine acting on the medicine of DNA chemical constitution, the medicine affecting Nucleic acid, the medicine acting on transcribed nucleic acid, topoisomerase enzyme inhibitor or disturb tubulin synthesis.
Preferably, described tumor is have one or more in the inherent multidrug-resistant carcinoma of P-glycoprotein overexpression, acquisition multidrug resistance entity tumor, hematological system tumor.
Preferably, described PEGization antitumor drug self assembly can be formed micelle, makes invisible nano particle or make active targeting tumor nanoparticle.Prepared micelle, invisible nano particle or active targeting tumor nanoparticle can produce EPR effect.Prepared micelle and invisible nano particle have tumor passive target and long blood circulation effect in vivo.
Preferably, the particle size range of described micelle, invisible nano particle or active targeting tumor nanoparticle is 1 ~ 200nm.
Compared with prior art, the present invention has following beneficial effect:
1, the PEG of medicine modifies is the process be coupled to by chemical method by the PEG of activation on medicine, i.e. PEGization; Compared with before modification, there is outstanding advantage after medicine PEGization: 1) dissolubility of medicine improves, 2) Increased Plasma Half-life, 3) pharmacokinetics improves, and 4) immunogenicity of protein drug and antigenicity decline.
2, antitumor drug (as rapamycin, paclitaxel and amycin etc.) self assembly can form invisible nano particle after PEGization, produces EPR effect, has tumor passive target and long blood circulation effect.Experiment in vitro shows, it has obvious reverse effect to MCF-7/ADR cell, and reversal index is respectively 3.02,3.33 and 2.05, and system toxicity declines to some extent, compares proto-drug, and PEG chemical medicine thing is to the IC of MCF-7 cell
50value rises 5.1,13.0 and 6.4 times respectively.This good characteristic can be used for the treatment of tumor multi-medicine drug-resistant.
Accompanying drawing explanation
By reading the detailed description done non-limiting example with reference to the following drawings, other features, objects and advantages of the present invention will become more obvious:
Fig. 1 is PEG-RAPA
1h NMR spectrogram;
Fig. 2 is after the rapamycin treatment MCF-7 cell with variable concentrations, by the survival rate of MTT colorimetric determination tumor cell;
Fig. 3 is after the rapamycin treatment MCF-7/ADR cell with variable concentrations, by the survival rate of MTT colorimetric determination tumor cell;
Fig. 4 is after the PEG-RAPA process MCF-7 cell with variable concentrations, by the survival rate of MTT colorimetric determination tumor cell;
Fig. 5 is after the PEG-RAPA process MCF-7/ADR cell with variable concentrations, by the survival rate of MTT colorimetric determination tumor cell;
Fig. 6 is PEG-PTX
1h NMR spectrogram;
Fig. 7 is after the taxol treatment MCF-7 cell with variable concentrations, by the survival rate of MTT colorimetric determination tumor cell;
Fig. 8 is after the taxol treatment MCF-7/ADR cell with variable concentrations, by the survival rate of MTT colorimetric determination tumor cell;
Fig. 9 is after the PEG-PTX process MCF-7 cell with variable concentrations, by the survival rate of MTT colorimetric determination tumor cell;
Figure 10 is after the PEG-PTX process MCF-7/ADR cell with variable concentrations, by the survival rate of MTT colorimetric determination tumor cell;
Figure 11 is PEG-DOX
1h NMR spectrogram;
Figure 12 is after the amycin process MCF-7 cell with variable concentrations, by the survival rate of MTT colorimetric determination tumor cell;
Figure 13 is after the amycin process MCF-7/ADR cell with variable concentrations, by the survival rate of MTT colorimetric determination tumor cell;
Figure 14 is after the PEG-DOX process MCF-7 cell with variable concentrations, by the survival rate of MTT colorimetric determination tumor cell;
Figure 15 is after the PEG-DOX process MCF-7/ADR cell with variable concentrations, by the survival rate of MTT colorimetric determination tumor cell.
