CN103251561A - Double-sensitive disintegrating nano-sized vesica medicine carrier preparation and preparation method thereof - Google Patents
Double-sensitive disintegrating nano-sized vesica medicine carrier preparation and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a double-sensitive disintegrating nano-sized vesica medicine carrier preparation and a preparation method thereof. The carrier preparation is a hollow nano-sized spherical vesica with a hydrophobic bimolecular membrane and an inner hydrophilic cavity, wherein the hydrophobic bimolecular membrane loads a hydrophobic medicine; and the inner hydrophilic cavity loads a hydrophilic medicine. The carrier preparation is formed by self-assembling a double-sensitive amphiphilic block copolymer through the hydrophobic effect by a solvent exchange method, wherein the double-sensitive amphiphilic block copolymer is formed by bridging reducing-sensitive disulfide bond and pH-sensitive carbon-nitrogen double bonds with polylysine protected by hydrophilic polyethylene glycol and hydrophobic carbobenzoxyl group. The carrier preparation can effectively utilize reduce environment and acidic environment of tumor cells, so that the carrier preparation is disintegrated to release medicines to realize targeted medicine release, and the bioavailability of the medicines is improved. Compared with the prior art, the carrier preparation has high stability and good biocompatibility and can reverse the medicine tolerance of chemotherapy to a certain degree.
Description
Technical field
The invention belongs to field of biomedical polymer materials, especially relate to Lazer's sense disintegratable formula nano vesicle pharmaceutical carrier preparation of a kind of amphipathic nature block polymer self assembly based on polyethylene glycol-lysine and preparation method thereof.
Background technology
Cancer (Cancer) also claims malignant tumor (Malignant neoplasm), and the disease that cause not normal by control growth and proliferation of cell mechanism.Cancerous cell except grow out of control, normal structure even transfer to other parts of health via body-internal-circulation system or lymphsystem arround also can local invading, human beings'health in serious threat.Chemotherapy is a kind of method the most frequently used in the treatment of cancer, but by small-molecule drug directly the mode of sending face problems, short as the small-molecule drug half-life, need frequent drug administration in order to reach therapeutic effect, and that small-molecule drug distributes in vivo is no selectively targeted, big etc. for the toxic and side effects of normal structure, the more important thing is that chemotherapy is that cancerous cell has produced drug resistance for small-molecule drug in patient's body for one of reason of the unable redemption of cancer patient, causes therapeutic effect to be had a greatly reduced quality.
At the wretched insufficiency that direct administering mode exists, pharmaceutical carrier becomes focus and is widely studied.A class carrier that wherein receives much concern is the nanoparticle that is formed by amphipathic copolymer self assembly, and is in the majority with micelle and vesicle in this nanoparticle.In being self-assembled into the process of micelle, the hydrophobic segment of amphipathic nature polyalcohol forms the kernel of micelle, and hydrophilic segment forms the shell of micelle, forms nucleocapsid structure; And in being self-assembled into the process of vesicle, amphipathic nature polyalcohol twines the hydrophilic inner-cavity structure that film forming surrounds a hollow.The hydrophobic inner core of micelle can the load dewatering medicament, can the load hydrophilic drugs in the hydrophilic inner chamber of vesicle, can the load dewatering medicament in the hydrophobic membrane, and in the toxic and side effects that can reduce under the parcel of carrier in the process that medicine transmitting.The hydrophilic shell of the nanoparticle that amphipathic nature polyalcohol forms can effectively improve the water solublity of hydrophobic drug, improves bioavailability greatly.
Polyethylene Glycol PEG is a kind of hydrophilic polymer, have excellent biocompatibility, non-immunogenic and with the blood constituent advantage such as little that interacts, being shown great attention in the field of polymer and medicine combination, is the most frequently used nanoparticle surface modified polymer.Through the nanoparticle after the PEG modification, can flee from engulfing of reticuloendothelial cell, improve long Circulation in the body, and be enriched in tumor locus by the EPR effect.The more traditional synthetic high polymer of polymer based on poly-polypeptide has a lot of advantages, excellent biological compatibility and can be assembled into stable orderly conformation.The synthetic polymer self assembly based on polypeptide is that nanoparticles such as micelle or vesicle have potential effect in medicine and gene delivery applications.
