CN115417889A - L-4-dihydroxyborophenylalanine-N-carboxylic acid internal anhydride monomer and polyamino acid as well as preparation method and application thereof - Google Patents
L-4-dihydroxyborophenylalanine-N-carboxylic acid internal anhydride monomer and polyamino acid as well as preparation method and application thereof Download PDFInfo
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- CN115417889A CN115417889A CN202210679578.9A CN202210679578A CN115417889A CN 115417889 A CN115417889 A CN 115417889A CN 202210679578 A CN202210679578 A CN 202210679578A CN 115417889 A CN115417889 A CN 115417889A
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- polyethylene glycol
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Abstract
The invention discloses an L-4-dihydroxy borophenylalanine-N-carboxylic acid internal anhydride monomer and polyamino acid, a preparation method and application thereof, constructs a polypeptide nano material with biological responsiveness and good biocompatibility, and particularly relates to L-4-dihydroxy borophenylalanineN-the synthesis of carboxyanhydrides, and the use of a range of polymers prepared by their ring-opening polymerization and for drug delivery. The polymer disclosed by the invention has excellent biocompatibility, can be used for preparing (tumor targeting) polymer micelles, and can be used for preparingThe loading and delivery device is suitable for high-efficiency loading and delivery of hydrophilic and hydrophobic chemical drugs, cis-1,2 or 1,3-diol drugs, polypeptide drugs, protein drugs, nucleic acid drugs and the like.
Description
Technical Field
The invention constructs a polypeptide nano material with biological responsiveness and good biocompatibility, and particularly relates to L-4-dihydroxy borophenylalanineN-the synthesis of carboxyanhydrides, and the use of a range of polymers prepared by their ring-opening polymerization and for drug delivery.
Background
Due to the unique characteristics of secondary structure, biocompatibility and the like, the polypeptide is widely applied to the fields of drug delivery, tissue engineering and the like. However, the existing polypeptide materials usually have the problems of insufficient functionality, complicated and fussy introduction of functional groups, harsh preparation conditions and the like. In addition, although the nano-drug based on polypeptide can improve the solubility and pharmacokinetics of the drug to a certain extent, reduce the toxicity to normal cells and widen the therapeutic window, the nano-drug still has the limitations of poor stability, uncontrollable drug release (namely, premature drug release during circulation and slow drug release at tumor sites) and the like. Therefore, it is a hot spot of research to construct a polypeptide nano-drug carrier with good biocompatibility and biological responsiveness (reduction responsiveness, pH responsiveness, ROS responsiveness, enzyme responsiveness, etc.) release.
Disclosure of Invention
The invention designs and synthesizes L-4-dihydroxy borophenylalanineN-carboxylactam monomer and initiation of L-4-dihydroxyboranophenylalanine with polyethylene glycolNCarboxylic anhydride monomers or/and other typesNRing opening polymerization of carboxyanhydride monomers produces a series of block copolymers that can self-assemble to form polymeric micelles for drug delivery.
In order to achieve the purpose, the invention adopts the technical scheme that: l-4-dihydroxyboranophenylalanine with structure of formula IN-carboxyanhydrides:
a linear block copolymer having the structure of formula II:
wherein R is 1 From the initiator polyethylene glycol, for its terminal functional group, preferably
，
，
，
Or
Etc.; r is 2 From other types of amino acids, preferably different types of amino acids are L-tyrosine,N ε -Boc-L-lysine,β-benzyl-L-aspartic acid; m is 70 to 210, x is 5 to 30, y is 0 to 15, and n is 5 to 45.
In the linear block copolymer with the structure shown in formula II, when y is 0, the linear block copolymer is L-4-dihydroxy borophenylalanine initiated by linear polyethylene glycolN-carboxylactam ring-opening polymerization to form polyethylene glycol-poly (L-4-dihydroxyborophenylalanine) copolymer; when y is not 0, the L-4-dihydroxyborophenylalanine is initiated by linear polyethylene glycolNCarboxylic anhydrides and other typesN-carboxyanhydride ring-opening polymerization to form polyethylene glycol-poly (L-4-dihydroxyborophenylalanine) -poly other types of amino acid copolymers; other types of amino acids refer to amino acids other than poly (L-4-dihydroxyborophenylalanine), such as L-tyrosine,N ε -Boc-L-lysine,β-benzyl-L-aspartic acid and the like.
In the present invention, and when y is 0, the polyethylene glycol-poly (L-4-dihydroxy borophenylalanine) copolymer is shown as formula III:
wherein R is 3 From the initiator polyethylene glycol, for its terminal functional groups, preferably
，
，
，
Or
Etc.; m is 70 to 210, n is 5 to 70; preferably, m is 90 to 150 and n is 10 to 30.
A branched block copolymer having the structure of formula iv:
wherein m is 20 to 150, n is 2 to 20, and x is 2 to 8; preferably m is 50 to 120, n is 4 to 8,x is 4 or 8; r 4 For the branching center of the initiator branched polyethylene glycol, four-arm or eight-arm polyethylene glycol ammonia is preferably used as the initiator in the invention.