Detailed description of the invention
Below in conjunction with the drawings and specific embodiments, the present invention is described in detail.Following examples will contribute to those skilled in the art and understand the present invention further, but not limit the present invention in any form.It should be pointed out that to those skilled in the art, without departing from the inventive concept of the premise, can also make certain adjustments and improvements.These all belong to protection scope of the present invention.
embodiment 1
For PEG-RAPA, the mensuration of its building-up process, physicochemical property and the reverse effect to MCF-7/ADR cell thereof are described:
The synthesis of PEG-RAPA: get mPEG-COOH88mg and be dissolved in the anhydrous methylene chloride of 10mL ice, then add the rapamycin of 107mg, the DMAP of DCC and 15mg of 30mg.Naturally room temperature is warming up to, stirring reaction 3d.Filter after completion of the reaction, absolute ether precipitates 2 times, then by precipitate vacuum drying and get final product.PEG-RAPA's (PEGization rapamycin)
1h NMR spectrogram as shown in Figure 1.
The preparation of PEG-RAPA micelle and particle size determination thereof: PEG-RAPA micelle adopts solid dispersion method preparation.Get the acetonitrile that 1mg PEG-RAPA is dissolved in 100 μ L, after naturally volatilizing, be dissolved in 2ml ultra-pure water, vortex 3min, the centrifugal 10min of ultrasonic 5min, 12000r/min, get supernatant with 0.45 μm of filtering with microporous membrane and get final product.
The particle diameter dynamic light scattering method (DLS) of PEG-RAPA micelle measures: experimental light sources is 4.0mWHe-Ne laser, optical maser wavelength 633nm, measures angle 173 °.All measuring tempeature are all 25 DEG C, and retest three times, averages.Experimental result is in table 1.
The mensuration of PEG-RAPA dissolubility: adopt weight reduction to measure.Getting a certain amount of PEG-RAPA is dissolved in the ultra-pure water of 2mL, is stirred well to and reaches dissolution equilibrium, filters, the PEG-RAPA of the undissolved drying of accurate weighing.The solvent volume of the dissolubility=total amount-undissolved amount of thing of getting it filled ()/add.More than experiment measures at 25 DEG C.Experimental result is in table 1.
The table dissolubility of 1PEG-RAPA and the particle diameter of PEG-RAPA micelle
| PEG chemical medicine thing | Dissolubility (mg/ml) | Particle diameter (nm) | PDI |
| PEG-RAPA | 16.7 | 55.7±2.2 | 0.132±0.007 |
The mould rope of thunder handkerchief its water solublity after PEGization increases greatly as shown in Table 1, and dissolubility becomes 16.7mg/mL (dissolubility amounting to into rapamycin is 5.01mg/mL).It self assembly can form micelle in water simultaneously, and particle diameter is 55.7nm, and uniform particle diameter, PDI is 0.132.
MCF-7/ADR cell measures the drug resistance multiple of rapamycin: MCF-7 and MCF-7/ADR cell is inoculated in 96 orifice plates with 4000, every hole respectively, every pore volume 200 μ L.After cell attachment, culture medium replaces with the culture medium containing free drug, continues to cultivate 48h.Then sucking-off culture medium solution, adds 1640 culture medium (not containing serum) of the 200 μ L containing 0.5mg/mL MTT.After 4h, MTT solution is sucked, and the DMSO solution adding 200 μ L dissolves.Then their light absorption values at 490nm place are measured by microplate reader.Each concentration do 5 parallel.Calculate cell proliferation suppression ratio by formula (1), and calculate the drug resistance multiple of medicine by following formula (2):
Cell proliferation suppression ratio=(control group A value-drug treating group A value)/control group A value × 100% (1)
Drug resistance multiple=IC
50(MCF-7/ADR cell)/IC
50(MCF-7 cell) (2)
Result is as shown in Fig. 2, Fig. 3 and table 2:
Table 2 rapamycin is to the IC of MCF-7 and MCF-7/ADR cell
50value and drug resistance multiple
MCF-7/ADR cell has very strong drug-resistant effect to rapamycin as shown in Table 2, can be used for the correlational study of multidrug resistance.
