CN106890336B - siRNA drug carrier polymer, preparation method thereof and application thereof in siRNA targeted delivery - Google Patents
siRNA drug carrier polymer, preparation method thereof and application thereof in siRNA targeted delivery Download PDFInfo
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Abstract
The invention belongs to the field of polymer chemistry and biomedical engineering, and particularly discloses a siRNA drug carrier polymer, a preparation method thereof and application thereof in siRNA targeted delivery. The nano-drug is based on a biocompatible cationic polymer carrier and polyethylene glycol-polyaspartic acid grafted polyethyleneimine (mPEG-PASp- (g-PEI)), and utilizes a surface modified CD36 single-chain antibody to realize the delivery of targeted siRNA of atherosclerotic plaque foam cells, reduce the expression of PAK1 in plaques and reduce the secretion of inflammatory factors at the downstream, thereby reducing the course of atherosclerosis and achieving the purpose of treating atherosclerosis.
Description
Technical Field
The invention relates to the field of polymer chemistry and biomedical engineering, in particular to a drug carrier polymer and application thereof in a targeted siRNA delivery carrier.
Background
Atherosclerosis (AS) can cause diseases such AS myocardial infarction, coronary heart disease, cerebral apoplexy and the like, and is a main cause of death in developed countries. In China, due to the fact that the living standard of people is improved, the relative and absolute incidence rate of the disease is increased due to the generated unhealthy life style, and atherosclerosis and complications thereof are found to jump over the main causes of death of people in China. Prevention, diagnosis and treatment of atherosclerosis are always a matter of intense interest. With the advancement of science and technology and the emphasis of government related department units, significant progress is made in this respect. At present, the conventional treatment mode for atherosclerosis mainly comprises lipid-lowering drugs such as statins and fibrates, and antioxidant drugs such as plant ketones, anthocyanidins and the like. However, these drug therapies have their own disadvantages, and it is difficult to achieve a satisfactory therapeutic effect.
In recent years, with the development of technologies, the RNA interference technology becomes an important novel therapeutic means, and the high-efficiency gene silencing effect thereof shows a very large application prospect. However, due to the delivery problems of siRNA, its clinical application still faces significant challenges. Firstly, due to the large molecular weight of siRNA molecules and negative charges carried by the siRNA molecules, the siRNA molecules are extremely difficult to penetrate through cell membranes to realize endocytosis; secondly, siRNA is very susceptible to nuclease degradation and usually cannot reach the focal site. The above problems have hindered the clinical use of siRNA. Therefore, a stable and efficient siRNA delivery system is the key to realizing RNA interference therapy. In addition, the stability and safety of siRNA delivery systems are also a concern, and the clinical application of conventional delivery systems such as liposomes and viruses is affected due to their insufficient stability and safety, respectively.
Preparation and performance of hyperbranched polyethyleneimine-poly (benzyl aspartate) copolymer are reported in "the chemical academy of higher schools" by Johnson, et al, No.6, 1280-1284. In the article, hyperbranched polyethyleneimine and poly benzyl aspartate copolymer is used as a drug carrier, so that the hyperbranched polyethyleneimine and poly benzyl aspartate copolymer can be well compounded with DNA, and the degradation of enzyme can be avoided.
Disclosure of Invention
The invention aims to solve the problems of poor stability of a gene drug carrier in vivo, short retention time, short circulation time and low probability of combination of a drug and a focus in the prior art, and provides a siRNA drug carrier polymer.
The invention also aims to provide an application of the siRNA drug carrier polymer in siRNA targeted delivery.
Another objective of the invention is to provide an siRNA medicament for treating atherosclerosis.
The purpose of the invention is realized by the following technical scheme:
a siRNA drug carrier polymer has a structure shown in formula (I):
(I)
wherein x is 45, m is 8-12, n is 6-12, and polyethyleneimine is a linear structure.
Polyethylene glycol with good biocompatibility is introduced into the siRNA drug carrier polymer shown in the formula (I), so that the stability of the drug can be improved, the attack of negative charge protein in serum and the like on the drug can be shielded, the circulation time of the carrier polymer in blood can be prolonged, and the targeting probability can be increased; the low molecular weight linear polyethyleneimine loaded gene is selected to greatly reduce the cationic toxicity of the gene and solve the problems of various immunoreactions and the like caused by excessive toxicity when the hyperbranched polyethyleneimine is applied in vivo, however, the low molecular weight linear polyethyleneimine composite gene has weak capability, so that the low molecular weight linear polyethyleneimine loaded gene is innovatively grafted on a degradable polyaspartic acid side chain, the cationic density can be improved, the gene loading capability is improved, and the toxicity of a cationic polymer is further reduced.