The invention discloses the L-4-dihydroxyboranophenylalanine-NA process for the preparation of carboxyanhydrides from L-4-dihydroxyborophenylalanine,αReacting-pinene and triphosgene serving as reactants in anhydrous tetrahydrofuran to prepare the L-4-dihydroxy boron phenylalanineAcid-dopedN-carboxyanhydrides. The specific reaction process is as follows: mixing L-4-dihydroxy borophenylalanine with ammonia under nitrogen protectionαAdding pinene into anhydrous tetrahydrofuran solution, dropping triphosgene solution in tetrahydrofuran solution, reaction at 50-60 deg.c for 3-7 hr, filtering out the reactant, concentrating the reaction liquid and precipitating in petroleum ether to obtain coarse product. The crude product is re-dissolved in tetrahydrofuran, re-precipitated and repeatedly carried out for 2 to 3 times to obtain the final white powder solid, namely the L-4-dihydroxy boron phenylalanine-NCarboxylic anhydrides (BPA-NCA).
In the technical scheme, L-4-dihydroxy boron phenylalanine,α-pinene and triphosgene in a molar ratio of 2:4 to 6:1 to 2, preferably 2:5:1.
the invention uses linear polyethylene glycol as an initiator and L-4-dihydroxy boron phenylalanineNThe carboxylic anhydride being a monomer, or L-4-dihydroxyborophenylalanineNCarboxylic anhydrides and other typesNAnd (3) taking carboxyl internal anhydride as a monomer, and carrying out ring-opening polymerization to obtain a linear block copolymer. Using branched polyethylene glycol as initiator, L-4-dihydroxy boron phenylalanineNAnd (3) taking carboxyl internal anhydride as a monomer, and carrying out ring-opening polymerization to obtain a branched block copolymer.
Preparation of the above-mentioned linear or branched block copolymers in organic solvents such asN, NDimethylformamide (DMF), dichloromethane (DCM), trichloromethane, tetrahydrofuran (THF), the preferred embodiment of the inventionN, N-Dimethylformamide (DMF) as solvent; the temperature of ring-opening polymerization is 30-90 ℃, and the preferable polymerization temperature of the invention is 80 ℃; the polymerization reaction time is 1 to 5 days, and the preferable reaction time in the invention is 3 days.
The invention discloses a targeting block copolymer, which is obtained by coupling a linear block copolymer with a structure shown in a formula II with a targeting molecule, or coupling a branched block copolymer with a structure shown in a formula IV with the targeting molecule. In the block polymer, the PEG terminal or the amino acid terminal can be chemically coupled with specific targeting molecules, including short peptides (ApoE, angiopep-2, cRGD, cNGQ and the like), small molecule targeting molecules (glucose, folic acid and the like), antibodies, antibody fragments and the like.
The invention further discloses an application of the block copolymer, especially an application of self-assembly of amphiphilic polymer polyethylene glycol-poly (L-4-dihydroxy borophenylalanine) into nano micelle in drug delivery; the medicine is hydrophilic and hydrophobic chemical medicine, cis-1,2 or 1,3-diol medicine, polypeptide medicine, protein medicine or nucleic acid medicine, preferably, the medicine is curcumin (Cur) and/or sorafenib tosylate (Sor). In particular to the application of the block copolymer, especially the amphiphilic polymer polyethylene glycol-poly (L-4-dihydroxy boron phenylalanine), in the preparation of a drug carrier. Because the polymer has proper hydrophilic-hydrophobic proportion, a series of polymer micelles with controllable sizes can be prepared by a solvent displacement method, and particularly, the polymer micelles are prepared by the solvent displacement method, namely, the block copolymer is dissolved in dimethyl sulfoxide (DMSO) or DMSON, NAnd (3) obtaining a polymer solution in Dimethylformamide (DMF), dropwise adding the polymer solution into buffer solutions such as HEPES or PB, and finally dialyzing by using a dialysis bag with the cut-off Molecular Weight (MWCO) of 7000 to remove the organic solvent to obtain the polymer micelle with the particle size of 18-200 nm. The invention can prepare the specific targeting polymer micelle by adjusting the proportion of the targeting block copolymer and the non-targeting block copolymer. In addition, a targeting molecule can be introduced to the surface of the prepared non-targeting polymer micelle in a post-modification mode, for example, short peptides (ApoE, angiopep-2, cRGD, cNGQ and the like), small molecule targeting molecules (glucose, folic acid and the like), antibodies, antibody fragments and the like are introduced to the PEG end of the micelle.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
prepared by the inventionα-amino acids-NThe carboxyl internal anhydride is a novel internal anhydride monomer, can obtain polypeptide with controllable performance through ring-opening polymerization, and compared with other polyamino acid, the polyamino acid has more excellent biological responsiveness and wider applicability.
The invention utilizes the polyethylene glycol ammonia as an initiator to obtain the polymer with controllable molecular weight and narrow molecular weight distribution through ring-opening polymerization, thereby greatly widening the variety of amphiphilic polypeptide.
The polymer disclosed by the invention has excellent biocompatibility, can be used for preparing (tumor-targeted) polymer micelles, and is suitable for efficient loading and delivery of hydrophilic and hydrophobic chemical drugs, drugs containing cis-1,2 or 1,3-diol, polypeptide drugs, protein drugs, nucleic acid drugs and the like.
The L-4-dihydroxy borophenylalanine rich in boron-10 is an important boron carrier for boron neutron capture treatment, the synthesis process disclosed by the invention is also suitable for synthesis of the polypeptide rich in boron-10, the obtained polypeptide is also suitable for the preparation process of the micelle, the application range of the L-4-dihydroxy borophenylalanine can be widened, and the L-4-dihydroxy borophenylalanine is expected to be used as a novel boron carrier for boron neutron capture treatment.
