CN114917360B - Construction method and application of small-particle-size nano system for co-delivery of small-molecule drug and siRNA - Google Patents
Construction method and application of small-particle-size nano system for co-delivery of small-molecule drug and siRNA Download PDFInfo
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- A61K47/62—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 a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
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Abstract
The invention belongs to the fields of polymer chemistry and biomedical engineering, and discloses a construction method and application of a small-particle-size nano system for co-delivery of small-molecule drugs and siRNA. The polymer can self-assemble under neutral condition, and the small molecular medicine is loaded on micelle cores, siRNA is compounded on subsurface layers, so that the nano medicine with smaller size is obtained, and the pancreatic stellate cells can be effectively and passively targeted. The CXCL12siRNA carried by the carrier can inhibit the expression of CXCL12, further inhibit the recruitment of tumor-related macrophages, myeloid-derived suppressor cells, regulatory T cells and other immunosuppressive cells, and simultaneously increase the infiltration of cytotoxic T cells at tumor sites, and the delivered small molecule drug calcipotriol can inhibit the activation of pancreatic stellate cells, inhibit the compact extracellular matrix generation of pancreatic cancer tissues, improve tumor microenvironment, and further combine PD-1 antibodies to achieve the effect of enhancing the pancreatic cancer immunotherapy effect.
Description
Technical Field
The invention relates to the field of macromolecule chemistry and biomedical engineering, in particular to a construction method and application of a small-particle-size nano system for co-delivery of small-molecule drugs and siRNA.
Technical Field
Currently, drugs for systemic treatment of pancreatic cancer mainly include chemotherapy drugs such as gemcitabine, paclitaxel, irinotecan, fluorouracil, oxaliplatin, and the like, as well as targeting drugs erlotinib and nimotuzumab. However, the special tumor microenvironment of pancreatic cancer limits the exertion of the therapeutic effect of the drug, and also leads to insensitivity of pancreatic cancer patients to treatment and poor prognosis effect.
The tumor microenvironment of pancreatic cancer mainly comprises pancreatic cancer cells and surrounding fibroblasts, immune cells, vascular endothelial cells, extracellular matrix, cytokines and other components. The dense extracellular matrix can form a physical barrier that impedes drug delivery to the tumor site; meanwhile, the aggregation of tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells and other immunosuppressive cells at the tumor site can also suppress the immune response of tumors. Therefore, from the perspective of tumor microenvironment, a new treatment strategy is searched, and the method has very important significance for improving the treatment effect of pancreatic cancer. The pancreatic stellate cells are important components of the tumor microenvironment of the pancreatic cancer, can be activated and proliferated in a large quantity under the stimulation of cytokines, and promote the growth of the pancreatic cancer by secreting extracellular matrixes, cytokines and the like. On the one hand, the extracellular matrix it secretes can form a physical barrier that impedes drug delivery and infiltration of effector T cells; on the other hand, the cytokine secreted by the tumor cell can not only directly act on the tumor cell to promote the proliferation and metastasis of the tumor cell, but also act on immune cells to induce formation of immunosuppressive tumor microenvironment. Therefore, pancreatic stellate cells can be an important target for pancreatic cancer treatment.
Chemokine 12 (CXCL 12), also known as stromal cell derived factor 1 (SDF-1), is a small molecule cytokine belonging to the chemokine protein family. Research reports indicate that chemokine 12 (CXCL 12) is secreted primarily by pancreatic stellate cells during pancreatic cancer progression and is involved in the formation of immunosuppressive tumor microenvironments. CXCL12 promotes tumor growth and metastasis by acting on CXCR4 receptors on the surfaces of tumor cells, T cells, monocytes, vascular endothelial cells, inhibits infiltration of cytotoxic T cells at the tumor site, and recruits inhibitory immune cells, e.g., to the tumor microenvironment, which mediates immunosuppression. Thus, inhibition of CXCL12 signaling pathways can also improve the tumor microenvironment of pancreatic cancer. In recent years, RNA interference technology has been greatly developed, and has a very broad application prospect in the field of treatment of various diseases including tumors due to the high-efficiency gene silencing effect. The RNA interference technology is utilized to down regulate CXCL12 expression of pancreatic stellate cells, so that the recruitment of immunosuppressive cells can be reduced, the aggregation of cytotoxic T cells can be increased, and the effect of improving the pancreatic cancer tumor microenvironment can be achieved. In addition, the research reports that the small molecule medicine calcipotriol reverses the activation of pancreatic stellate cells, and can inhibit CXCL12 secretion while reducing the secretion of extracellular matrix of the pancreatic stellate cells. Therefore, the CXCL12 small interfering RNA and the small molecular medicine calcipotriol are combined to achieve the effect of synergistically improving the pancreatic cancer tumor microenvironment, and the combined immunosuppressant PD-1 can achieve the effect of enhancing the pancreatic cancer immunotherapy.