Preferably, in the siRNA drug carrier polymer shown in the formula (I), m is 10, and n is 10. The reasonable control of the polymerization degree can effectively improve the circulation time of the drug carrier polymer in blood, and is more favorable for improving the targeting probability.
Preferably, the siRNA drug carrier polymer shown in the formula (I) is a nano-scale particle after loading the gene drug, and the particle size is 129.8 +/-23.9 nm. The nanostructures further improve the biocompatibility of the polymer.
A preparation method of siRNA drug carrier polymer shown in formula (I) comprises the following steps:
s1 synthesis of polyethyleneimine: ring-opening polymerization of 2-ethyl-oxazoline to synthesize poly (2-ethyl-oxazoline) (PEOX); then hydrochloric acid is used for removing the protecting group to obtain Polyethyleneimine (PEI);
s2 synthesis of polyethylene glycol-poly (benzyl aspartate): polyethylene glycol-amino is used as a macroinitiator to initiate ring-opening polymerization of benzyl aspartate (BLA-NCA) to obtain polyethylene glycol-benzyl aspartate;
s3. Synthesis of siRNA drug Carrier: the polyethyleneimine is directly used for ammonolysis of the polyethylene glycol-poly benzyl aspartate to obtain the siRNA drug carrier (mPEG-PASp-g-PEI).
Polyethylene glycol (PEG) with good biocompatibility is introduced into the siRNA drug carrier polymer shown in the formula (I), so that the circulation effect of the carrier in blood can be improved. The polyethyleneimine structure can be well combined with siRNA, and siRNA transmission is realized.
The siRNA drug carrier polymer shown in the formula (I) is used as a targeted siRNA delivery carrier.
Preferably, the polyethyleneimine structure in the siRNA drug carrier polymer shown in the formula (I) is connected with the siRNA drug.
An siRNA medicament for treating atherosclerosis comprises an siRNA medicament carrier polymer shown in a formula (I), siRNA connected with a polyethyleneimine structure in the carrier polymer, and a targeting molecule connected with a polyaspartic acid structure in the carrier polymer.
In the siRNA drug carrier, a polyethyleneimine structure is connected with siRNA, and a polyaspartic acid structure is connected with a targeting molecule. The siRNA can play a role in treating atherosclerosis as a gene drug, and the targeting molecules can guide the drug to gather at the focus of infection, thereby improving targeting property and improving treatment effect.
Preferably, the siRNA is capable of down-regulating the expression of PAK1 gene in atherosclerotic plaques.
Preferably, the sequence of the siRNA is: the sense strand is 5 'GCU UCA GGC ACA GUG UAU ATT 3' and the antisense strand is 5 'UAU ACA CUG UGC CUG AAG CTT 3' respectively.
The siRNA can down-regulate the expression of PAK1 gene in atherosclerotic plaque, the expression of PAK1, the expression of PAK1 gene in foam cells and the expression of downstream inflammatory factors, and has the function of treating atherosclerosis.
Preferably, the targeting molecule is a CD36 antibody. The target of the atherosclerotic plaque foam cells is realized, and the single-chain antibody CD36 is selected to modify the nano-drug, so that the enrichment and the mediated efficient cell uptake of the nano-drug at the plaque position are realized.
Preferably, the targeting molecule is modified on maleimide and then is connected to an siRNA drug carrier. The targeting molecule is connected with the siRNA drug carrier through maleimide, and the maleimide has rich functional groups and is easy to combine with drug molecules.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a drug carrier polymer and is applied to siRNA delivery carriers. The polymer has a polyethylene glycol structure, so that the biocompatibility is increased, the circulation effect of the carrier in blood is enhanced, and the targeting probability of the medicament is increased. Grafting polyethyleneimine onto a degradable aspartic acid side chain improves the cation density, increases the loading capacity of the polymer on genes, and reduces the toxicity of the cation polymer. When the antibody is used, the antibody is connected to the primary amino group of the polymer main chain, and the antibody can be gathered at the corresponding focus, so that the targeting property of the drug is further increased.
Drawings
FIG. 1 is a structural formula of a drug carrier polymer.
FIG. 2 is a diagram of gel blocking electrophoresis to verify the complexing ability of non-target (A) and target (B) polymers to siRNA.
FIG. 3 is a graph of particle size and TEM image of non-target complex (A, C) and targeting complex (B, D) nanoparticles.
Fig. 4 is a cytotoxicity test of non-target (a, C) and targeting (B, D) polymers, complexes: MTT method.
FIG. 5 is a graph of mRNA level (A) and protein level (B, C) to evaluate the interference effect of siRNA complexes.
Detailed Description
The invention is further illustrated by the following figures and examples in conjunction with the description. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention. Experimental procedures, in which specific conditions are not indicated in the examples below, are generally carried out according to conditions conventional in the art or as recommended by the manufacturer. Any insubstantial changes and substitutions made by those skilled in the art based on the present invention are intended to be covered by the claims.