The preparation method is simple, and the raw materials are widely available, so that the method has a good application prospect.
Drawings
FIG. 1 is a reaction scheme of example two, example three, and example four.
FIG. 2 shows the nuclear magnetic hydrogen spectrum (A) and nuclear magnetic carbon spectrum (B) of BPA-NCA in example one and PEG in example two 5k -PBPA 4k Infrared monitor during Synthesis (C) and PEG 5k -PBPA 4k Nuclear magnetic hydrogen spectrum (D).
FIG. 3 is PEG of example III 5k -P(Tyr 1k -BPA 4k ) Nuclear magnetic hydrogen spectrum (A) of (D), PEG 5k -P(BLA 1k -BPA 4k ) Nuclear magnetic hydrogen spectrum (B) of (A), PEG 5k -P(Lys 1k -BPA 4k ) Nuclear magnetic hydrogen spectrum (C) of (A) and 4-arm-PEG 20k -PBPA 3k Nuclear magnetic hydrogen spectrum (D).
FIG. 4 shows ApoE-PEG of example four 5k -PBPA 4k Nuclear magnetic hydrogen spectrum (A), 4-arm-PEG 20k -PBPA 1.5k -nuclear magnetic hydrogen spectrum (B) of Glucose.
FIG. 5 is the particle size distribution (in-line TEM image) of the drug Cur and Sor encapsulated micelles formed by self-assembly of the polymer PEG-PBPA in the fifth example (A), dilution, serum and long-term storage stability (B) and in vitro responsiveness (C) and in vitro release (D).
FIG. 6 is a graph showing the cytotoxicity results of the six hollow polymer micelles on L929 mouse fibroblasts, U87 MG-luc human brain glioma cells and B16F10 mouse melanoma cells (A), the toxicity of free Cur and Sor and single drug-loaded micelles PBN-Cur and PBN-Sor on U87 MG-luc cells (B), the cytotoxicity of polymer micelle-loaded curcumin and sorafenib tosylate on U87 MG-luc mouse melanoma cells (C) and the long-term inhibition effect of cells (D).
FIG. 7 shows the hemolysis test (A) and the hemolysis ratio (B) of erythrocytes treated with Cur, sor, PBN-Cur, PBN-Sor, PBN-Cur/Sor (low) and PBN-Cur/Sor (high).
FIG. 8 is the cell cycle arrest (B) of Cur, sor, PBN-Cur, PBN-Sor, and PBN-Cur/Sor (Cur: 1.5. Mu.g/mL, sor: 1.5. Mu.g/mL) treated U87 MG-luc cells with apoptosis (A) and U87 MG-luc cells treated with Cur and PBN-Cur (Cur: 1.5. Mu.g/mL).
FIG. 9 is boron-10 rich 10 BPA-NCA (A) and mPEG-P 10 BPA NMR spectrum (B).
Detailed Description
The invention discloses L-4-dihydroxy boron phenylalanine for the first timeNThe carboxyl internal anhydride is complexed with cis-1,2 or 1,3-dihydroxy compounds, monosaccharides, polysaccharides, nucleic acids and the like to form reversible five-membered or six-membered ring lactone or boron nitrogen coordination effect for combination, so that carriers such as nano drugs or hydrogel are constructed, stable and efficient entrapment of various drugs can be realized, the formed boric acid ester bond and boron nitrogen coordination effect are dynamic effects, the entrapped drugs can be dissociated and released under certain conditions (such as ROS and low pH), and the carboxyl internal anhydride can also have high-expression sialic acid effect on the surface of tumor cells. Therefore, the invention is used in the fields of biosensing, drug delivery and the like.
The above-mentioned L-4-dihydroxyborophenylalanine-NThe scheme for the preparation of carboxyanhydrides (BPA-NCA) can be represented as follows:
the invention also discloses the method for initiating the L-4-dihydroxy boron phenylalanine-containing agent by using linear or branched polyethylene glycol as an initiatorNA block copolymer (polyethylene glycol-poly (L-4-dihydroxyborane) copolymer) prepared by ring-opening polymerization of carboxyl internal anhydride monomer, wherein the molecular weight of the polyethylene glycol is 2000-40000, and the molecular weight of the poly (L-4-dihydroxyborane) is 1000-50000.
The linear block copolymer is initiated with the L-4-dihydroxyboranophenylalanine-NThe carboxyl internal anhydride monomer is prepared by ring-opening polymerization, and the chemical structural formula is shown as follows:
wherein m is 70 to 210, n is 5 to 70; preferably m is 90 to 150, n is 10 to 30; r 3 For the terminal functional group of the polyethylene glycol initiator, the invention preferably selects the polyethylene glycol amine initiator, and the molecular formula is as follows:
wherein R is 3 Preferably, it is
，
，
，
Or
And the like.
The branched polymer is obtained by initiating the L-4-dihydroxy boron phenylalanine-NThe carboxyl internal anhydride monomer is prepared by ring-opening polymerization, and the chemical structural formula is as follows:
wherein m is 20 to 150, n is 2 to 20, and x is 2 to 8; preferably m is 50 to 120, n is 4 to 8,x is 4 or 8; r 2 For the branching center of the branched polyethylene glycol initiator, the prior four-arm or eight-arm polyethylene glycol ammonia is preferably used as the initiator in the invention.
