CN108478804B - Polyacrylic acid-S-S-drug copolymer and preparation method thereof - Google Patents
Polyacrylic acid-S-S-drug copolymer and preparation method thereof Download PDFInfo
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- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
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- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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Abstract
The invention discloses a polyacrylic acid-S-S-drug copolymer and a preparation method thereof. Belongs to the fields of polymer chemistry and pharmaceutical preparations. Preparing a drug derivative from the drug and cystamine dihydrochloride; polyacrylic acid and a drug derivative are condensed to form a polyacrylic acid-S-S-drug copolymer which can spontaneously form an amphiphilic polymer micelle in an aqueous solution, a connecting bond is a disulfide bond and can be broken in response at a pathological change part to release a drug, and in addition, the polyacrylic acid can well improve the water solubility of the drug and can be used for preparing a redox sensitive polymer prodrug for improving the solubility of an insoluble drug. The invention also discloses a preparation method of the PAA-S-S-GA copolymer and application of the PAA-S-S-GA copolymer as an anticancer drug carrier.
Description
Technical Field
The invention relates to the field of medicinal preparations and polymer chemistry, in particular to a redox type medicinal preparation capable of effectively improving the water solubility of an insoluble medicament and a preparation method thereof.
Background
In the 70 s of the 20 th century, researchers first proposed the idea of covalently conjugating water-soluble polymers to chemotherapeutic drugs, and since then, with the development of synthesis and polymers, it has become a rapidly developing field, and this conjugate began to enter the clinic in the 90 s of the 20 th century, as poly (L-glutamic acid) -paclitaxel copolymer. Other conjugates are also under development, such as polyethylene glycol-camptothecin, with polyethylene glycol as the carrier. Polyethylene glycol is an FDA approved hydrophilic polymer and has low toxicity and immunogenicity, but it is a fact that even at a tumor site, the polyethylene glycol linker may be difficult to break to release the drug, resulting in a significant decrease in anticancer effect. The tumor microenvironment sensitive drug delivery system which is rapidly developed at present can responsively release drugs, and provides a new strategy for overcoming the obstacles of drug solubility and site-specific delivery of chemotherapeutic drugs.
Gambogic Acid (GA, C)38H44O8) Is one of the main active compounds with anti-tumor effect, and is used as an extract in the Chinese medicinal gamboge for thousands of years. GA has been proved to have an anti-tumor effect in many tumor types, and becomes a hot spot of anti-tumor research of natural products in recent years, and the clinical research of the anti-tumor is limited due to the fact that GA has large toxic and side effects, poor water solubility and low selectivity.
Glutathione (GSH) is a naturally occurring tripeptide in the human body, and the glutathione content in tumor tissues and cells is high, but the glutathione content in normal cells of cancer patients is lower compared with that of healthy people, and because the GSH content in tumor cells often generates drug resistance to chemotherapy, some researchers try to reduce the GSH content in cancer cells by using GSH-consuming drugs such as buthionine-sulfimide (BSO). However, the use of BSO has limited and no specific effects, and the drugs can also lower the GSH content in normal cells, thereby further worsening the side effects caused by radiotherapy and chemotherapy. High-concentration glutathione in tumor parts can reduce disulfide bonds, while low-concentration glutathione in normal tissues and blood vessels can stably exist, and the high-concentration glutathione can be oxidized after the disulfide bonds are reduced, so that the glutathione is consumed.
Polyacrylic acid has good biocompatibility, is nontoxic and harmless, can be modified, and small molecular drug polyacrylic acid polymer selectively enters tumor cells through high permeability, lymphatic return barrier and endocytosis of solid tumor tissues, so that the toxic and side effects of the drug are reduced, and the retention time of the drug at tumor parts is prolonged.
Therefore, it is of practical significance to develop a drug preparation which is sensitive to the pH condition of tumor tissues, enzyme systems and the like to connect chemotherapeutic drugs and water-soluble polymers, so as to ensure the solubility of the drugs in water and release the drugs from conjugates at tumor sites in time.