PEG-RAPA measures the cytotoxic effect of MCF-7 cell the reverse exponential sum of MCF-7/ADR cell: be inoculated in 96 orifice plates by MCF-7/ADR, MCF-7 cell being in exponential phase with the density in 4000/hole, every pore volume 200 μ L, is placed in incubator and cultivates.After cell attachment, culture medium replaces with the culture medium containing PEG-RAPA, continues to cultivate 48h.Then sucking-off culture medium solution, adds 1640 culture medium (not containing serum) of the 200 μ L containing 0.5mg/mLMTT.After 4h, MTT solution is sucked, and the DMSO solution adding 200 μ L dissolves.Then their light absorption values at 490nm place are measured by microplate reader.Each concentration do 5 parallel.Calculate cell proliferation suppression ratio by formula (1), and calculate reverse index by following formula (3).
Reverse index=IC
50(chemotherapeutics)/IC
50(PEG chemical medicine thing) (3)
Experimental result is as shown in Fig. 4, Fig. 5 and table 3:
Table 3PEG-RAPA is to the IC of MCF-7/ADR, MCF-7 cell
50value and reverse index
Table 3 result shows that rapamycin strengthens to some extent the toxicity of MCF-7/ADR cell after PEGization, and reversing index is 3.02, and have stronger reversing effect, decline to some extent simultaneously to the toxicity of MCF-7 cell, decline multiple is 5.1.
embodiment 2
For PEG-PTX, the mensuration of its building-up process, physicochemical property and the reverse effect to MCF-7/ADR cell thereof are described:
The synthesis of PEG-PTX: get mPEG-COOH88mg, is dissolved in 10mL anhydrous methylene chloride, ice bath to 0 DEG C, then adds the paclitaxel of 100mg, the DMAP of the DCC of 30mg, 15mg, and stirring reaction, is warming up to room temperature naturally, reaction 3d.Filter after completion of the reaction, and use ice ether sedimentation, then by precipitate vacuum drying and get final product.PEG-PTX's (PEG-Toxol)
1h NMR spectrogram as shown in Figure 6.
The preparation of PEG-PTX micelle and particle size determination thereof: PEG-PTX micelle adopts solid dispersion method preparation.Get the acetonitrile that 1mg PEG-PTX is dissolved in 100 μ L, after naturally volatilizing, be dissolved in 2ml ultra-pure water, vortex 3min, the centrifugal 10min of ultrasonic 5min, 12000r/min, get supernatant with 0.45 μm of filtering with microporous membrane and get final product.
The particle diameter dynamic light scattering method (DLS) of PEG-PTX micelle measures: experimental light sources is 4.0mWHe-Ne laser, optical maser wavelength 633nm, measures angle 173 °.All measuring tempeature are all 25 DEG C, and retest three times, averages.Experimental result is in table 4.
The particle diameter of table 4PEG-PTX micelle and PDI
| PEG chemical medicine thing | Particle diameter (nm) | PDI |
| PEG-PTX | 53.4±3.4 | 0.170±0.010 |
PEG-PTX self assembly can form micelle in water as shown in Table 4, and its size is 53.4nm, PDI is 0.170.
MCF-7/ADR cell measures the drug resistance multiple of paclitaxel: MCF-7 and MCF-7/ADR cell is inoculated in 96 orifice plates with 4000, every hole respectively, every pore volume 200 μ L.After cell attachment, culture medium replaces with the culture medium containing free drug, continues to cultivate 48h.Then sucking-off culture medium solution, adds 1640 culture medium (not containing serum) of the 200 μ L containing 0.5mg/mL MTT.After 4h, MTT solution is sucked, and the DMSO solution adding 200 μ L dissolves.Then their light absorption values at 490nm place are measured by microplate reader.Each concentration do 5 parallel.Calculate cell proliferation suppression ratio by formula (1), and press the drug resistance multiple that formula (2) calculates medicine.
Experimental result is as shown in Fig. 7, Fig. 8 and table 5:
Table 5 paclitaxel is to the IC of MCF-7 and MCF-7/ADR cell
50value and drug resistance multiple
MCF-7/ADR cell has very strong drug-resistant effect to paclitaxel as shown in Table 5, can be used for the correlational study of multidrug resistance.