Four-arm polyethylene glycol ammonia:
eight-arm polyethylene glycol ammonia:
the invention also discloses the method for initiating the L-4-dihydroxy boron phenylalanine-NCarboxylic anhydride monomers and other typesNBlock copolymers prepared by random copolymerization of carboxyanhydride monomers, where the molecular weight of the polyethylene glycol is 2000 to 20000, poly (amino acid-co-L-4-dihydroxyboranophenylalanine) having a molecular weight of 1000 to 50000, amino acids here referring to other typesN-products obtained by polymerization of carboxylic anhydride monomers. The L-4-dihydroxy boron phenylalanine-initiated by using linear polyethylene glycol as initiatorNCarboxylic anhydride monomers and other typesN-carboxyl anhydride monomer is randomly copolymerized to prepare a block copolymer, and the chemical structural formula is as follows:
wherein m is 70 to 210, x is 5 to 30,y is 0 to 15, n is 5 to 45; r 1 For the terminal functional group of the polyethylene glycol initiator, preference is given according to the inventionα-methoxy-ω-amino-polyethylene glycol andαmaleimide-ω-amino-polyethylene glycol as initiator; r 2 The amino acids are of different types and are, L-tyrosine is preferably used in the invention,N ε -Boc-L-lysine,β-benzyl-L-aspartic acid.
The above polymers are prepared in organic solvents such asN, NDimethylformamide (DMF), dichloromethane (DCM), trichloromethane, tetrahydrofuran (THF), the preferred method of the inventionN, N-Dimethylformamide (DMF) as solvent; the temperature of ring-opening polymerization is 30-90 ℃, and the preferable polymerization temperature of the invention is 80 ℃; the polymerization reaction time is 1 to 5 days, and the preferable reaction time in the invention is 3 days.
Referring to FIG. 1, the raw materials used in the present invention are commercially available products, and the specific preparation method and testing method are conventional techniques, and the present invention will be further described with reference to the accompanying drawings and examples:
example L-4-Dihydroxyborophenylalanine-NSynthesis of-Carboxylic anhydrides (BPA-NCA)
Under a nitrogen atmosphere, L-4-dihydroxyboranophenylalanine (500 mg,2.39 mmol) andα-pinene (948 μ L,5.97 mmol) is added into a dried three-necked round bottom flask, then anhydrous tetrahydrofuran (THF, 150 mL) is added, then triphosgene THF solution is dripped into the suspension, the reaction system is placed in an oil bath at 55 ℃ and stirred uniformly, after 5 hours of reaction, the reaction liquid is naturally cooled to room temperature, filtered by a sand core funnel, and then the clear supernatant reaction liquid is concentrated to 10 mL by rotary evaporation, and then precipitated in precooled petroleum ether to obtain a crude product; then the crude product is dissolved in tetrahydrofuran again, and then the precipitation is carried out again for 3 times to obtain white powder solid, namely L-4-dihydroxy boron phenylalanine-NCarboxyanhydride monomer (BPA-NCA, yield: 60%). The nuclear magnetic characterization of BPA-NCA is shown in figure 2, 1 H NMR (400 MHz, DMSO-d 6 , δ): 9.09 (s, 1H, -CONH-), 8.03 (s, 2H, -B(OH) 2 ), 7.71 and 7.14 (d, J = 7.6 Hz, 4H, -C 6 H 4 -), 4.79 (t, J = 5.2 Hz, 1H, -COCHNH-), 3.03 (d, J = 5.2 Hz, 2H, -C 6 H 4 CH 2 -); 13 C NMR (100 MHz, DMSO-d 6 , δ) 171.27, 152.09, 137.05, 134.67, 133.31, 129.19, 58.62, 36.81 the elemental analysis of BPA-NCA is C, 53.19, H, 4.85, N, 5.53 (theory: C, 51.11; H, 4.29; N, 5.96); mass Spectrometry MS (m/z): 235.1 (theory: 235.1).
EXAMPLES preparation of diblock copolymer PEG-PBPA
The invention uses polyethylene glycol with amino at the tail end as an initiator to initiate L-4-dihydroxy boron phenylalanine-NRing-opening polymerization of carboxyanhydrides by adjusting the reaction of polyethylene glycol with L-4-dihydroxyboranophenylalanineNThe molar ratio of the carboxylic anhydrides allows the preparation of the polymer PEG-PBPA (Table 1) with different chain lengths. To synthesize PEG-PBPA (B)M n = 5.0-4.0 kg/mol) as an example: under the nitrogen atmosphere, PEG-NH 2 Adding (0.25 g, 0.05 mmol) DMF solution into a closed reactor, adding BPA-NCA (0.25 g,1.06 mmol) DMF solution into the closed reactor under the condition of stirring, and reacting for 3 days in a constant temperature oil bath at 80 ℃ (carbonyl stretching peak 1770 cm of corresponding BPA-NCA monomer in an infrared spectrogram -1 And 1845 cm -1 Complete disappearance, indicating complete polymerization). After the reaction was completed, the polymer solution was precipitated with ice in anhydrous ether, centrifuged, then redissolved with methanol, the precipitation was repeated 3 times, the solid precipitate was collected and vacuum-dried for 48 hours to obtain a white solid product, yield: 81 percent. The nuclear magnetic characterization of the PEG-PBPA block copolymer is shown in figure 2. 1 H NMR (DMSO-d 6 /CD 3 OD (v/v = 2/1), 400 MHz, δ): 7.68 and 7.22 (-C 6 H 4 B(OH) 2 ), 4.49 (-COCHNH-), 3.51 (-OCH 2 CH 2 O-), 2.96-2.78 (-C 6 H 4 CH 2 -)。
