CN116751338B - Deoxynojirimycin modified double-targeting polymer carrier, double-targeting nano drug delivery system, and preparation method and application thereof - Google Patents
Deoxynojirimycin modified double-targeting polymer carrier, double-targeting nano drug delivery system, and preparation method and application thereof Download PDFInfo
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- CN116751338B CN116751338B CN202310657185.2A CN202310657185A CN116751338B CN 116751338 B CN116751338 B CN 116751338B CN 202310657185 A CN202310657185 A CN 202310657185A CN 116751338 B CN116751338 B CN 116751338B
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- deoxynojirimycin
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Abstract
The invention belongs to the field of targeting carriers and drug delivery systems, and particularly relates to a deoxynojirimycin modified double-targeting polymer carrier, a double-targeting nano drug delivery system, and a preparation method and application thereof. The deoxynojirimycin modified double-targeting polymer carrier is a deoxynojirimycin modified amphiphilic block copolymer, contains targeting groups deoxynojirimycin, hydrophilic groups N- (2-hydroxypropyl) methacrylamide and hydrophobic groups methacrylic acid derivatives, and can form targeting nanoparticles through self-assembly. The double-targeting polymer carrier provided by the invention utilizes deoxynojirimycin on the surface of the nano carrier to identify SGLT1 and OCTN2 which are highly expressed on the top side membrane of intestinal epithelial cells so as to mediate the entry of nanoparticles into cells, has good targeting efficiency, can realize efficient cell uptake, improves the oral absorption of drugs, and has wide application prospects in the field of preparation of targeted oral drugs.
Description
Technical Field
The invention belongs to the field of targeting carriers and drug delivery systems, and particularly relates to a deoxynojirimycin modified double-targeting polymer carrier, a double-targeting nano drug delivery system, and a preparation method and application thereof.
Background
While nano-delivery systems can protect the drug from degradation by gastrointestinal enzymes, they allow for efficient absorption of the drug into the blood circulation and must overcome the mucous barrier and epithelial cell absorption barrier. The mucus layer prevents pathogens and bacteria from entering the gastrointestinal tract, while also preventing nanoparticles from reaching the surface of the intestinal epithelial cell layer. In addition, transepithelial absorption of the barrier is also a key factor affecting drug absorption. After the nano-carrier penetrates through the mucus layer, the nano-carrier needs to have stronger transepithelial cell absorption capacity, so that the acting time of the nano-carrier and the mucus layer can be reduced, the rapid cell uptake of the nano-particles is realized, and the oral bioavailability of the medicine is improved.
At present, targeted modification of an oral nano drug delivery system is an effective strategy for improving the cell entry efficiency of nano drugs. The ligand is modified on the surface of the nano-carrier, so that the ligand can be identified and combined with a specific receptor, the active targeting of the nano-carrier is realized, the transmembrane transport capacity of a nano-drug delivery system is enhanced, and the oral bioavailability of the drug is improved (Journal of Controlled Release,2020, (322) 486-508). Studies have shown that single ligand modified nanocarriers have strong affinity for the receptor, but the targeting depends on the expression level of the receptor and binding to the receptor is easily saturated, resulting in limited oral targeting efficiency (Nano Today,2018, (18) 65-85). The dual-ligand modified nano-carrier can avoid saturation phenomenon of receptor binding by targeting a plurality of receptors, and improve targeting efficiency while overcoming multiple absorption barriers. However, the interaction between ligands of the dual ligand modified nano drug delivery system is common, and the targeting effect of the dual ligand modified nano drug delivery system is influenced. Therefore, the construction of the novel single ligand modified double-targeting nano drug delivery system is expected to overcome the difficult problem of the existing ligand modified drug delivery system while realizing efficient cell uptake, and has important significance.
Research shows that the small molecule ligand has definite structure, good gastrointestinal stability, can modify nano carrier through simple chemical coupling, and can be used for targeting nano drug delivery system. Deoxynojirimycin (1-Deoxynojirimycin, DNJ) is polyhydroxy alkaloid, is natural iminosugar, has good biological safety and no gastrointestinal side effect, belongs to an alpha-1, 4-glucose structural analogue, is expected to simulate the absorption path of glucose, and is taken into cells by utilizing sodium-glucose cotransporter 1 (SGLT 1). In addition, the nitrogen atom on DNJ is a positive group, has structural characteristics similar to that of an organic cation/carnitine transporter 2 (OCTN 2) substrate, and is expected to be introduced into cells through the mediation of the OCTN 2. However, there is currently no report on the construction of ligand-targeted oral nano-drug delivery systems based on DNJ. In addition, both SGLT1 and OCTN2 are present on the apical side of intestinal epithelial cell membranes and are potential targets for drug delivery. Water-soluble N- (2-hydroxypropyl) methacrylamide (HPMA) is a hydrophilic methacrylamide derivative synthesized by a monomer, is used as a drug carrier, has good biocompatibility and safety, contains a plurality of hydroxyl groups on the chain, can be used as an active site for modification of drugs and ligands, and has been introduced into clinical trials (Polym Chem,2017,8 (34): 4983-4987). Meanwhile, researches prove that the hydrophilic HPMA polymer has mucous inertia, can improve mucous permeation capacity of nanoparticles and overcome mucous barriers (Journal of Controlled Release 222,222 (2016) 67-77). However, the current research only uses HPMA as a mucous inert coating material, and has no targeting effect.