In recent years, the development of polymer nano-carriers has shown great potential in reducing toxic and side effects of medicines and drug co-delivery, however, the development of the polymer nano-carriers is limited by a dense matrix microenvironment of pancreatic cancer, and the size of a currently reported small molecule and siRNA co-carrier system is about 100nm, so that the small molecule and siRNA co-carrier system cannot effectively penetrate at a tumor part. Therefore, how to enrich the pancreatic cancer tissues and exert the anti-tumor effect by the co-carried siRNA and the small molecule drug is also an important problem to be solved in clinic.
Disclosure of Invention
The invention aims to prepare a polymer carrier co-supported calcipotriol and CXCL12-siRNA small-particle diameter nano-drug, and overcome drug and effect T cell permeation obstruction caused by compact extracellular matrix in pancreatic cancer tumor microenvironment.
It is another object of the present invention to provide a carrier polymer for co-delivery of small molecule drugs with nucleic acid drugs.
Another object of the present invention is to provide a method for preparing the above-mentioned carrier polymer.
The aim of the invention is realized by the following technical scheme:
a carrier polymer for co-delivery of small molecule drugs and siRNA has a structure shown in the following formula (I):
wherein m is 15, k is 10, and p is 20.
The preparation method of the carrier polymer for co-delivery of the small molecule drug and the siRNA comprises the following steps:
s1, synthesizing polyethylene glycol-poly amino acid benzyl ester:
the method comprises the steps of using polyethylene glycol-amino as a macromolecular initiator, firstly initiating polymerization of lysine benzyl ester anhydride, and then adding ring-opening copolymerization of poly-aspartic benzyl ester anhydride and poly-phenylalanine anhydride to obtain polyethylene glycol-poly-amino acid benzyl ester;
s2, ammonolysis of poly-aspartic acid benzyl ester:
ammonolysis of poly (benzyl aspartate) segment in polyethylene glycol-poly (benzyl amino acid) with N, N-diisopropyl ethylenediamine (DIP), and introducing acid sensitive group;
s3, synthesizing a polymer (I):
removing benzyl protecting group of polylysine in the polymer obtained in S2 by using hydrogen bromide to obtain carrier polymer shown in a formula (I).
Preferably, to achieve a small particle size of the polymer carrier, the polyethylene glycol has a molecular weight of 2000Da and a backbone molecular weight of about 14kDa. The reasonable control of polymer molecules can effectively improve the circulation time of the drug carrier polymer in blood and is more beneficial to the permeation of nano-drugs in pancreatic cancer parts.
The molar ratio of the polyethylene glycol-amino group, the lysine benzyl ester anhydride, the polyaspartic acid benzyl ester anhydride and the polyphenyl alanine anhydride in the step S1 is 1:15:10:20.
The molar ratio of the N, N-diisopropyl ethylenediamine to the polyethylene glycol-poly amino acid benzyl ester in the step S1 is 30:1.
the carrier polymer shown in the formula (I) is applied to the co-delivery carrier of small molecule drugs and siRNA.
A medicine for treating pancreatic cancer is prepared by co-carrying small molecule medicine and SiRNA with carrier polymer shown in formula (I).
The polymer shown in the formula (I) has smaller particle size after self-assembly and loading of a small molecule drug and an siRNA drug, and can be effectively enriched in pancreatic cancer.
Compared with the prior art, the invention has the following beneficial effects:
the polyethylene glycol introduced into the polymer has good biocompatibility, can form a hydration layer on the surface of the polymer carrier, effectively shield the adsorption of negatively charged protein in the body to the polymer carrier, and avoid the clearance of a reticuloendothelial system to the nano-drug, thereby improving the stability of the nano-drug in vivo; the positively charged polylysine blocks and the siRNA can form a compound by the compound action of the positively and negatively charged polyelectrolyte, and the siRNA is loaded on the payload; the phenylalanine block provides hydrophobicity and rigidity, which is beneficial to forming nano-micelle with smaller particle size; in addition, grafting N, N-Diisopropylethylenediamine (DIP) onto degradable polyaspartic acid side chains can impart pH-sensitive drug release capability to micelles. The invention provides a carrier polymer capable of jointly conveying a small molecular medicine and a nucleic acid medicine, and the nano medicine obtained after medicine co-loading has smaller size, can be effectively aggregated in pancreatic cancer with compact matrixes and acts on pancreatic stellate cells. The pancreatic stellate cells are used as therapeutic targets, the delivered siRNA can down regulate the expression of cell chemotactic factor 12, and the small molecular medicine calcipotriol can inhibit the activation of the pancreatic stellate cells, so that the synergistic therapeutic effect is achieved.