Similarly, with 4/8 arm PEG-NH 2 For the initiator synthesis of bases BBranched polymers of PA. For example, a four-armed PEG-NH dissolved in anhydrous DMF 2 (1.32 g,0.066 mmol) was added to a BPA-NCA (0.250 g,1.06 mmol) solution under a nitrogen atmosphere, and the reaction was carried out at 80 ℃ for 24 hours. After the reaction is finished, the polymer solution is precipitated by ice anhydrous ether, centrifuged, then re-dissolved by methanol, the precipitation is repeated for 3 times, the solid precipitate is collected and dried in vacuum for 48 hours to obtain 4-arm-PEG-PBPA (A), (B), (C)M n = 20.0-3.0 kg/mol). 1 H NMR (400 MHz, DMSO-d 6 /CD 3 OD(v/v = 2/1), δ):7.68 and 7.22 (-C 6 H 4 B(OH) 2 ), 4.50 (-COCHNH-), 3.51 (-OCH 2 CH 2 O-), 2.98-2.74 (-C 6 H 4 CH 2 -) according to the formula (I); the same procedure, using eight-arm PEG-NH 2 Obtaining 8-arm-PEG-PBPA (B)M n = 20.0-12.0 kg/mol), 1 H NMR (400 MHz, DMSO-d 6 /CD 3 OD (v/v = 2/1),δ):7.68 and 7.22 (-C 6 H 4 B(OH) 2 ), 4.50 (-COCHNH-), 3.51 (-OCH 2 CH 2 O-), 2.98-2.74 (-C 6 H 4 CH 2 -)。
Examples triblock copolymer PEG-P (Tyr-co-BPA)、PEG-P(Lys-co-BPA) and PEG-P (BLA-co-BPA) and the like
The invention uses linear polyethylene glycol as an initiator to initiate the L-4-dihydroxy boron phenylalanine-NCarboxylic anhydride monomers and other typesNRandom copolymerization of-carboxyanhydride monomers (e.g., tyr-NCA, lys (Boc) -NCA, and BLA-NCA) to obtain polymers with different molecular structures, different hydrophilicity and hydrophobicity, and different propertiesCharge and various functional groups of phenylboronic acid-based polypeptide materials (table 3). To synthesize PEG-P (Tyr-co-BPA)（M n = 5.0-1.0-4.0-kg/mol) as an example: using methoxy polyethylene glycol ammonia as an initiator, and reacting PEG-NH in a nitrogen environment 2 A solution of (0.25 g,1.06 mmol) in DMF was added to a solution of Tyr-NCA (0.121 g, 0.396 mmol) and BPA-NCA (0.25 g,1.06 mmol) in DMF and reacted at 80 ℃ for 3 days. After the reaction was complete, the polymer solution was precipitated with ice dry ether, centrifuged, then redissolved with methanol, the precipitation was repeated 3 times, the solid precipitate was collected and dried in vacuo for 48 hours to give an off-white product, yield: 78 percent. PEG-P (Tyr-co-BPA) block copolymer see FIG. 3 for nuclear magnetic characterization. 1 H NMR (DMSO-d 6 /CD 3 OD (v/v = 2/1), 400 MHz, δ): 7.68 and 7.22 (-C 6 H 4 B(OH) 2 ), 6.95 and 6.61 (-C 6 H 4 OH), 4.47 and 4.37 (-COCHNH-), 3.52 (-OCH 2 CH 2 O-), 2.82-2.63 (-C 6 H 4 CH 2 -)。
PEG-P(Lys(Boc)-co-BPA)、PEG-P(BLA-coSynthesis of-BPA) and 4-arm-PEG-PBPA following the same protocol as described above, PEG-P (Lys (Boc) -co-BPA) in trifluoroacetic acid to yield PEG-P (Lys-co-BPA)。
Example Synthesis of four ApoE-modified PEG-PBPA polymers (ApoE-PEG-PBPA)
Referring to the method, the invention uses the polyethylene glycol modified by maleimide as an initiator to initiate the L-4-dihydroxyboranophenylalanine-NCarboxyanhydride monomers and/or other typesNThe carboxyanhydride monomer to (Mal-PEG-PBA or Mal-PEG-P (BPA-coTyr), and the like, and then the PEG end of the block polymer can be chemically coupled with specific targeting molecules such as ApoE, angiopep-2, cRGD and the like. For the synthesis of ApoE-PEG-PBPA: in a nitrogen atmosphereNext, mal-PEG-PBPA (100 mg, 0.011 mmol) and ApoE peptide (30.7 mg, 0.013 mmol) were dissolved in deoxygenated DMSO/CH 3 OH (v/v = 9/1, 0.1 mL) at 37 ℃ for 24 hours to give a polypeptide solution. After the reaction is finished, the polypeptide solution is placed in DMSO/CH 3 Dialysis against OH for 24 hours, followed by dialysis against secondary water to displace the organic solvent, and final lyophilization afforded the product ApoE-PEG-PBPA as a white solid, in yield: and 78 percent. The nuclear magnetic characterization of ApoE-PEG-PBPA block copolymer is shown in figure 4A. 1 H NMR (400 MHz, DMSO-d 6 /CD 3 OD(v/v = 2/1), δ): 7.68 and 7.22 (-C 6 H 4 B(OH) 2 ), 4.49 (-COCHNH-), 3.51 (-OCH 2 CH 2 O-), 2.98-2.74 (-CH 2 NH-), 0.78-2.41 (ApoE). The grafting efficiency of ApoE was 92% as determined by 9,10-phenanthrenequinone. Similarly, glucose molecules can be modified at the end of the polymer, and FIG. 4B shows the nuclear magnetic spectrum of the glucose-modified polymer, yield: 82 percent. Approximately 3.6 modifications of glucose to the polymer 4-arm-PEG-PBPA could be calculated by nuclear magnetic resonance.