Example 1
An siRNA drug carrier polymer, the structure of which is shown as follows:
（I）
wherein x is 45, m is 8, n is 6, and polyethyleneimine is in a linear structure.
The polymer is nano-scale particles after loading gene medicine, and the particle size is 129.8 +/-23.9 nm.
Synthesis of siRNA drug carrier polymer shown in formula (I)
S1 synthesis of polyethyleneimine: ring-opening polymerization of 2-ethyl-oxazoline to synthesize poly (2-ethyl-oxazoline) (PEOX); then hydrochloric acid is used for removing the protecting group to obtain Polyethyleneimine (PEI);
the linear Polyethyleneimine (PEI) is synthesized by the following reaction mechanism and process:
poly (2-ethyl-oxazoline) (PEOX) was synthesized first. After being dried in vacuum for 2 h at normal temperature, methyl p-toluenesulfonate (2 mmol) is dissolved in 15 mL of freshly distilled acetonitrile, and then 2-ethyl-oxazoline (24 mmol) is added into a reaction bottle, 85○C, refluxing for 72 h; cooling, soaking the reaction bottle in ice water bath, introducing dry ammonia gas (passing through calcium oxide and sodium hydroxide drying tower) for 1 hr to terminate polymerization, removing acetonitrile by rotary evaporation, dissolving with chloroform, precipitating in large amount of diethyl ether, centrifugingDrying to obtain yellowish poly (2-ethyl-oxazoline) (PEOX).
PEOX is deprotected by hydrochloric acid to obtain linear polyethyleneimine. PEOX (2 mmol) was dissolved in 10 mL of hydrochloric acid (10%), 100○C, refluxing and reacting for 12 h, cooling, then enabling the reaction system to become milky white, adjusting the pH value to 12 by using a sodium hydroxide solution, clarifying the solution when the pH value is 5-9, and recovering to be milky white and turbid when the pH value is larger than 9. Centrifuging to take the lower layer precipitate, washing with deionized water for three times, and lyophilizing to obtain light yellow powder, namely, PEI-NH (PEI-NH) with ammonia-terminated base line2）。
S2 synthesis of polyethylene glycol-poly (benzyl aspartate): polyethylene glycol-amino is used as a macroinitiator to initiate ring-opening polymerization of benzyl aspartate (BLA-NCA) to obtain polyethylene glycol-benzyl aspartate;
the synthesis of polyethylene glycol-poly (benzyl aspartate), the reaction mechanism and process are as follows:
PEG-NH2 (0.6 mmol) 70 oc, vacuum drying for 4 hours, cooling, then under the protection of nitrogen, firstly using 20 mL of newly steamed CH2Cl2After dissolution, a solution of benzyloxycarbonyl aspartic anhydride (BLA-NCA) in DMF (6 mmol dissolved in 2 mL of anhydrous DMF) was added thereto, and the mixture was stirred well, whereby a large number of small bubbles were formed at the beginning of the reaction. Sealed reaction flask, 35oThe reaction was heated and stirred in an oil bath of C for 72 h. After the reaction is finished, the precipitate is put into a large amount of cold anhydrous ether (about 500 mL), and is centrifuged and washed with anhydrous ether, and is dried in vacuum to obtain PEG-PBLA-NH2。
S3 synthesis of siRNA drug carrier polymer: and directly aminolyzing polyethylene glycol-poly benzyl aspartate with polyethyleneimine to obtain the siRNA drug carrier polymer.
Drug siRNA carrier polymer (C)mPEG-PAsp-(g-PEI)), the reaction mechanism and process are as follows:
mPEI-PBLA (0.2 mmol) and PEI (10 mmol) were dissolved in 30 mL of anhydrous DMSO, 35oC, after heating and stirring in oil bath for reaction for 48 hours, dialyzing the mixture in deionized water for three days by using a dialysis bag (3.5 kDa) to remove excess PEI, and then freeze-drying to obtain siRNA drug carrier polymer (C)mPEG-PAsp-(g-PEI)）。
Example 2
An siRNA drug carrier polymer, the structure of which is shown as follows:
wherein x is 45, m is 12, n is 12, and polyethyleneimine is in a linear structure.
The synthesis method differs from example 1 in that the reflux reaction time at step S185 ℃ is 130 hours, and the heating and stirring reaction in an oil bath at 35 ℃ in step S2 is 144 hours.
Example 3
An siRNA drug carrier polymer, the structure of which is shown as follows:
wherein x is 45, m is 10, n is 10, and polyethyleneimine is in a linear structure.
The synthesis method differs from example 1 in that the reflux reaction time at step S185 ℃ is 100 hours, and the heating and stirring reaction in an oil bath at 35 ℃ in step S2 is 100 hours.
Example 4
Use of an siRNA carrier polymer in siRNA delivery.