At the drug resistance problem in the chemotherapy process, escape the identifying of mdr cell with nanoparticle as the pharmaceutical carrier packaging medicine, become one of method of reversing drug resistance behavior gradually.
The nanoparticle that common amphipathic nature polyalcohol self assembly forms can not be identified tumor locus and normal position, can not distinguish in the cell and extracellular environment, it is significant as pharmaceutical carrier therefore to study the intelligent polymer nano-particle with sensitivity that can discharge medicine in tumor is delicate.
Summary of the invention
Purpose of the present invention is exactly Lazer's sense disintegratable formula nano vesicle pharmaceutical carrier preparation that provides in order to overcome the defective that above-mentioned prior art exists a kind of amphipathic nature block polymer self assembly based on polyethylene glycol-lysine and preparation method thereof, has reversed the drug resistance that produces in the chemotherapy process to a certain extent.
Purpose of the present invention can be achieved through the following technical solutions:
A kind of Lazer sense disintegratable formula nano vesicle pharmaceutical carrier preparation, this carrier formulation is the nanometer sphere-like vesicle with hollow of hydrophobic bimolecular film and hydrophilic inner chamber; Utilize the solvent exchange method to form by the hydrophobic interaction self assembly by Lazer's sense amphipathic nature block polymer.
Described hydrophobic bimolecular film load dewatering medicament, described hydrophilic inner chamber load hydrophilic drugs.
Described Lazer sense amphipathic nature block polymer is formed by the responsive disulfide bond of reduction and the carbon-to-nitrogen double bon bridging hydrophilic polyglycol of pH sensitivity and the polylysine of hydrophobicity benzyloxycarbonyl group protection; Described reduction sensitivity is glutathion (GSH) sensitivity.Reduction is responsive to realize that by disulfide bond the pH sensitivity is realized by carbon-to-nitrogen double bon.
The dosage form of described carrier formulation is lyophilized injectable powder, and the particle size range of described carrier formulation is the 100-500 nanometer.
The preparation method of a kind of Lazer sense disintegratable formula nano vesicle pharmaceutical carrier preparation may further comprise the steps:
(1) preparation of ε-benzyloxycarbonyl group protection lysine (Z-Lys NCA); Triphosgene is dissolved in the anhydrous tetrahydro furan, under argon shield, dropwise join then in the anhydrous tetrahydro furan suspension of lysine monomer, be stirred and heated to 50 ℃, stopped reaction and natural cooling when treating the solution clarification, it is 5: 1 normal hexane/oxolane recrystallization 2~3 times with volume ratio, sucking filtration, the room temperature vacuum drying obtains Z-Lys NCA powder;
(2) polylysine is (with PzLL
nExpression, n 〉=1 wherein) preparation: ethylamine hydrochloride and Z-Lys NCA are dissolved in anhydrous N, in the dinethylformamide (DMF), under argon shield, carry out ring-opening polymerization, react 5h under elder generation's ice bath, continue reaction 72h then under the room temperature, dialysis, lyophilizing obtains containing the polylysine of n chain link, n 〉=1 wherein, the n value is more big, and chain link is more long, also is that the hydrophobic segment in the amphipathic nature polyalcohol is more long;
(3) contain the end carboxyl polylysine (PzLL of disulfide bond
n-SS-COOH) preparation: dithio dipropyl acid, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl) and N-hydroxy-succinamide (NHS) are dissolved in anhydrous N; in the dinethylformamide (DMF); under nitrogen protection, stir 24h under the room temperature; obtain reactant liquor; to be dissolved in anhydrous N; polylysine in the dinethylformamide dropwise splashes in the above-mentioned reactant liquor; stirring at normal temperature reaction 48h; after reaction finishes; dialysis, lyophilizing obtains containing the end carboxyl polylysine (PzLL of disulfide bond
n-SS-COOH) powder;
(4) contain the amino polylysine (PzLL of end of disulfide bond
n-SS-NH