Drawings
FIG. 1 is a molecular structural formula of carrier polymer PEG-PLL-P (Asp (DIP) -co-Phe);
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of PEG-PLL (z) -P (BLA-co-Phe);
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of PEG-PLL (z) -P (Asp (DIP) -co-Phe;
FIG. 4 shows a nuclear magnetic resonance hydrogen spectrum of PEG-PLL-P (Asp (DIP) -co-Phe)
FIG. 5 shows the capacity of polymer drug loaded micelles to load siRNA in gel blocking experiments;
FIG. 6 is a nano-drug transmission electron microscope image obtained after loading small molecule drug calcipotriol and nucleic acid drug CXCL 12-siRNA.
Detailed Description
The invention is further illustrated in the following description, in conjunction with the accompanying drawings and specific embodiments. These examples are only for illustrating the present invention and are not intended to limit the scope of the present invention. The experimental procedures used in the examples below, without specific reference to conditions, are generally performed under conditions conventional in the art or recommended by the manufacturer. Any insubstantial changes and substitutions made by those skilled in the art in light of the above teachings are intended to be within the scope of the invention as claimed.
Example 1
A novel carrier polymer for co-delivery of nucleic acid and small molecule drug comprises polyethylene glycol, polylysine, polyaspartic acid grafted N, N-diisopropylethylenediamine copolymerized phenylalanine, and has the structure shown as follows:
the polymer is loaded with small molecular drugs and gene drugs and then is nano-sized particles with the particle size of 45+/-6.4 nm.
Synthesis of Polymer (I)
S1, synthesis of polyethylene glycol-poly amino acid benzyl ester (PEG-PLL (z) -P (BLA-co-Phe)):
firstly, using polyethylene glycol-amino as a macromolecular initiator to initiate ring-opening polymerization of benzyl-protected lysine anhydride, and then initiating copolymerization of aspartic acid benzyl ester anhydride and phenylalanine anhydride after the reaction is completed to obtain polyethylene glycol-polyamino acid benzyl ester, wherein the reaction mechanism and process are as follows:
1g of PEG-NH was taken 2 Adding into a reaction bottle, vacuum drying at 80deg.C for 4 hr, dissolving 1.5g lysine anhydride in 2mL anhydrous DMF, adding into the reaction bottle, and cooling to 35deg.CAfter 48h of reaction, a mixed solution of 1g of benzyl aspartate anhydride (BLA-NCA) and 1.6g of phenylalanine anhydride (Phe-NCA) dissolved in 3mL of anhydrous DMF was added, and the reaction was continued at 35℃for 48h. The reaction solution was then precipitated by adding about 400mL of diethyl ether and refrigerated at-20℃for 12h, after returning to room temperature, centrifuged, the precipitate was washed with diethyl ether and dried under vacuum to give polyethylene glycol-poly-amino acid benzyl ester (PEG-PLL (z) -P (BLA-co-Phe)). The nuclear magnetism of the product is shown in figure 2.
S2 Synthesis of PEG-PLL (z) -P (Asp (DIP) -co-Phe:
the poly (benzyl aspartate) segment of the block polymer was ammonolyzed with N, N-Diisopropylethylenediamine (DIP). 1.5g of PEG-PLL (z) -P (BLA-co-Phe) was dissolved in anhydrous DMSO, 3g of DIP (excess) was added, and after reaction at 35℃for 24 hours, the polymer solution was dialyzed against methanol (dialysis against 3.5 kDa) for 2 days, and the methanol was removed by rotary evaporation to give PEG-PLL (z) -P (Asp (DIP) -co-Phe). The nuclear magnetism of the product is shown in figure 3.
S3, synthesizing a polymer (I):
the benzyl protecting group of the polylysine block in PEG-PLL (z) -P (Asp (DIP) -co-Phe) was removed with HBr to give the final product (I). After 1g of PEG-PLL (z) -P (Asp (DIP) -co-Phe) was dissolved in 10mL of trifluoroacetic acid, 3mL of HBr in acetic acid was added under ice-bath conditions, and the ice-bath was removed and stirred for 2h. Subsequently, the reaction solution was precipitated in a large amount of cold diethyl ether, filtered, washed and dried to obtain a crude product. After the crude product is dissolved in water (DMSO may be added to aid dissolution), it is dialyzed in neutral water for 2 days and lyophilized to obtain the final product PEG-PLL-P (Asp (DIP) -co-Phe), i.e., polymer (I). The nuclear magnetism of the product is shown in figure 4.