PEG-PTX measures the cytotoxic effect of MCF-7 cell the reverse exponential sum of MCF-7/ADR cell: be inoculated in 96 orifice plates by MCF-7/ADR, MCF-7 cell being in exponential phase with the density in 4000/hole, every pore volume 200 μ L, is placed in incubator and cultivates.After cell attachment, culture medium replaces with the culture medium containing PEG-PTX, continues to cultivate 48h.Then sucking-off culture medium solution, adds 1640 culture medium (not containing serum) of the 200 μ L containing 0.5mg/mLMTT.After 4h, MTT solution is sucked, and the DMSO solution adding 200 μ L dissolves.Then their light absorption values at 490nm place are measured by microplate reader.Each concentration do 5 parallel.Calculate cell proliferation suppression ratio by formula (1), and press formula (3) calculating reverse index.
Experimental result is as shown in Fig. 9, Figure 10 and table 6:
Table 6PEG-PTX is to the IC of MCF-7/ADR, MCF-7 cell
50value and reverse index
Table 6 result shows that paclitaxel strengthens to some extent the toxicity of MCF-7/ADR cell after PEGization, and reversing index is 3.33, and have stronger reversing effect, decline to some extent simultaneously to the toxicity of MCF-7 cell, decline multiple is 13.0.
embodiment 3
For PEG-DOX, the mensuration of its building-up process, physicochemical property and the reverse effect to MCF-7/ADR cell thereof are described:
The synthesis of PEG-DOX: get 210mg mPEG-COOH, 58mg doxorubicin hydrochloride, 23mgNHS, 20mgDCC, 12mgTEA, in 10ml anhydrous methylene chloride, react 3d under room temperature lucifuge nitrogen, filter, dialysis, lyophilization and get final product.PEG-DOX's (PEG amycin)
1h NMR spectrogram as shown in figure 11.
The preparation of PEG-DOX micelle and particle size determination thereof: PEG-DOX micelle adopts solid dispersion method preparation.Get the acetonitrile that 1mg PEG-DOX is dissolved in 100 μ L, after naturally volatilizing, be dissolved in 2ml ultra-pure water, vortex 3min, the centrifugal 10min of ultrasonic 5min, 12000r/min, get supernatant with 0.45 μm of filtering with microporous membrane and get final product.
The particle diameter dynamic light scattering method (DLS) of PEG-DOX micelle measures: experimental light sources is 4.0mWHe-Ne laser, optical maser wavelength 633nm, measures angle 173 °.All measuring tempeature are all 25 DEG C, and retest three times, averages.Experimental result is in table 7.
The particle diameter of table 7PEG-DOX micelle and PDI
| PEG chemical medicine thing | Particle diameter (nm) | PDI |
| PEG-DOX | 51.7±2.1 | 0.161±0.006 |
PEG-DOX self assembly can form micelle in water as shown in Table 7, and its size is 51.7, PDI is 0.161.
MCF-7/ADR cell measures the drug resistance multiple of amycin: MCF-7 and MCF-7/ADR cell is inoculated in 96 orifice plates with 4000, every hole respectively, every pore volume 200 μ L.After cell attachment, culture medium replaces with the culture medium containing free drug, continues to cultivate 48h.Then sucking-off culture medium solution, adds 1640 culture medium (not containing serum) of the 200 μ L containing 0.5mg/mL MTT.After 4h, MTT solution is sucked, and the DMSO solution adding 200 μ L dissolves.Then their light absorption values at 490nm place are measured by microplate reader.Each concentration do 5 parallel.Calculate cell proliferation suppression ratio by formula (1), and press the drug resistance multiple that formula (2) calculates medicine.
Experimental result is as shown in Figure 12, Figure 13 and table 8:
Table 8 amycin is to the IC of MCF-7 and MCF-7/ADR cell
50value and drug resistance multiple
MCF-7/ADR cell has very strong drug-resistant effect to Ah mould's rope as shown in Table 8, can be used for the correlational study of multidrug resistance.