Disclosure of Invention
Based on the above problems, the invention aims to provide a deoxynojirimycin modified double-targeting polymer carrier, which creatively uses DNJ as a targeting ligand to be modified on an HPMA amphiphilic polymer to form the double-targeting polymer carrier, wherein the carrier can obtain positively charged nanoparticles through self-assembly. Research shows that the nanoparticle serving as a drug delivery system can efficiently penetrate mucus to reach the surface of an intestinal epithelial cell layer, and targets sodium-glucose cotransporter 1 (SGLT 1) and organic cation/carnitine transporter 2 (OCTN 2) expressed by intestinal epithelial cells, so that efficient cell uptake is realized, and the oral absorption of the drug is improved.
The invention also aims to provide a preparation method of the deoxynojirimycin modified double-targeting polymer carrier, which is suitable for industrial production of the deoxynojirimycin modified double-targeting polymer carrier.
Another object of the present invention is to provide a deoxynojirimycin modified dual targeting nanodelivery system.
The invention also aims to provide application of the deoxynojirimycin modified double-targeting nano drug delivery system.
In order to achieve the above purpose, the invention adopts the following technical scheme:
The deoxynojirimycin modified double-targeting polymer carrier is a deoxynojirimycin modified amphiphilic copolymer, and the structural formula of the deoxynojirimycin modified amphiphilic copolymer is shown as formula I:
Wherein, in the formula I, n is an integer of 1 to 18; the structural unit in the bracket a is an N- (2-hydroxypropyl) methacrylamide unit, and the mol percentage is 50-80 mol%; the structural unit in the brackets is a deoxynojirimycin modified methyl methacrylate unit, and the molar weight percentage is 10-40 mol%; and c, the structural units in brackets are methacrylate units, and the mol percentage is 10-20 mol%.
The deoxynojirimycin modified double-targeting polymer carrier provided by the invention contains targeting groups deoxynojirimycin, hydrophilic groups N- (2-hydroxypropyl) methacrylamide and hydrophobic groups methacrylic acid derivatives, and can form targeting nanoparticles through self-assembly. The inventors have found for the first time that the targeting nanoparticle serving as a nanoparticle with positive charges can efficiently penetrate mucus to reach the surface of intestinal epithelial cell layers although having an adhesion effect on mucus, has good mucus penetrating capacity, can target sodium-glucose cotransporter 1 (SGLT 1) and organic cation/carnitine transporter 2 (OCTN 2) transporters on the top side of intestinal epithelial cell membranes, overcomes absorption barriers, realizes efficient cell uptake and efficient drug delivery, and improves oral absorption of drugs.
Further, the methacrylic acid derivative is a methacrylate ester.
Further preferably, in formula I, the molar percentage of structural units in brackets a is 80mol%; b the molar percentage of structural units in brackets is 10mol%; c the molar percentage of structural units in brackets is 10mol%.
The preparation method of the deoxynojirimycin modified double-targeting polymer carrier comprises the following steps:
(1) Stirring deoxynojirimycin and 2- (bromomethyl) methyl acrylate in an organic solvent under the action of alkali to react to obtain a deoxynojirimycin modified methyl methacrylate monomer which is marked as M-DNJ;
(2) M-DNJ, N- (2-hydroxypropyl) methacrylamide and methacrylate are used as reaction monomers, and polymerization reaction is carried out in a reaction solvent under the action of an initiator, so that the deoxynojirimycin modified double-targeting polymer carrier is obtained and is marked as DNJ-pHPMA-FAs.
According to the preparation method of the deoxynojirimycin modified double-targeting polymer carrier, firstly, M-DNJ is synthesized, the monomer and hydrophilic HPMA are used as hydrophilic chain segments, methacrylate (FAs) is used as hydrophobic chain segments, and DNJ modified amphiphilic HPMA copolymer (DNJ-pHPMA-FAs) is formed through polymerization, so that the synthesis process is mild, the process is simple, and the preparation method is suitable for preparation and application of the double-targeting polymer carrier.
Preferably, in step (1), the organic solvent is one or more of acetonitrile, methanol, ethanol and dimethyl sulfoxide; the alkali is potassium hydroxide or sodium hydroxide; in the step (2), the initiator is azodiisobutyronitrile; the methacrylate is one or more of hexyl methacrylate, dodecyl methacrylate and stearyl methacrylate; the reaction solvent is one or more of N, N-dimethylformamide, dimethyl sulfoxide and methanol.
Preferably, in the step (1), the mol ratio of the deoxynojirimycin to the 2- (bromomethyl) acrylic acid methyl ester is 1: (0.1-5); more preferably, the molar ratio of deoxynojirimycin to methyl 2- (bromomethyl) acrylate is (1-2): 1.
In the step (2), the molar ratio of the N- (2-hydroxypropyl) methacrylamide to the M-DNJ to the methacrylate is (50-80) to (10-40) to (10-20). More preferably, the molar ratio of N- (2-hydroxypropyl) methacrylamide, M-DNJ and methacrylate is 80:10:10.
Preferably, the mass percentages of the initiator, the reaction solvent and the total mass of the three reaction monomers are 2.4%, 85.1% and 12.5%, respectively.