2) preparation: the end carboxyl polylysine (PzLL that will contain disulfide bond
n-SS-COOH), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide be dissolved in anhydrous N; in the dinethylformamide; stirring at normal temperature 24h under nitrogen protection; obtain reactant liquor, then above-mentioned reactant liquor is dropwise splashed into the anhydrous N of excessive ethylenediamine, in the dinethylformamide solution; stirring at normal temperature 48h under nitrogen protection; after reaction finished, dialysis, lyophilizing obtained containing the amino polylysine (PzLL of end of disulfide bond
n-SS-NH
2) powder;
(5) Lazer's sense amphipathic nature block polymer (PzLL
n-SS-NC-mPEG) preparation: the amino poly-lycine (PzLL of end that will contain disulfide bond
n-SS-NH
2) powder and methoxy poly (ethylene glycol) aldehyde (mPEG-CHO) is dissolved in anhydrous N, in the dinethylformamide, evacuation leads to nitrogen, stirring reaction 24h under the room temperature, and dialysis, lyophilizing obtain containing the sense amphipathic nature block polymer (PzLL of Lazer of disulfide bond and carbon-to-nitrogen double bon
n-SS-NC-mPEG);
(6) with oxolane and the sense amphipathic nature block polymer (PzLL of deionized water dissolving Lazer
n-SS-NC-mPEG), obtain the sense amphipathic nature block polymer (PzLL of Lazer
n-SS-NC-mPEG) oil-water mixture; Use the oxolane solubilizing hydrophobic drug, obtain the dewatering medicament oil solution; Use the deionized water dissolving hydrophilic drugs, obtain the hydrophilic drugs aqueous solution; Dewatering medicament oil solution and hydrophilic drugs aqueous solution are joined the sense amphipathic nature block polymer (PzLL of Lazer respectively
n-SS-NC-mPEG) in the oil-water mixture, stir 5~8h, and the immigration bag filter carries out the lucifuge dialysis, repeatedly change hydrophilic drugs or dewatering medicament that water is removed oxolane and is not written into, after dialysis finishes, lyophilizing forms the pharmaceutical carrier powder formulation, is Lazer's sense disintegratable formula nano vesicle pharmaceutical carrier preparation.
Lysine monomer described in the step (1) is the lysine of benzyloxycarbonyl group protection.
The mol ratio of the ethylamine hydrochloride described in the step (2) and ε-benzyloxycarbonyl group protection lysine is 1: (5~15);
The mol ratio of the polylysine described in the step (3), dithio dipropyl acid, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide is 1: 8: (10~12): (10~12);
The mol ratio of the end carboxyl polylysine that contains disulfide bond described in the step (4), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide and ethylenediamine is 1: (1.2~1.5): (1.2~1.5): 8;
The mol ratio of the amino polylysine of the end that contains disulfide bond described in the step (5) and methoxy poly (ethylene glycol) aldehyde is 1: 1.2;
The ratio of the weight portion of Lazer sense amphipathic nature block polymer, dewatering medicament and the hydrophilic drugs described in the step (6) is (3~10): (3~10): (3~10); In the described Lazer sense amphipathic nature block polymer oil-water mixture, the ratio of the weight portion of Lazer sense amphipathic nature block polymer, oxolane and deionized water is (3~10): (3~10): (9~30); In the described dewatering medicament oil solution, dewatering medicament is (3~10) with the ratio of the weight portion of oxolane: (1~3); In the described hydrophilic drugs aqueous solution, hydrophilic drugs is (3~10) with the ratio of the weight portion of deionized water: (1~3).
Dialysis described in step (2), step (3) and the step (4) is all carried out in specification is the bag filter of MWCO1KDa; Dialysis described in step (5) and the step (6) is carried out in specification is the bag filter of MWCO3.5Kda.Wherein, MwCO namely stays the minimum molecular weight of the biomacromolecule in the bag filter, and Kda represents the mass fraction of molecular weight.
The molecular weight of the methoxy poly (ethylene glycol) aldehyde described in the step (5) is 2000.
Hydrophilic drugs described in the step (6) is selected from doxorubicin hydrochloride or gemcitabine hydrochlorate, and dewatering medicament is selected from methotrexate, paclitaxel or camptothecine.