An siRNA medicament for treating atherosclerosis comprises an siRNA medicament carrier polymer, siRNA connected with a polyethyleneimine structure in the carrier polymer, and a targeting molecule connected with a polyaspartic acid structure in the carrier polymer.
The siRNA can down-regulate the expression of PAK1 gene in atherosclerotic plaques.
The siRNA sequence is as follows: the sense strand is 5 'GCU UCA GGC ACA GUG UAU ATT 3' and the antisense strand is 5 'UAU ACA CUG UGC CUG AAG CTT 3' respectively.
The targeting molecule is a CD36 antibody.
The targeting molecule is modified on maleimide and then connected to an siRNA drug carrier.
Taking the polymer prepared in the example 1, connecting maleimide (Mal) on a primary amino group of a main chain to obtain mPEG-PASp- (g-PEI) -Mal, dissolving in water, mixing with an aqueous solution of siRNA in proportion, strongly shaking for 30 s, and standing for 30 min to obtain the compound. Antibody CD36 was attached to the maleimide (MAl) terminus. The ability to load siRNA was then verified by gel block electrophoresis (see figure 2). The morphology of the complex before and after attachment of siRNA was determined by TEM (see FIG. 3).
The survival rate of cells after the polymer and the compound are incubated with Raw264.7 cells is detected by adopting an MTT method, the toxicity of the nanoparticles to the cells is evaluated, and the results are shown in figure 4, wherein the pure nanocomposite and the siRNA-loaded nanocomposite both show extremely small cytotoxicity.
The effect of the nano-polymer loaded anti-PAK1 siRNA on silencing PAK1 gene in oxidized low density lipoprotein (oxLDL) -induced Raw264.7 cells was evaluated at mRNA level and protein level by real-time PCR and Western blot experiments, respectively, as shown in FIG. 5. In real-time PCR experiments, the mRNA expression level of PAK1 was significantly reduced compared to oxLDL-induced group after nanocomposite treatment. Similar results were obtained in the Western blot experiments, and at the same time, the targeting group significantly improved the efficiency of silencing oxidized low density lipoprotein (oxLDL) -induced raw264.7 cell PAK1 gene compared to the non-CD 36 targeting nanocomposite group, i.e., the targeted composite carrying anti-PAK1 siRNA incubated with oxLDL-induced raw264.7 cells significantly reduced the expression of PAK1 gene compared to cells incubated with oxidized low density lipoprotein (oxLDL) -induced group and non-CD 36 targeting nanocomposite group.
Claims (8)
1. An siRNA drug carrier polymer is characterized in that the structure is shown as formula (I):
wherein x is 45, m is 8-12, n is 6-12, and polyethyleneimine is a linear structure;
the siRNA drug carrier polymer is prepared by the following preparation method:
s1, synthesizing polyethyleneimine: ring-opening polymerization of 2-ethyl-oxazoline to synthesize poly (2-ethyl-oxazoline); then hydrochloric acid is used for removing the protecting group to obtain linear polyethyleneimine;
s2, synthesis of polyethylene glycol-poly (benzyl aspartate): polyethylene glycol-amino is used as a macroinitiator to initiate ring-opening polymerization of benzyl aspartate to obtain polyethylene glycol-benzyl polyaspartate;
s3, synthesizing an siRNA drug carrier: directly ammonolyzing polyethylene glycol-poly benzyl aspartate by polyethyleneimine to obtain an siRNA drug carrier;
in the siRNA drug carrier polymer, siRNA is connected with a polyethyleneimine structure, and targeting molecules are connected with a polyaspartic acid structure in the carrier polymer.
2. An siRNA drug carrier polymer according to claim 1 wherein m is 10 and n is 10.
3. The use of the siRNA drug carrier polymer of claim 1 in siRNA targeted delivery.
4. An siRNA drug for treating atherosclerosis, comprising the siRNA drug carrier polymer of claim 1, siRNA linked to polyethyleneimine structure in the carrier polymer, and a targeting molecule linked to polyaspartic acid structure in the carrier polymer.
5. An siRNA drug for treating atherosclerosis according to claim 4, characterized in that said siRNA is capable of down-regulating the expression of PAK1 gene in atherosclerotic plaques.
6. An siRNA medicament for treating atherosclerosis according to claim 4 or 5, characterized in that the sequence of said siRNA is: sense strand 5 'GCU UCA GGC ACA GUG UAU ATT 3', antisense strand 5 'UAU ACA CUG UGC CUG AAG CTT 3'.
7. An siRNA medicament for treating atherosclerosis according to claim 4, characterized in that said targeting molecule is CD36 antibody.
8. An siRNA drug for treating atherosclerosis according to claim 4 or 7, characterized in that said targeting molecule is modified on maleimide and then linked to an siRNA drug carrier.
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