The reaction mechanism and process of S1 and S2 are as follows:
example 2
The polymer (I) is combined with small molecule drug and siRNA and applied to the treatment of pancreatic cancer.
The siRNA sequences used in the examples are: sense strand 5'CCA GAG CCA ACG UCA AGC AUC UGAA3', antisense strand 5'UUC AGA UGC UUG ACG UUG GCU CUGG3'.
20mg of the polymer (I) prepared in example 1 was dissolved in 2mL of a mixed solution of chloroform and DMSO together with 2mg of calcipotriol, and the solution was subjected to ultrasonic emulsification into 20mL of deionized water, then the chloroform was removed by rotary evaporation, and DMSO was removed by dialysis in water for 2 days, and the solution was concentrated to prepare a drug-loaded polymer micelle solution. The ability to load siRNA was then verified by gel blocking electrophoresis experiments (see fig. 5). Mixing the drug-loaded micelle with the aqueous solution of siRNA according to the N/P ratio of 6, strongly oscillating for 30s, and standing for 30min to obtain the nano drug of the composite siRNA. The size and morphology were characterized by transmission electron microscopy. As shown in FIG. 6, the nano-drug has a spherical structure with a diameter of about 40 nm.
The siRNA can down regulate CXCL12 gene expression, reduce tumor-related macrophages, myeloid-derived suppressor cells, regulatory T cells and other immunosuppressive cells from gathering at tumor sites, and increase the recruitment of cytotoxic T cells; in addition, the co-delivered small molecule drug calcipotriol can inhibit activation of pancreatic stellate cells, reduce secretion of extracellular matrixes, and inhibit expression of CXCL12, so that the effect of synergistically regulating immune microenvironment is achieved, and finally, the immune treatment effect of PD-1 antibodies in pancreatic cancer can be enhanced.
Comparative example 1
The difference from example 1 is that the ratio of acid sensitive PAsp (DIP) and hydrophobic moiety PPhe of drug carrier (I) is different, i.e. k in formula (I) and p are 15, 15 or 20, 10 respectively, and compared with the drug carrying efficiency of the structure in example 1, the obtained nano drug size and small molecular drug acid sensitive release condition are studied with great importance, and more required nano drug is screened.
When the k and p values are 15 and 15 respectively, the size of the obtained final nano-drug is 76+/-8.5 nm; when the k and p values are 20 and 10 respectively, the final nano-drug size is 106+/-12.4 nm. Since the phenylalanine block is reduced, the hydrophobicity of the polymer is correspondingly deteriorated.
Claims (4)
1. The carrier polymer for co-delivery of small molecule drugs and siRNA is characterized by having a structure shown in the following formula (I):
wherein m is 15, k is 10, and p is 20.
2. A process for preparing the carrier polymer of claim 1, comprising the steps of:
s1, synthesizing polyethylene glycol-poly amino acid benzyl ester:
the method comprises the steps of using polyethylene glycol-amino as a macromolecular initiator, firstly initiating polymerization of lysine benzyl ester anhydride, and then adding polyaspartic acid benzyl ester anhydride and polyaniline anhydride for ring-opening copolymerization to obtain polyethylene glycol-polyamino acid benzyl ester;
s2, ammonolysis of poly-aspartic acid benzyl ester:
ammonolysis of poly (benzyl aspartate) segment in polyethylene glycol-poly (benzyl amino acid) with N, N-diisopropyl ethylenediamine, and introducing acid sensitive group;
s3, synthesizing a polymer (I):
removing benzyl protecting group of polylysine in the polymer obtained in S2 by using hydrogen bromide to obtain carrier polymer shown in a formula (I).
3. The use of a carrier polymer of formula (I) according to claim 1 for the preparation of a co-delivery carrier for small molecule drugs and siRNA.
4. A nano-drug for treating pancreatic cancer, which is obtained by co-carrying a small molecule drug and siRNA by a carrier polymer shown in a formula (I) in claim 1;
the small molecule drug is calcipotriol;
the sequence of the siRNA is as follows: sense strand 5'CCA GAG CCA ACG UCA AGC AUC UGAA3', antisense strand 5'UUC AGA UGC UUG ACG UUG GCU CUGG3'.
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