Further preferably, in the step (1), the temperature of the stirring reaction is 10-45 ℃ and the time is 2-8 hours; in the step (2), the temperature of the polymerization reaction is 40-60 ℃ and the time is 12-24 h.
The deoxynojirimycin modified double-targeting nano drug delivery system is obtained by self-assembling the deoxynojirimycin modified double-targeting polymer carrier and the drug to be loaded.
The self-assembled deoxynojirimycin modified double-targeting nano drug delivery system is a nano drug delivery system with a core-shell structure, wherein the nano drug delivery system is hydrophilic outside and hydrophobic inside, has good mucous penetration capability, and can identify SGLT1 and OCTN2 which are highly expressed on the top side of intestinal epithelial cell membranes, so that nano particles are mediated to enter cells, the cellular uptake is enhanced, and the oral absorption of drugs is improved.
The self-assembly process of DNJ-pHPMA-FAs is not particularly limited, and conventional methods in the pharmaceutical field can be adopted. Further, the self-assembly is performed by a film dispersion method, an emulsion solvent volatilization method, a nano precipitation method or a high-pressure homogenization method. Through the self-assembly process, a nano drug delivery system with a core-shell structure and outside hydrophilic and inside hydrophobic is formed.
Further preferably, the self-assembly is performed using a thin film dispersion method; the technological process of the film dispersion method is as follows: and dissolving DNJ-pHPMA-FAs and the drug to be loaded in a solvent, evaporating the solvent to form a film, dispersing the film by adopting deionized water, and detecting and exceeding to obtain the double-targeting nano drug delivery system. DNJ-pHPMA-FAs are used as targeting nano-carriers, and a DNJ modified double-targeting nano-delivery system can be effectively prepared by a film dispersion method.
Preferably, the drug to be loaded is selected from antidiabetic, anticancer, antiinflammatory, antiviral drugs.
More preferably, the solvent used in the film dispersion method is methanol; the mass concentration of DNJ-pHPMA-FAs in the solvent is 1-20 mg/mL; the mass concentration of the drug to be loaded in the solvent is 1-10 mg/mL.
More preferably, the antidiabetic agent is one or more of insulin, exenatide, liraglutide, metformin, nateglinide, miglitol; the anticancer drug is one or more of paclitaxel, docetaxel, doxorubicin, paclitaxel, cisplatin, 5-fluorouracil, hydroxycamptothecin, chang Chunjian, gemcitabine and vinblastine sulfate; the anti-inflammatory drug is one or more of tetracycline, amoxicillin, ampicillin, metronidazole, tinidazole, levofloxacin, gatifloxacin, furazolidone, gentamicin and rifamycin; the antiviral drug is one or more of oseltamivir, lamivudine, zidovudine, emtricitabine, acyclovir, ganciclovir and valacyclovir.
The invention relates to application of a double-targeting nano drug delivery system modified by deoxynojirimycin, in particular to application in preparation of oral drugs for resisting diabetes, cancer, inflammation and virus.
In the application of the deoxynojirimycin modified double-targeting nano drug delivery system in pharmacy, the deoxynojirimycin modified double-targeting nano drug delivery system and pharmaceutically acceptable excipients can be prepared into pharmaceutically acceptable dosage forms such as emulsion, macromolecule solution, drops, powder, tablets, capsules and the like. In addition, the double-targeting nano drug delivery system modified by the deoxynojirimycin can be applied to but not limited to the application of anti-diabetes, anti-cancer, anti-inflammatory, antiviral and the like after being used for encapsulating proper drugs.
Compared with the prior art, the invention has the beneficial effects that:
(1) The deoxynojirimycin modified double-targeting polymer carrier provided by the invention utilizes DNJ on the surface of the nano carrier to identify sodium-glucose cotransporter 1 (SGLT 1) and organic cation/carnitine transporter 2 (OCTN 2) which are highly expressed on the top side membrane of intestinal epithelial cells to mediate the nano particles to enter cells, so that the targeting efficiency is good, and the uptake of the cells is improved. In addition, the small molecular deoxynojirimycin is used as a ligand, the structure is clear, the biological safety is good, and experiments prove that the carrier has the capacity of double targeting intestinal epithelial cell surface receptors, and can effectively improve the uptake of cells.
(2) According to the deoxynojirimycin modified double-targeting nano drug delivery system provided by the invention, the surface of the nano particle obtained after self-assembly is provided with positive charges, so that the residence time of intestinal tracts can be prolonged, and the interaction with intestinal epithelial cells can be improved. And researches show that the positive charge nanoparticle has good mucous penetration capability although having adhesion effect on mucous, can efficiently penetrate mucous to reach the surface of an intestinal epithelial cell layer, and is beneficial to playing a double-targeting effect.
(3) The application of the deoxynojirimycin modified double-targeting nano drug delivery system provided by the invention takes the polymer DNJ-pHPMA-FAs as a targeting nano carrier to encapsulate therapeutic drugs, can be applied to but not limited to the application of anti-diabetes, anti-cancer, anti-inflammatory, antiviral and the like, and has wide application prospect in the preparation field of targeted oral drugs.