Example pentaPEG-PBPA Polymer micelles (PBN) loaded with curcumin and sorafenib tosylate and in vitro Release
Mixing the polymer PEG-PBPA (B)M n = 5.0-4.0 kg/mol), drug curcumin (Cur), sorafenib tosylate (Sor) were dissolved in DMSO solutions, mixed in certain amounts and added drop wise to HEPES, PB buffer solution or ultra pure water in a stirred state, then dialysis bag with cut-off molecular weight of 7000 was used to remove organic solvent and free drug, the dialysis process was performed in HEPES, PB buffer or pure water pH = 7.4 (table 4). Taking the case of co-entrapped Cur and Sor (theoretical drug loading of 10 wt percent): after 10. Mu.L of the dissolved PEG-PBPA polymer solution (100 mg/mL), 5.55. Mu.L of Cur solution and 5.55. Mu.L of Sor solution were mixed well, added dropwise to 979. Mu.L of HEPES buffer solution and dialyzed against HEPES buffer solution to remove the organic solvent and the drug not entrapped. Finally, the size of the polymer micelle was 95 as measured by dynamic light scattering particle size analyzer (DLS)nm, narrow particle size distribution (<0.2). The actual drug loading of Cur and Sor reached 7.8 wt% and 9.8 wt%, respectively, as determined by HPLC. Moreover, the polymer micelle has good stability under the conditions of high dilution (50 times), 10% Fetal Bovine Serum (FBS) and long-term standing at 4 ℃.
In vitro release experiments for Cur and Sor were performed in a constant temperature shaker at 37 deg.C and 200 rpm. Specifically, 1.0 mL PBN-Cur/Sor (Cur and Sor drug loading of 10 wt%) micellar solution was transferred into release bags (MWCO = 12-14 KD) and submerged in 25.0 mL release media at different conditions (pH 7.4, 100 μ M H) 2 O 2 ) In the process, 5.0 mL release medium is aspirated at a predetermined time point and an equal volume of fresh release medium is replenished, after all samples were freeze-dried and reconstituted with 0.3 mL of acetonitrile, the Cur and Sor contents were determined by HPLC. FIG. 5D shows the relationship between the cumulative release of Cur and Sor and time, from which it can be seen that the drug-loaded micelle can release the drug by diffusion.
Example six MTT method for testing cytotoxicity of empty and drug-loaded micelles
Toxicity of the empty polymer micelle PBN to tumor cells (B16F 10 cells, U87 MG-luc cells) and normal murine fibroblasts (L929 cells) was evaluated by the MTT method. The method specifically comprises the following steps: cells were plated in 96-well plates (80. Mu.L, 5X 10) 3 Individual cells/well) were incubated in an incubator at 37 ℃ for 24 hours, and then 20 μ L of PBN micelle solutions of different concentration gradients were added to each well to give final concentrations in the wells of 0.05, 0.1, 0.2, 0.5, 0.75, and 1.0 mg/mL. After 48 hours of incubation, an additional 10. Mu.L of MTT solution at a concentration of 5.0 mg/mL was added to each well and incubation was continued for an additional 4 hours, the medium was removed from the wells and 150. Mu.L of DMSO was added to solubilize purple formazan crystals produced by the interaction of MTT with living cells, and finally the absorbance at 570 nm was measured for each well in the well plate by a multi-functional plate reader. Cell viability was determined by the ratio of absorbance of each sample group to the blank control group to which an equal volume of PBS was added. Each timeThe set 5 parallel wells. FIG. 6A shows the polymer PEG-PBPA (B: (B))M n = 5.0-4.0 kg/mol) cytotoxicity results of self-assembled micelles on B16F10, U87 MG-luc and L929 and it can be seen that when the concentration of the polymeric micelles is increased from 0.1 to 1.0 MG/mL, the survival rate of all groups of cells is still higher than 80%, indicating that the polymeric micelles have good biocompatibility.
The drug-loaded micelles (PBN-Cur, PBN-Sor and PBN-Cur/Sor) of example five were investigated for toxicity to U87 MG-luc cells, and the cell culture procedure was identical to that described above. MTT was added after 48 hours of incubation with cells by adding PBN-Cur, PBN-Sor (final concentrations of Cur or Sor were 0.01, 0.1, 0.5, 1,2, 4, 6, 8 and 10. Mu.g/mL) at various gradient concentrations and PBN-Cur/Sor at various drug ratios, and treatment and absorbance measurements were consistent with those described above. The experimental results are shown in FIG. 6B&C, the result in the figure shows that Cur and Sor both show a certain killing effect, and the killing effect of PBN-Cur and PBN-Sor is improved compared with that of free drugs. For the combined action of the two drugs on U87 MG-luc, the synergistic effect on tumor cells (CI = C) is achieved when the mass ratio of the two drugs is 1/1 CA /C A +C CB /C B ；C CA : IC of combination drug A, B 50 Concentration, C CB : IC of B in combination with A, B 50 Concentration, C A And C B IC of A and B respectively 50 Concentration) was most significant, its half-lethal concentration (IC) 50 ) It was 1.47. Mu.g/mL. The micelle disclosed by the invention has good capability of delivering Cur and Sor, realizes effective release and finally kills tumor cells.