Disclosure of Invention
The invention aims to provide a high molecular polymer prodrug capable of intelligently responding to release drugs, which is characterized in that polyacrylic acid and indissolvable drugs are connected to a disulfide bond through a covalent bond, so that the water solubility of the indissolvable drugs is improved, and meanwhile, the disulfide bond can be hydrolyzed and broken due to the high content of reduced glutathione in tumor tissues and tumor cells, so that the tumor tissues can be targeted, and the toxic and side effects on normal cells can be reduced.
The technical scheme adopted by the invention is as follows: a polyacrylic acid-S-S-drug copolymer having the structural formula shown in (I):
wherein x is 5 to 10 mol%, y is 90 to 95 mol%, and R is a pharmaceutical compound having a carboxyl group. Preferably, the pharmaceutical compound having a carboxyl group is selected from gambogic acid, rhein, valsartan, methotrexate, exenatide acetate, IDN-6556, AGI-1067, azaserine, chlorophenylalanine, N-acetyl-L-phenylalanine and N-acetyl-L-valine. More preferably, the pharmaceutical compound with carboxyl is gambogic acid.
Preferably, the polyacrylic acid-S-S-drug copolymer has a polyacrylic acid segment with a weight average molecular weight of 50 kDa.
The preparation method of the polyacrylic acid-S-S-drug copolymer comprises the following steps: 1) preparing a drug derivative from the drug and cystamine dihydrochloride; 2) then the polyacrylic acid and the drug derivative are condensed into polyacrylic acid-S-S-drug copolymer.
A preparation method of polyacrylic acid-S-S-gambogic acid copolymer comprises the following steps:
1) dissolving gambogic acid in dichloromethane, stirring to completely dissolve, adding EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) and HOBT (1-hydroxybenzotriazole) under ice bath, stirring at room temperature in a dark place overnight, adding cystamine dihydrochloride into the reaction solution, adding methanol for dissolving assistance, adjusting pH to 7.4 with triethylamine, stirring for 24h, and using NaHCO to obtain a product3Washing with water solution, drying the organic layer with anhydrous sodium sulfate, filtering, removing dichloromethane by rotary evaporation under reduced pressure, and vacuum drying to obtain gambogic acid derivative;
2) dissolving polyacrylic acid (PAA) in DMF, stirring to be completely dissolved, adding EDC and HOBT in ice bath, and stirring overnight in a dark place to obtain a mixed solution A; dissolving the gambogic acid derivative in DMF, dropwise adding the solution into the mixed solution A in ice bath, stirring for 24h, dropwise adding the reacted solution into ice water, collecting the precipitate, dissolving the precipitate with water, dialyzing for two days, and freeze-drying to obtain the polyacrylic acid-S-S-gambogic acid copolymer. Preferably, the weight ratio of the gambogic acid to the polyacrylic acid is (1.2-1.3): 1. The dialysis bag has a molecular weight of 50kDa, and the dialysis medium is distilled water.
The polyacrylic acid-S-S-gambogic acid copolymer has a structural formula shown as (II):
wherein x is 5 to 10 mol% and y is 90 to 95 mol%.
Compared with the prior art, the invention has the following beneficial effects:
the polymer drug copolymer improves the water solubility of the insoluble gambogic acid, is linked by a disulfide bond, has good release response performance, enhances the targeting property of the copolymerization drug, greatly prolongs the retention time of the anticancer drug in tumors, and tests on the critical micelle concentration show that the polymer drug copolymer is easy to form micelles, and cell experiments show that the polymer drug copolymer has good inhibition effect on liver cancer. The polymer drug copolymer has the function of targeted intelligent drug release, the particle size is about 160nm, the accumulation of nano particles at a tumor part is facilitated, and after responsive fracture, the drug is released, and the penetration of the drug is facilitated. The invention designs and develops a polyacrylic acid-S-S-gambogic acid copolymer drug delivery system by adopting a polyacrylic acid polymer targeted drug delivery technology and taking high-concentration glutathione at a tumor part as a target spot, increases the targeted therapeutic effect of gambogic acid, reduces toxic and side effects and further improves the bioavailability.