Drawings
FIG. 1 is a synthetic route for a dual targeting polymer carrier (DNJ-pHPMA-FAs) of example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of deoxynojirimycin modified methyl methacrylate monomer (M-DNJ) in example 1 of the present invention;
FIG. 3 is an infrared spectrum of deoxynojirimycin modified methyl methacrylate monomer (M-DNJ) in example 1 of the present invention;
FIG. 4 is a nuclear magnetic resonance hydrogen spectrum of a dual targeting polymer carrier (DNJ-pHPMA-FAs) in example 1 of the present invention;
FIG. 5 is a graph of particle size analysis of a dual targeting nanodelivery system (DNJ-PF-PNP nanoparticle) according to example 1 of the present invention;
FIG. 6 is a transmission electron microscope image of a dual targeting nano drug delivery system (DNJ-PF-PNP nanoparticle) according to example 1 of the present invention;
FIG. 7 is a graph showing the cellular uptake of the dual targeting nanodelivery system (DNJ-PF-PNP nanoparticle) of example 1 of the present invention;
FIG. 8 is a graph showing the results of immunofluorescence co-localization analysis of active targeting ability of the dual targeting nanodelivery system (DNJ-PF-PNP nanoparticle) of example 1 according to the present invention;
FIG. 9 is a graph showing the fluorescence intensity statistics of mucus penetration by a dual-targeting nanodelivery system (DNJ-PF-PNP nanoparticle) according to example 1 of the present invention;
FIG. 10 is a graph of blood glucose versus time following insulin administration to diabetic rats using the dual targeting nanodelivery system (DNJ-PF-PNP nanoparticle) of example 1 of the present invention.
Detailed Description
The technical scheme of the present invention is further described below with reference to specific embodiments and drawings, but the scope of the present invention is not limited thereto.
Example 1
The deoxynojirimycin modified double-targeting polymer carrier is a deoxynojirimycin modified amphiphilic copolymer; the amphiphilic copolymer is obtained by polymerizing a hydrophilic chain segment and a hydrophobic chain segment; the hydrophilic chain segment is N- (2-hydroxypropyl) methacrylamide and deoxynojirimycin; the hydrophobic chain segment is methacrylic acid derivative; the methacrylic acid derivative is methacrylate.
The structural formula of the amphiphilic copolymer is shown as formula I:
Wherein, in formula i, n=11; a the structural unit in brackets is an N- (2-hydroxypropyl) methacrylamide unit, and the mole percentage is 80mol%; the structural unit in the brackets is a deoxynojirimycin modified methyl methacrylate unit, and the mol percentage is 10mol%; c the structural units in brackets are methacrylate units, and the molar percentage is 10mol%.
The preparation method of the deoxynojirimycin modified double-targeting polymer carrier comprises the following steps:
(1) Preparation of deoxynojirimycin modified methyl methacrylate monomer: 0.3g of Deoxynojirimycin (DNJ), 0.329g of 2- (bromomethyl) acrylic acid methyl ester and 0.206g of potassium hydroxide are placed in a 50mL round bottom flask, 5mL of acetonitrile is taken as an organic solvent, after the reactants are completely dissolved by oscillation, the mixture is stirred and reacted for 5 hours at the temperature of 40 ℃ in an oil bath, and a crude product obtained after the reaction is purified by adopting a silica gel column chromatography to obtain 0.19g of deoxynojirimycin modified methyl methacrylate monomer which is marked as M-DNJ.
Wherein, the mol ratio of the deoxynojirimycin to the 2- (bromomethyl) acrylic acid methyl ester is 1:1.
(2) The synthetic route diagram of this step is shown in fig. 1, and specifically comprises the following steps: 53mg of M-DNJ, 226mg of N- (2-hydroxypropyl) methacrylamide (HPMA) and 50mg of methacrylate (2-methyl-2-dodecyl acrylate) are taken as reaction monomers, the reaction monomers are placed in an ampoule bottle, 62.67mg of Azodiisobutyronitrile (AIBN) is added as an initiator, 2.35mL of N, N-Dimethylformamide (DMF) is finally added as a reaction solvent, the ampoule bottle is sealed by an alcohol blast lamp in a melting mode, and the reaction is carried out for 24 hours under 50 ℃ in an oil bath under stirring. After the reaction is finished, the DMF as an organic solvent is removed, the product is dissolved by deionized water, dialyzed for 48 hours, and then freeze-dried, so as to obtain 189.2mg of light yellow deoxynojirimycin modified amphiphilic solid polymer, namely the deoxynojirimycin modified double-targeting polymer carrier, which is marked as DNJ-pHPMA-FAs.
Wherein the mol ratio of the (2-hydroxypropyl) methacrylamide to the M-DNJ to the methacrylate is 80:10:10, and the mass percentages of AIBN, DMF and the total mass of the three reaction monomers are 2.4 percent, 85.1 percent and 12.5 percent respectively.
The deoxynojirimycin modified double-targeting nano drug delivery system is obtained by self-assembling the deoxynojirimycin modified double-targeting polymer carrier and the drug to be loaded. The medicine to be loaded is antidiabetic insulin, self-assembly is carried out by adopting a film dispersion method, and the specific preparation process is as follows:
10mg of DNJ-pHPMA-FAs and 10mg of insulin phospholipid complex are dissolved in 5mL of methanol, then the methanol serving as an organic solvent is removed by rotary evaporation at 40 ℃ to form a film, the film is dissolved and dispersed by 2mL of deionized water, and then the film is subjected to probing in an ice-water bath for more than 2 times (150W, working 3s, intermittent 5s and 2 min), so as to obtain self-assembled polymer nanoparticles, namely a double-targeting nano drug delivery system, which is marked as DNJ-PF-PNP nanoparticles.