In addition, the cytotoxicity of PBN-Cur, PBN-Sor and PBN-Cur/Sor is verified by a cell clone formation experiment. The method comprises the following specific steps: u87 MG-luc cells (2X 10) 5 One cell/well) were inoculated in a 6-well plate, and after 24 hours of culture, cur, sor, PBN-Cur, PBN-Sor, and PBN-Cur/Sor (Cur: 1.5. Mu.g/mL, sor: 1.5. Mu.g/mL, cur/Sor: 1.5/1.5. Mu.g/mL) were added, respectively, to conduct incubation for 48 hours. The cells were then trypsinized, and each sample set of cells (300 cells/well) was reseeded in a 6-well plate and placed in a cell incubator for 9 days, each timeThe culture medium was changed every three days. Finally, the culture medium is sucked off, the cells are fixed by 4% paraformaldehyde solution for 15 minutes after being soaked and washed by PBS for 2 times, then the cells in the holes are dyed by crystal violet dyeing liquid, and finally, the crystal violet is slowly washed off and air-dried. As can be seen from FIG. 6D, both PBN-Cur (Cur: 1.5. Mu.g/mL) and PBN-Sor (Sor: 1.5. Mu.g/mL) have a certain effect of inhibiting tumor cell proliferation for a long time, the inhibition effect of the PBN-Sor group is slightly better than that of the PBN-Cur group, and the PBN-Cur/Sor group with dual drug combination has the most excellent inhibition effect, which is consistent with the MTT experiment result.
Example hemolysis results of drug-loaded micelles
In this experiment, deionized water was used as a positive control, and 0.9% NaCl was used as a negative control, to study the hemolysis of Cur, sor, PBN-Cur, PBN-Sor, PBN-Cur/Sor (low) and PBN-Cur/Sor (high) (FIG. 7A). The drug concentration was set at 50. Mu.g/mL, except for the PBN-Cur/Sor (high; cur: 110. Mu.g/mL, sor: 110. Mu.g/mL) group. The results in fig. 7B show that free Sor has significant hematologic toxicity, inducing a hemolysis rate of about 45% at a concentration of 50 μ g/mL, while the nano-drug PBN-Sor at the same concentration showed only slight hemolysis (HR of 4.3%). In addition, low concentration (Cur: 50. Mu.g/mL; sor: 50. Mu.g/mL) and high concentration of PBN-Cur/Sor also showed excellent blood compatibility, with HR of about 2.3%, providing an effective strategy for simultaneous intravenous injection of Cur and Sor.
Example apoptosis and cell cloning experiments with eight drug loaded micelles
The invention adopts Annexin V-FITC/Propidium Iodide (PI) double staining technology, and utilizes a flow cytometer to research the apoptosis effect of Cur, sor, PBN-Cur, PBN-Sor and PBN-Cur/Sor on U87 MG-luc cells. Specifically, U87 MG-luc cells (2X 10) in logarithmic growth phase were taken 5 One cell/well) were inoculated in a 6-well plate, incubated overnight in an incubator with either Cur, sor, PBN-Cur, PBN-Sor, or PBN-Cur/Sor (Cur: 1.5. Mu.g/mL, sor: 1.5. Mu.g/mL, cur/Sor: 1.5/1.5. Mu.g/mL) added per well for 48 hours of co-incubation, the medium was then discarded and washed 2 times with PBS, cells were digested with pancreatin (EDTA-free) and collected by centrifugation, washed 2 times with 4 ℃ pre-cooled PBS and 100. Mu.L of binding buffer was addedCell resuspension (1X 10) with the washing solution (binding buffer) 6 Each cell/mL), 100 mu L of cell suspension is transferred into a flow tube, 5 mu L of Annexin V-FITC staining solution and 10 mu L of PI staining solution are sequentially added, after uniform mixing, the cells are stained for 15 minutes in a dark place at room temperature, and finally 400 mu L of PBS is added, after uniform mixing, the percentage of the cells in each apoptosis stage is detected by a flow cytometer. The control group was treated with the same double-stained sample as the sample group. In addition, the early-wither sample was prepared by treating the cells in a water bath at 50 ℃ for 5 minutes, and the late-wither sample was prepared by treating the cells with 4% paraformaldehyde for 5 minutes. All data were analyzed using Flowjo software. As can be seen in FIG. 8A, the PBN-Cur/Sor treatment caused over 50% apoptosis, significantly higher than PBN-Cur (7.1%), PBN-Sor (23.4%), cur (6.8%) and Sor (21.5%).
In addition, cur is reported to have the capability of inhibiting the cell cycle, so PBN-Cur is also tested for the cell cycle blocking capability of U87 MG-luc cells correspondingly. Specifically, U87 MG-luc cells (2X 10) 5 One cell/well) were seeded in 6-well plates and after 24 hours of incubation Cur or PBN-Cur (Cur: 1.5. Mu.g/mL) was added and incubated for an additional 24 hours. And then pancreatin is used for digesting and collecting cells, the cells are washed for 3 times by PBS precooled at 4 ℃, finally the cells are dispersed in the PBS of 1.0 mL, the cell suspension is dripped into 95% ethanol which is shaken at constant speed by 4.0 mL, the cells are fixed for 24 hours at 4 ℃, and then the cells are dyed for 30 minutes by a cell cycle kit, and the cell cycle detection is carried out by a flow cytometer. As can be seen from FIG. 8B, most of the PBS group was in the G1 phase (67.28%), the S phase cells were only 23.98%, the G2/M phase content was only 8.74%, and the cycle arrest of the U87 MG-luc cells by Cur and PBN-Cur was better than that of the PBS group, and the PBN-Cur group was slightly higher than that of the Cur group.