The polymer-drug copolymer has redox response performance, good water solubility and small toxic and side effects, and the hydrophilic section is polyacrylic acid. In aqueous solution, amphiphilic polymer micelles are formed spontaneously due to the hydrophilic and hydrophobic effects, and the drug can be released at the tumor site in a response manner. The polymer-drug copolymer provided by the invention can be used as an anticancer drug carrier, and can effectively improve the water solubility of insoluble drugs.
Drawings
FIG. 1 shows the particle size and potential variation of the prepared PAA-S-S-GA copolymer at different hydration volumes.
FIG. 2a is a graph of the particle size distribution at the optimal hydration volume for the prepared PAA-S-S-GA.
FIG. 2b is a zeta potential plot at optimal hydration volume for the prepared PAA-S-S-GA.
FIG. 3 is a CMC graph of the prepared PAA-S-S-GA.
FIG. 4 is a DSC chart of the prepared PAA-S-S-GA.
FIG. 5 is a graph showing the variation of drug release of PAA-S-S-GA prepared at different concentrations of glutathione.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
EXAMPLE 1 polyacrylic acid-S-S-gambogic acid copolymer (PAA-S-S-GA)
(I) preparation method
1. Dissolving 1.57g gambogic acid in 50mL dichloromethane, stirring to complete dissolution, adding 620mg EDC and 438mg HOBT under ice bath, stirring overnight at room temperature in a dark place to obtain a bright yellow reaction solution, adding 1.69g cystamine dihydrochloride into the reaction solution, adding 10mL methanol for dissolution assistance, adjusting the pH to 7.4 with triethylamine, stirring for 24h, and adding NaHCO into the obtained reaction solution3After the water solution is washed for three times, the organic layer is added with anhydrous sodium sulfate for drying, filtered, decompressed and evaporated to remove dichloromethane, and dried in vacuum to obtain a yellow oily compound, namely the gambogic acid derivative, which is directly subjected to the next reaction.
m/z:763.3[M+H]+；1H NMR(CDCl3)8.64(s,1H)，6.71(d,1H)，6.58(d,1H)，6.14(t,1H)，5.60(d,1H)，5.3(m,1H)，5.13(m,1H)，4.92(s,2H)，3.48(q,1H)，3.4(m,1H)，3.22(m,1H)，2.95(m,1H)，2.86(m,1H)，2.64(m,1H)，2.35(m,1H)，2.15(br,2H)，2.1(m,1H)，2.01(m,3H)，1.87(s,3H)，1.73(s,6H)，1.61(d,6H)，1.47(s,3H)，1.35(s,3H)，1.3(s,3H)。
2. Dissolving 1.25g polyacrylic acid (M50kDa) in 20ml DMF, stirring to dissolve completely, adding 620mg EDC and 438mg HOBT under ice bath, and stirring overnight in dark to obtain colorless transparent mixed solution A. Dissolving the gambogic acid derivative in 20mL of DMF, dropwise adding the solution into the mixed solution A in ice bath, stirring for 24h, dropwise adding the solution after reaction into a large amount of ice water, collecting the precipitate, dissolving the precipitate with water, dialyzing (the molecular weight of a dialysis bag is 50kDa, and a dialysis medium is distilled water) for two days, removing small molecular drugs and impurities, and freeze-drying to obtain yellow fluffy solid, namely the polyacrylic acid-S-S-gambogic acid copolymer, which is recorded as polyacrylic acid-S-S-PAA.
IR(KBr,cm-1) 3442, 2974, 2926, 2845, 2574, 1716, 1640, 1263, 1172, 1101, 1039, 947, 813; compared with polyacrylic acid alone, other chemical shifts appear in one-dimensional H spectrum1H NMR (DMSO)7.46-7.60(m,2H),6.55(m,1H), 5.57-5.63(m,1H), 5.33(m,1H),5.06(br,2H), can demonstrate the success of the synthesis of polymeric drug linkers.