Example 2
The deoxynojirimycin modified double-targeting polymer carrier is a deoxynojirimycin modified amphiphilic copolymer; the amphiphilic copolymer is obtained by polymerizing a hydrophilic chain segment and a hydrophobic chain segment; the hydrophilic chain segment is N- (2-hydroxypropyl) methacrylamide and deoxynojirimycin; the hydrophobic chain segment is methacrylic acid derivative; the methacrylic acid derivative is methacrylate.
The structural formula of the amphiphilic copolymer is shown as formula I:
Wherein, in formula i, n=11; a the structural unit in brackets is an N- (2-hydroxypropyl) methacrylamide unit, and the molar percentage is 70mol%; the structural unit in the brackets is a deoxynojirimycin modified methyl methacrylate unit, and the molar weight percentage is 20mol%; c the structural units in brackets are methacrylate units, and the molar percentage is 10mol%.
The preparation method of the deoxynojirimycin modified double-targeting polymer carrier comprises the following steps:
(1) Preparation of deoxynojirimycin modified methyl methacrylate monomer: 0.5g of Deoxynojirimycin (DNJ), 0.274g of 2- (bromomethyl) acrylic acid methyl ester and 0.343g of potassium hydroxide are placed in a 50mL round bottom flask, 10mL of acetonitrile is taken as an organic solvent, after the reactant is completely dissolved by oscillation, the mixture is stirred and reacted for 8 hours at the temperature of 40 ℃ in an oil bath, and a crude product obtained after the reaction is purified by adopting a silica gel column chromatography to obtain 0.35g of deoxynojirimycin modified methyl methacrylate monomer which is marked as M-DNJ.
Wherein, the mol ratio of the deoxynojirimycin to the 2- (bromomethyl) acrylic acid methyl ester is 2:1.
(2) The synthetic route diagram of this step is shown in fig. 1, and specifically comprises the following steps: 102.6mg of M-DNJ, 197.0mg of N- (2-hydroxypropyl) methacrylamide (HPMA) and 50mg of methacrylate (2-methyl-2-dodecyl acrylate) are taken as reaction monomers, the reaction monomers are placed in an ampoule bottle, 67.12mg of Azodiisobutyronitrile (AIBN) is added as an initiator, 2.52mL of N, N-Dimethylformamide (DMF) is finally added as a reaction solvent, the ampoule bottle is sealed by an alcohol blast lamp in a melting way, and the reaction is carried out for 24 hours under the condition of 50 ℃ in an oil bath under stirring. After the reaction is finished, removing an organic solvent DMF, dissolving the product with deionized water, dialyzing for 48 hours, and then freeze-drying to obtain 165.6mg of light yellow deoxynojirimycin modified amphiphilic solid polymer, namely the deoxynojirimycin modified double-targeting polymer carrier, which is marked as DNJ-pHPMA-FAs.
Wherein, the mol ratio of N- (2-hydroxypropyl) methacrylamide, M-DNJ and methacrylate is 70:20:10; the mass percentages of AIBN, DMF and the total mass of the three reaction monomers are 2.4%, 85.1% and 12.5% respectively.
The deoxynojirimycin modified double-targeting nano drug delivery system is obtained by self-assembling the deoxynojirimycin modified double-targeting polymer carrier and the drug to be loaded. The medicine to be loaded is antidiabetic insulin, self-assembly is carried out by adopting a film dispersion method, and the specific preparation process is as follows:
20mg of DNJ-pHPMA-FAs12 and 5mg of insulin phospholipid complex are dissolved in 5mL of methanol, then the organic solvent methanol is removed by rotary evaporation at 40 ℃ to form a film, the film is dissolved and dispersed by 2mL of deionized water, and then the film is subjected to probing in an ice-water bath for more than 2 times (150W, working 3s, intermittent 5s and 2 min), so as to obtain self-assembled polymer nanoparticles, namely a double-targeting nano drug delivery system, which is marked as DNJ-PF-PNP.
In other examples, 2-methyl-2-dodecyl acrylate may be replaced with hexyl methacrylate, stearyl methacrylate or the like, which can achieve technical effects equivalent to those of examples 1 and 2.
Test example 1 structural characterization of a double-targeting Polymer Carrier
The results of nuclear magnetic resonance hydrogen spectrum and infrared spectrum analysis of the DNJ modified methyl methacrylate monomer (M-DNJ) prepared in example 1 of the present invention are shown in FIGS. 2 to 3.