PEG-DOX measures the cytotoxic effect of MCF-7 cell the reverse exponential sum of MCF-7/ADR cell: be inoculated in 96 orifice plates by MCF-7/ADR, MCF-7 cell being in exponential phase with the density in 4000/hole, every pore volume 200 μ L, is placed in incubator and cultivates.After cell attachment, culture medium replaces with the culture medium containing PEG-DOX, continues to cultivate 48h.Then sucking-off culture medium solution, adds 1640 culture medium (not containing serum) of the 200 μ L containing 0.5mg/mLMTT.After 4h, MTT solution is sucked, and the DMSO solution adding 200 μ L dissolves.Then their light absorption values at 490nm place are measured by microplate reader.Each concentration do 5 parallel.Calculate cell proliferation suppression ratio by formula (1), and press formula (3) calculating reverse index.
Experimental result is as shown in Figure 14, Figure 15 and table 9:
Table 9PEG-DOX is to the IC of MCF-7/ADR, MCF-7 cell
50value and reverse index
Table 9 result shows that amycin strengthens to some extent the toxicity of MCF-7/ADR cell after PEGization, and reversing index is 2.05, and have stronger reversing effect, decline to some extent simultaneously to the toxicity of MCF-7 cell, decline multiple is 6.4.
In sum, PEGization antitumor drug of the present invention has the effect of obvious reverse multiple drug resistance of tumor.Further its principle is described below: multidrug resistance produces primarily of the mediation of P-gp glycoprotein, and rapamycin, paclitaxel and amycin are all the substrates of P-gp, above-mentioned antitumor drug changes its chemical constitution (becoming prodrug) after PEGization, from instead of the substrate of P-gp, so can reverse multidrug drug resistance.In the same way, those medicines that can produce drug resistance also can reverse multidrug drug resistance after PEGization.
Above specific embodiments of the invention are described.It is to be appreciated that the present invention is not limited to above-mentioned particular implementation, those skilled in the art can make various distortion or amendment within the scope of the claims, and this does not affect flesh and blood of the present invention.
Claims (10)
1. a PEGization antitumor drug, is characterized in that, described PEGization antitumor drug obtains by the PEG of activation being coupled to preparation on antitumor drug.
2. PEGization antitumor drug as claimed in claim 1, it is characterized in that, the number-average molecular weight of described PEG is 0.1K ~ 1000K.
3. PEGization antitumor drug as claimed in claim 1, it is characterized in that, described PEGization antitumor drug can connect target head.
4. PEGization antitumor drug as claimed in claim 3, it is characterized in that, described target head comprises folic acid, biotin, RGD, antibody or aptamer.
5. the purposes of PEGization antitumor drug in the medicine preparing reverse multiple drug resistance of tumor according to any one of Claims 1 to 4.
6. purposes as claimed in claim 5, it is characterized in that, the antitumor drug in described PEGization antitumor drug comprises the antitumor drug of cell toxicant class.
7. purposes as claimed in claim 6, it is characterized in that, the antitumor drug of described cell toxicant class is the medicine acting on the medicine of DNA chemical constitution, the medicine affecting Nucleic acid, the medicine acting on transcribed nucleic acid, topoisomerase enzyme inhibitor or disturb tubulin synthesis.
8. purposes as claimed in claim 5, is characterized in that, described tumor is have one or more in the inherent multidrug-resistant carcinoma of P-glycoprotein overexpression, acquisition multidrug resistance entity tumor, hematological system tumor.
9. purposes as claimed in claim 5, is characterized in that, described PEGization antitumor drug self assembly can be formed micelle, makes invisible nano particle or make active targeting tumor nanoparticle.
10. purposes as claimed in claim 9, it is characterized in that, the particle size range of described micelle, invisible nano particle or active targeting tumor nanoparticle is 1 ~ 200nm.
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| CN115160559A (en) * | 2021-04-02 | 2022-10-11 | 杭州宜生医药科技发展有限公司 | PEG rapamycin compound and preparation method and application thereof |
| CN115160559B (en) * | 2021-04-02 | 2024-02-02 | 杭州宜生医药科技发展有限公司 | PEGylated rapamycin compound and preparation method and application thereof |
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