(II) PAA-S-S-GA hydration volume study
10mg of PAA-S-S-GA is taken out and respectively dispersed in PBS buffer solution with the concentration of 10mmol/L, 15mL, 20mL, 30mL, 40mL and 60mL, and stirred for ten minutes at room temperature to form nano micelle solution, so as to respectively obtain the PAA-S-S-GA with the concentration of 0.67mg/mL, 0.50mg/mL, 0.33mg/mL, 0.25mg/mL and 0.17mg/mL, and the particle size and the zeta potential are compared. As shown in FIG. 1, when the concentration of PAA-S-S-GA is 0.33mg/mL, the particle size distribution is better, the particle size is about 160nm, and the zeta potential absolute value is high, which indicates that the micelle stability and dispersibility are good, and the particle size distribution and zeta potential at the optimal concentration (0.33mg/mL) are shown in FIG. 2a and FIG. 2 b.
(III) PAA-S-S-GA Critical Micelle Concentration (CMC)
The critical micelle concentration of the polymer is detected by a pyrene fluorescence probe method, and an acetone solution of pyrene is prepared, wherein the concentration is 1 × 10-4mg/mL. 10mg of PAA-S-S-GA was transferred to 1Adding 100 mu L of the prepared pyrene solution into centrifuge tubes respectively, drying by using nitrogen, adding 5mL of PAA-S-S-GA polymer solution with different concentrations into each centrifuge tube, wherein the final concentration of pyrene in each centrifuge tube is 2 × 10-6mg/mL. The prepared solution is equilibrated at room temperature for 24h for detection. The detection conditions are as follows: the excitation wavelength is 334nm, the excitation slit is 5nm, the emission wavelength range is 350 nm-500 nm, the emission slit is 5nm, and the scanning speed is 240 nm/min. The concentrations of the PAA-S-S-GA polymer are respectively 0.0005, 0.001, 0.0025, 0.005, 0.01, 0.025, 0.05, 0.1, 0.25 and 0.5mg/mL, the ratio of the peak heights at 373nm and 384nm is taken as an ordinate Y, the logarithm of the concentration of the polymer solution is taken as an abscissa X, the result is plotted as shown in FIG. 3, the concentration at the intersection point of two straight lines in the graph is the CMC value of the polymer, and the CMC of the polymer is inferred to be about 0.01mg/mL, have lower critical micelle concentration and can still maintain certain stability after being diluted by a certain multiple. Thus, the PAA-S-S-GA copolymer has good water solubility and stability.
DSC detection of (tetra) PAA-S-S-GA
DSC detection is carried out on GA, PAA-S-S-GA and the physical mixture of GA and PAA respectively, the temperature range is 25-230 ℃, the result is shown in figure 4, and the curves are GA, PAA, the physical mixture of GA and PAA-S-GA from top to bottom in sequence. As can be seen from FIG. 4, the GA curve shows a large peak at 80 ℃. Similar to the physical mixing curves of PAA and GA. While neither the DSC curves of PAA nor PAA-S-S-GA show large peaks of GA, with less deviation from the straight line. This indicates that GA is oxidized in the PAA-S-S-GA in an amorphous or molecular state, and that free crystalline GA is hardly present.
(V) examination of glutathione sensitivity Release degree of PAA-S-S-GA
1mL of PAA-S-S-GA was taken and transferred into dialysis bags (MWCO, 50kDa) using 10mL of PBS (pH7.4), 0.1% (w/v) SDS and GSH (0mM, 2mM, 10mM, 40mM) as release media at a release time of 48h and a temperature of 37 ℃ while using the GSH-free dialysate group as a control, and 1mL of dialysate was taken at different time intervals for HPLC analysis while supplementing with 1mL of the corresponding fresh buffer to restore the volume. The concentration of the released drug was measured by high performance liquid chromatography, and the results are shown in FIG. 5. As can be seen from FIG. 5, at glutathione concentrations of 0mM and 2mM, the copolymer was hardly broken and the release amount was small, indicating that it could maintain a certain stability at low glutathione concentration, while at glutathione concentrations of 10mM and 40mM, the release was rapid, and about 70% of the release amount could be reached in 10 hours, indicating that it had excellent response performance.