The hydrogen spectrum characterization result of fig. 2 is ：1H NMR(400MHz,Methanol-d4)δ6.28(t,J＝1.0Hz,1H),5.86-5.81(m,1H),4.06-3.96(m,2H),3.86(dd,J＝12.4,2.5Hz,1H),3.76(s,3H),3.40-3.30(m,4H),3.14(t,J＝9.1Hz,1H),3.00(dd,J＝11.2,4.8Hz,1H),2.79(d,J＝13.9Hz,1H),2.09(dt,J＝9.4,2.6Hz,1H),1.93(t,J＝10.9Hz,1H)., and the infrared spectrum analysis result of fig. 3 shows that the absorption peak of the compound DNJ at 3344.05cm -1 is a characteristic absorption peak of hydroxyl, and the compound M-DNJ at 3380.54cm -1 and 1718.54cm -1 shows corresponding obvious telescopic peaks which respectively represent the telescopic peaks of hydroxyl and carbonyl. As can be seen from FIG. 2 in combination with FIG. 3, the deoxynojirimycin modified methyl methacrylate monomer M-DNJ is successfully prepared, and has a relative molecular weight of 261 and a structural formula as follows:
further, the polymer DNJ-pHPMA-FAs prepared in example 1 was subjected to nuclear magnetic resonance hydrogen analysis, and the results are shown in FIG. 4.
The characterization result of fig. 4 shows that ：1H NMR(400MHz,DMSO-d6)δ7.18(s,1H),4.69(s,3H),4.63(d,J＝15.2Hz,2H),3.84(s,1H),3.67(s,3H),2.92(s,5H),1.72(s,1H),1.56(s,3H),1.27(q,J＝8.2,5.6Hz,27H),1.17(d,J＝11.0Hz,4H),1.04-0.98(m,16H),0.94(s,3H),0.89-0.83(m,8H),0.83-0.77(m,5H). through nuclear magnetic resonance hydrogen spectrum analysis can prove that the structure of the obtained polymer is identical with the structure shown in the formula I, and the invention successfully synthesizes the double-targeting polymer nano carrier DNJ-pHPMA-FAs. The polymer nanocarriers were tested and their molecular weights and dispersibility indices (PDIs) are shown in table 1:
TABLE 1
| Project | Example 1 |
| Appearance of | Pale yellow powder |
| Molecular weight | 19.6kDa |
| Dispersion Index (PDI) | 1.45 |
Test example 2 particle size, potential and morphology analysis of double-targeting nanodelivery System DNJ-PF-PNP
The dual targeting nano drug delivery system (i.e., DNJ-PF-PNP nanoparticles) prepared in example 1 was subjected to particle size, potential and morphology analysis, and the results are shown in fig. 5 to 6.
As is clear from FIG. 5, the average particle size of DNJ-PF-PNP nanoparticles was 90.02nm, the particle size distribution was uniform, and the Zeta potential was 20.41mV. As can be seen from fig. 6, the nanoparticle of the present invention has a remarkable core-shell structure, and is round-like.
Test example 3 cell uptake assay for double targeting nanodrug delivery systems
Cell uptake assays of the dual targeting nanodelivery system (DNJ-PF-PNP nanoparticle) of example 1 were performed, with specific assays: caco-2 cells were seeded at 2X 10 5 cells/well in 12-well plates with climbing plates and when cultured until the cell density reached about 70%, they were subjected to drug administration. The treatment of administration was performed by washing 3 times with PBS, and then diluting DiD-labeled DNJ-PF-PNP and PF-PNP (control group, not modified with deoxynojirimycin, the same other) with medium, respectively, and incubating with cells for 4 hours. After incubation, cells were fixed with 4% paraformaldehyde solution for 15min, washed 3 times with PBS, stained with DAPI dye for 10min, and washed 3 times with PBS. And placing the climbing sheet on a glass slide, and observing the uptake behavior of the Caco-2 cells on the polymer nanoparticles under a laser confocal microscope. The results of the cell uptake experiments are shown in FIG. 7.
As shown in FIG. 7, DNJ modified DNJ-PF-PNP nanoparticles can significantly improve the uptake capacity of Caco-2 cells compared with non-DNJ modified nanoparticles PF-PNP.
Test example 4 immunofluorescence Co-localization assay of Dual targeting nanodelivery System DNJ-PF-PNP
To further investigate the role of SGLT1 and OCTN2 in DNJ-PF-PNP transmembrane transport, the immunofluorescence co-localization assay of DNJ-PF-PNP nanoparticles of example 1 was performed. The test principle is as follows: after Caco-2 cells are incubated with fluorescent DiD-marked polymer nanoparticles DNJ-PF-PNP, immunofluorescence staining is carried out on SGLT1 and OCTN2 transporters, firstly, whether SGLT1 and OCTN2 exist on the Caco-2 cells is verified, and secondly, the co-localization condition of the polymer nanoparticles and the SGLT1 and OCTN2 is inspected. The specific operation process is as follows: caco-2 cells were seeded at 2X10 5 cells/well in 12-well plates with climbing plates and when cultured until the cell density reached about 70%, they were subjected to drug administration. The cells were incubated with DiD-labeled DNJ-PF-PNP (DiD 1. Mu.g/mL) for 4h by washing with PBS solution 2 times, and the cells were gently washed with PBS solution 3 times. Cell fixation was performed with 4% paraformaldehyde solution, then excess solution was washed off with PBS, the cells were covered with blocking solution, blocked for 15min at room temperature, blocking solution was discarded, diluted primary antibody was directly added, and incubated overnight at refrigerator 4 ℃. Washing with PBS for 3min, adding green Dylight 488-labeled secondary antibody to incubate Caco-2 cells for 2h, washing off excessive dye solution with PBS solution, adding DAPI dye solution to dye nuclei for 10min, and washing cells with PBS solution for 3 times. The slide was placed on a slide with an anti-fluorescence quencher drop, and the co-localization of DNJ-PF-PNP and transporter was observed using a confocal microscope. The results are shown in FIG. 8.