Example eight boron-10 enriched 10 BPA-NCA and mPEG-P 10 Synthesis of BPA
10 Synthesis of BPA-NCA and mPEG-P 10 The synthesis of BPA followed example one and example two, respectively. The only difference was that during the monomer synthesis, BPA enriched in boron-10 was used, FIG. 9A&And B is the characterization. 10 Of BPA-NCA 1 H NMR (400 MHz, DMSO-d 6 , δ): 9.09 (s, 1H), 8.03 (s, 2H), 7.71 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 7.6 Hz, 2H), 4.79 (t, J = 5.2 Hz, 1H), 3.03 (d, J = 5.2 Hz, 2H)。mPEG-P 10 Of BPA 1 H NMR (DMSO-d 6 /CD 3 OD (v/v = 2/1), 400 MHz, δ): 7.68 (-C 6 H 2 B(OH) 2 ), 7.22 (-C 6 H 2 CH 2 -), 4.49 (-COCHNH-), 3.51 (-OCH 2 CH 2 O-), 3.26-2.85 (-C 6 H 4 CH 2 -)。
Claims (10)
1. L-4-dihydroxyborophenylalanine with structure of formula IN-carboxyanhydrides:
2. l-4-dihydroxyboranophenylalanine as described in claim 1NA process for producing a carboxyanhydride, characterized in that a mixture of L-4-dihydroxyborophenylalanine,α-pinene and triphosgene as reactants, and reacting in a solvent to prepare the L-4-dihydroxy boron phenylalanine-N-carboxyanhydrides.
3. A linear block copolymer having the structure of formula II:
wherein R is 1 From the initiator polyethylene glycol; r 2 From other types of amino acids; m is 70 to 210, x is 5 to 30, y is 0 to 15, and n is 5 to 45.
4. A process for preparing a linear block copolymer according to claim 3,linear polyethylene glycol is taken as an initiator, L-4-dihydroxy boron phenylalanine is taken as a monomer or L-4-dihydroxy boron phenylalanine and other typesNAnd (3) taking carboxyl internal anhydride as a monomer, and carrying out ring-opening polymerization to obtain a linear block copolymer.
5. A branched block copolymer having the structure of formula iv:
wherein m is 20 to 150, n is 2 to 20, and x is 2 to 8; r 4 Is the branching center of initiator branched polyethylene glycol.
6. The method for producing a branched block copolymer according to claim 5, wherein the branched block copolymer is obtained by ring-opening polymerization using branched polyethylene glycol as an initiator and L-4-dihydroxyborophenylalanine as a monomer.
7. A targeted block copolymer obtained by coupling a linear block copolymer according to claim 3 to a targeting molecule or by coupling a branched block copolymer according to claim 5 to a targeting molecule.
8. A drug delivery system obtained by loading a drug with the linear block copolymer of claim 3 or the branched block copolymer of claim 5; or obtained by coupling targeting molecules after loading the linear block copolymer of claim 3 or the branched block copolymer of claim 5 with drugs; or a drug co-loaded linear block copolymer according to claim 3 with a targeted block copolymer according to claim 7; or a branched block copolymer as defined in claim 5 co-loaded with a drug as defined in claim 7.
9. L-4-dihydroxyborophenylalanine as claimed in claim 1N-carboxyanhydrides, as claimed in claim 3Use of a linear block copolymer, a branched block copolymer according to claim 5, a targeted block copolymer according to claim 7 or a drug delivery system according to claim 8 for the preparation of a medicament.
10. L-4-dihydroxyborophenylalanine as claimed in claim 1N-carboxylactam, the linear block copolymer according to claim 3, the branched block copolymer according to claim 5, the targeted block copolymer according to claim 7, for the preparation of a pharmaceutical carrier.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116655729A (en) * | 2023-05-25 | 2023-08-29 | 重庆高硼生物科技有限公司 | BPA oligomer and targeting compound thereof, preparation method and application |
| CN117357659A (en) * | 2023-12-05 | 2024-01-09 | 暨南大学 | Construction and application of boric acid modified polyalanine-based nano prodrug |
| CN117582518A (en) * | 2023-11-22 | 2024-02-23 | 东莞市人民医院 | Multi-arm polyethylene glycol-BPA boron drug, preparation method and application thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116655729A (en) * | 2023-05-25 | 2023-08-29 | 重庆高硼生物科技有限公司 | BPA oligomer and targeting compound thereof, preparation method and application |
| CN117582518A (en) * | 2023-11-22 | 2024-02-23 | 东莞市人民医院 | Multi-arm polyethylene glycol-BPA boron drug, preparation method and application thereof |
| CN117357659A (en) * | 2023-12-05 | 2024-01-09 | 暨南大学 | Construction and application of boric acid modified polyalanine-based nano prodrug |
| CN117357659B (en) * | 2023-12-05 | 2024-03-12 | 暨南大学 | Construction and application of boric acid modified polyalanine-based nano prodrug |
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