(VI) pharmacodynamic test of PAA-S-S-GA
The prepared PAA-S-S-GA is taken as a test sample, and shows excellent anti-tumor effect shown in the following pharmacodynamic test:
method for determining growth inhibitory activity (GI50) on HepG-2 cells: after trypsinization, tumor cells were dispersed into individual cells and suspended in DMEM medium containing penicillin (25U/mL) and streptomycin (25. mu.g/mL). Cells were seeded in 96-well plates at 37 ℃ with 5% CO2Culturing for 24h under the condition of 100% relative humidity, discarding the culture solution, adding culture solution containing a series of test samples (equivalent to an equal amount of gambogic acid) with each concentration provided with parallel wells, culturing for 24h, discarding the culture solution containing the test samples, adding conventional culture solution, culturing for 48h, discarding the culture solution, replacing with culture solution containing thiazole blue (MTT, product of Sigma company, USA) with a final concentration of 0.5mg/mL, continuously incubating for 4h, adding DMSO for dissolving, completely dissolving the purple crystals for 1h, and detecting the Optical Density (OD) at 570nm/630nm by an SK601 type microplate reader (product of Seikagaku corporation, Japan). Calculating the half growth inhibition rate of the tested sample on the tumor cells according to the following formula:
inhibition rate (T-T)0)/(C-T0)×100％
T represents the OD value of the cells in the test sample group
T0Indicates the OD value of the control plate cells at the time of addition of the test sample
TABLE 1
Table 1 shows the inhibitory effect of PAA-S-S-GA copolymer and gambogic acid on HepG-2 liver cancer cells, and it can be seen from Table 1 that the compound of the present invention (polyacrylic acid-S-S-gambogic acid copolymer) shows excellent targeted antitumor effect and is effective as an antitumor agent for preventing and treating diseases, particularly treating liver cancer.
Claims (7)
1. The polyacrylic acid-S-S-drug copolymer is characterized in that the polyacrylic acid-S-S-drug copolymer is a polyacrylic acid-S-S-gambogic acid copolymer and has a structural formula shown as (II):
wherein x is 5 to 10 mol% and y is 90 to 95 mol%.
2. The polyacrylic acid-S-drug copolymer of claim 1, wherein the polyacrylic acid segment has a weight average molecular weight of 50 kDa.
3. The method of claim 1, comprising the steps of: 1) preparing a drug derivative from the drug and cystamine dihydrochloride; 2) then the polyacrylic acid and the drug derivative are condensed into polyacrylic acid-S-S-drug copolymer.
4. The method for preparing polyacrylic acid-S-S-drug copolymer according to claim 3, comprising the steps of:
1) dissolving gambogic acid in dichloromethane, stirring to dissolve completely, adding EDC and HOBT under ice bath, stirring overnight at room temperature in a dark place, adding cystamine dihydrochloride into the reaction solution, adding methanol for assisting dissolution, regulating p H to 7.4 with triethylamine, stirring for 24h, and adding NaHCO into the obtained product3Washing with water solution, drying the organic layer with anhydrous sodium sulfate, filtering, removing dichloromethane by rotary evaporation under reduced pressure, and vacuum drying to obtain gambogic acid derivative;
2) dissolving polyacrylic acid in DMF, stirring to be completely dissolved, adding EDC and HOBT in ice bath, and stirring overnight in a dark place to obtain a mixed solution A; dissolving the gambogic acid derivative in DMF, dropwise adding the solution into the mixed solution A in ice bath, stirring for 24h, dropwise adding the reacted solution into ice water, collecting the precipitate, dissolving the precipitate with water, dialyzing for two days, and freeze-drying to obtain the polyacrylic acid-S-S-gambogic acid copolymer.
5. The method for preparing a polyacrylic acid-S-S-drug copolymer according to claim 4, wherein the ratio of gambogic acid to polyacrylic acid (1.2-1.3): 1 is calculated by mass.
6. The method of claim 4, wherein in step 2), the molecular weight of the dialysis bag is 50kDa, and the dialysis medium is distilled water.
7. The use of a polyacrylic acid-S-gambogic acid copolymer of claim 1 in the preparation of an anti-tumor pharmaceutical preparation.
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