As can be seen from FIG. 8, SGLT1 and OCTN2 are present on Caco-2 cells, the expression level of both are high, and DNJ-PF-PNP red fluorescence and green fluorescence have high overlap, which indicates that the nanoparticle has strong co-localization with SGLT1 and OCTN2, thereby confirming that DNJ-PF-PNP can realize efficient cell uptake through both transporters of SGLT1 and OCTN 2.
Test example 5 mucus penetration test of targeted nanodelivery System DNJ-PF-PNP
Mucus penetration assay of DNJ-PF-PNP nanoparticles of example 1: SD rats fasted and were free to drink. After anesthetizing the rats, they were fixed on the console. The abdominal cavity is dissected, the intestinal section is exposed, the jejunum part is found, and the intestinal section with the length of about 3cm is taken for ligation. DiD-labeled DNJ-PF-PNP and PF-PNP (control, supra) were slowly injected into each ligated intestinal segment, respectively. After each time point of administration, rats were sacrificed, sections of ligature intestine were removed and each injected with 100 μl of Alexa Fluor 488-labeled wheat germ agglutinin solution to dye mucus, then sections of intestine were cut longitudinally, inverted in confocal dishes, and subjected to 3D scanning with a laser confocal microscope. Then semi-quantitative analysis is carried out on fluorescence intensity of the nanoparticles in the deep mucus layer by using Image J software, data processing and analysis are carried out by using GRAPHPAD PRISM 8.0.2 software, and the test result is shown in FIG. 9.
As can be seen from fig. 9, different mucous permeation behaviors are exhibited according to the administration time. Compared with 0.25h, the fluorescence of the nanoparticles at other time points is enhanced, and the fluorescence intensity of the DNJ-PF-PNP group is higher than that of the PF-PNP group which is not modified by deoxynojirimycin, so that the nanoparticles have the capability of penetrating mucus, can overcome the mucus barrier to reach the intestinal epithelial cell layer, and play a double-targeting role.
Test example 6 hypoglycemic Effect test of targeting nanodelivery System DNJ-PF-PNP
This test example carries out the analytical test of the hypoglycemic effect of the DNJ-PF-PNP nanoparticle-loaded insulin of example 1 on diabetic rats: the type i diabetic rat model was induced by single intraperitoneal injection of streptozotocin (Streptozotocin, STZ). Normal SD rats were fasted for 16h and were free to drink water. STZ was dissolved in ice-cold citric acid-sodium citrate buffer (0.1 m, ph 4.5) and formulated as a 1% strength solution, immediately for rapid intraperitoneal injection at a dose of 70mg/kg, depending on rat body weight. The rats were kept with sufficient water and food daily after injection, and after one week the model rats were fasted for 12 hours and blood glucose levels were determined from tail vein blood collection. When the fasting blood glucose value of the rat is higher than 16.7mmol/L, the modeling is considered to be successful, and the rat can be regarded as a diabetic rat for subsequent pharmacodynamics investigation.
Type i diabetic rats were randomly divided into 4 groups of 5 rats each. Rats were fasted prior to the experiment but ensured adequate drinking water. Each test group was operated as follows: (1) DNJ-PF-PNP group: oral gavage administration of DNJ-PF-PNP (100 IU/kg); (2) PF-PNP group: PF-PNP (100 IU/kg) (3) Saline group was administered orally by gavage: oral gavage administration of physiological saline; (4) Free TNS group: oral gavage administration of free insulin solution (100 IU/kg); (5) Insulin solution group: a free insulin solution (5 IU/kg) was injected subcutaneously. Rats were bled by tail vein at 0.5, 1,2, 3, 4, 6, 8, 10 hours before and after dosing, and blood glucose levels at various time points were measured with a glucometer and a blood glucose time profile was drawn. The test results are shown in FIG. 10.
As can be seen from fig. 10, no significant hypoglycemic effect was observed after oral administration of the insulin solution and physiological saline, indicating that insulin was easily degraded by the gastrointestinal tract and the absorption efficiency was too low. After the free insulin is injected subcutaneously, the blood sugar level of the rat is rapidly reduced, so that a strong blood sugar reducing effect is achieved, but the action time is short, and the blood sugar is rapidly increased. Compared with a comparison PF-PNP group, the DNJ-PF-PNP can generate good blood sugar reducing effect after oral gastric lavage administration, can obviously prolong the action time of reducing blood sugar, and maintains blood sugar at a lower level, so that the DNJ-PF-PNP nano-particles have good gastrointestinal stability, can overcome an oral absorption barrier and improve the oral absorption of insulin.
In conclusion, the double-targeting polymer carrier modified by deoxynojirimycin provided by the invention utilizes DNJ on the surface of the nano carrier to identify sodium-glucose cotransporter 1 (SGLT 1) and organic cation/carnitine transporter 2 (OCTN 2) which are highly expressed on the top side membrane of intestinal epithelial cells to mediate the nanoparticle to enter cells, so that the targeting efficiency is good, and the uptake of the cells is improved. In addition, the self-assembled nanoparticle surface has positive charges and an adhesion effect, can increase intestinal residence time, improve interaction with intestinal epithelial cells, can efficiently penetrate mucus to reach the surface of the intestinal epithelial cell layer, plays a double-targeting effect, and has wide application prospect in the preparation field of targeted oral medicines.
Claims (10)
1. The deoxynojirimycin modified double-targeting polymer carrier is characterized in that the deoxynojirimycin modified double-targeting polymer carrier is a deoxynojirimycin modified amphiphilic copolymer, and the structural formula of the deoxynojirimycin modified double-targeting polymer carrier is shown as formula I:
Wherein, in the formula I, n is an integer of 1 to 18; the structural unit in the bracket a is an N- (2-hydroxypropyl) methacrylamide unit, and the mol percentage is 50-80 mol%; the structural unit in the brackets is a deoxynojirimycin modified methyl methacrylate unit, and the molar weight percentage is 10-40 mol%; and c, the structural units in brackets are methacrylate units, and the mol percentage is 10-20 mol%.
2. The deoxynojirimycin modified double-targeting polymer carrier according to claim 1, wherein in formula i, the molar percentage of the structural units in brackets a is 80mol%; b the molar percentage of structural units in brackets is 10mol%; c the molar percentage of structural units in brackets is 10mol%.
3. The method for preparing the deoxynojirimycin modified double-targeting polymer carrier according to claim 1, comprising the following steps:
(1) Stirring deoxynojirimycin and 2- (bromomethyl) methyl acrylate in an organic solvent under the action of alkali to react to obtain a deoxynojirimycin modified methyl methacrylate monomer which is marked as M-DNJ;
(2) M-DNJ, N- (2-hydroxypropyl) methacrylamide and methacrylate are used as reaction monomers, and polymerization reaction is carried out in a reaction solvent under the action of an initiator, so that the deoxynojirimycin modified double-targeting polymer carrier is obtained and is marked as DNJ-pHPMA-FAs.
4. The method for preparing a deoxynojirimycin modified double-targeting polymer carrier according to claim 3, wherein in the step (1), the organic solvent is one or more of acetonitrile, methanol, ethanol and dimethyl sulfoxide; the alkali is potassium hydroxide or sodium hydroxide; in the step (2), the initiator is azodiisobutyronitrile; the methacrylate is one or more of hexyl methacrylate, dodecyl methacrylate and stearyl methacrylate; the reaction solvent is one or more of N, N-dimethylformamide, dimethyl sulfoxide and methanol.
5. The method for preparing a deoxynojirimycin modified double-targeting polymer carrier according to claim 3, wherein in the step (1), the mol ratio of the deoxynojirimycin to the 2- (bromomethyl) acrylic acid methyl ester is 1:0.1-5; in the step (2), the molar ratio of the N- (2-hydroxypropyl) methacrylamide to the M-DNJ to the methacrylate is (50-80) to (10-40) to (10-20); the mass percentages of the initiator, the reaction solvent and the total mass of the three reaction monomers are 2.4%, 85.1% and 12.5% respectively; in the step (1), the temperature of the stirring reaction is 10-45 ℃ and the time is 2-8h; in the step (2), the temperature of the polymerization reaction is 40-60 ℃ and the time is 12-24 h.
6. A deoxynojirimycin modified double-targeting nano drug delivery system, which is characterized in that the deoxynojirimycin modified double-targeting nano drug delivery system is obtained by self-assembling a deoxynojirimycin modified double-targeting polymer carrier according to claim 1 or 2 and a drug to be loaded.
7. The deoxynojirimycin modified dual-targeting nano drug delivery system according to claim 6, wherein the self-assembly is performed by a thin film dispersion method, an emulsifying solvent evaporation method, a nano precipitation method or a high pressure homogenization method.
8. The deoxynojirimycin modified dual targeting nanodelivery system of claim 6 or 7, wherein said self-assembly is performed using a thin film dispersion method; the technological process of the film dispersion method is as follows: dissolving DNJ-pHPMA-FAs and a drug to be loaded in a solvent, evaporating the solvent to form a film, dispersing the film by deionized water, and detecting to obtain a double-targeting nano drug delivery system; the drug to be loaded is selected from antidiabetic, anticancer, anti-inflammatory or antiviral drugs.
9. The deoxynojirimycin modified double-targeting nano drug delivery system according to claim 8, wherein the solvent used in the thin film dispersion method is methanol; the mass concentration of DNJ-pHPMA-FAs in the solvent is 1-20 mg/mL; the mass concentration of the drug to be loaded in the solvent is 1-10 mg/mL; the antidiabetic drug is one or more of insulin, exenatide, liraglutide, metformin, nateglinide and miglitol; the anticancer drug is one or more of paclitaxel, docetaxel, doxorubicin, paclitaxel, cisplatin, 5-fluorouracil, hydroxycamptothecin, chang Chunjian, gemcitabine and vinblastine sulfate; the anti-inflammatory drug is one or more of tetracycline, amoxicillin, ampicillin, metronidazole, tinidazole, levofloxacin, gatifloxacin, furazolidone, gentamicin and rifamycin; the antiviral drug is one or more of oseltamivir, lamivudine, zidovudine, emtricitabine, acyclovir, ganciclovir and valacyclovir.
10. Use of a deoxynojirimycin modified dual targeting nano drug delivery system according to any of claims 6-9 for the preparation of an anti-diabetic, anti-cancer, anti-inflammatory, anti-viral oral drug.
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