The present invention prepares the polylysine of controlled chain link by the ring-opening polymerisation of holding amino micromolecule to cause Z-Lys NCA, utilize the responsive disulfide bond of reduction and the carbon-to-nitrogen double bon of pH sensitivity that the hydrophilic section Polyethylene Glycol is connected to the polymer molecule chain end then, be specially and utilize cystamine to introduce the responsive disulfide bond of reduction, carbon-to-nitrogen double bon by schiff base reaction introducing pH sensitivity forms amphipathic block.Utilize this copolymer to adopt the self assembly of solvent exchange method to prepare the nanoparticle of the hydrophilic inner chamber parcel of hollow hydrophilic drugs, the hydrophobic medicine of hydrophobic film layer load, after this nano-medicament carrier enters cell, can utilize reproducibility environment and sour environment in the tumor cell to impel its selectivity disintegrate, thereby realize that the targeting of medicine in tumor cell discharges.
Compared with prior art, the invention provides a kind of disintegratable formula multifunctional nano pharmaceutical carrier preparation that has dual biological responding based on polyethylene glycol-lysine and preparation method thereof, adopt the self assembly of solvent exchange method to form the vesicle structure with the hydrophilic inner chamber of hollow and hydrophobic film layer, but but this structure not only load hydrophilic drugs but also load dewatering medicament; Introducing has the responsive disulfide bond of reduction and the carbon-to-nitrogen double bon of pH sensitivity, can effectively utilize reducing environment and sour environment in the tumor cell to make the carrier disintegrate discharge medicine realization targeting drug release, improves drug bioavailability; Select macromolecule PEG and synthetic polypeptide for use, the carrier formulation for preparing has stability, the excellent biological compatibility of height; In addition, pharmaceutical pack is rolled in the drug resistance that can also reverse to a certain extent in the nanoparticle in the chemotherapy.
Description of drawings
Fig. 1 is the dynamic mechanical light scattering diagram (particle diameter and distribution) of Lazer's sense disintegratable formula nano vesicle pharmaceutical carrier preparation aqueous solution among the embodiment 3;
Fig. 2 is the transmission electron microscope picture of Lazer's sense disintegratable formula nano vesicle pharmaceutical carrier preparation among the embodiment 3.
The specific embodiment
The present invention is described in detail below in conjunction with the drawings and specific embodiments.
Embodiment 1
The preparation of amphipathic nature block polymer
(1) preparation of Z-Lys NCA: with 3g; the lysine of 23mmol benzyloxycarbonyl group protection is suspended in the 50mL anhydrous tetrahydro furan (THF); with 2.7g, the triphosgene of 9mmol is dissolved in the anhydrous THF of 20mL and dropwise adds in the above-mentioned suspension under argon shield, is stirred and heated to 50 ℃.Stopped reaction and natural cooling when treating the solution clarification, and usefulness normal hexane/oxolane (5: 1, v: v) recrystallization is 2~3 times, sucking filtration, the room temperature vacuum drying obtains product Z-LysNCA powder;
(2) PzLL
5Preparation: the ethylamine hydrochloride of 2mmol and the Z-Lys NCA of 10mmol are dissolved in the anhydrous N of 20mL; in the dinethylformamide (DMF); under argon shield, carry out ring-opening polymerization; react 5h under elder generation's ice bath; continue reaction 72h then under the room temperature; reaction solution is moved into bag filter (MWCO1KDa) dialysis, and lyophilizing obtains polylysine PzLL
5
(3) PzLL
5The preparation of-SS-COOH: with the acid of 16mmol dithio dipropyl; 12mmol1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl); 12mmol N-hydroxy-succinamide (NHS) is dissolved in the 10mL dry DMF, stirs 24h under the room temperature under nitrogen protection.With 2mmol PzLL
5Be dissolved in the dry DMF of 15mL, and dropwise splash in the above-mentioned reactant liquor, stirring at normal temperature reaction 48h.After reaction finishes, dialysis (MWCO1KDa), lyophilizing obtains PzLL
5-SS-COOH powder;
(4) PzLL
5-SS-NH
2Preparation: with 1mmol PzLL
5-SS-COOH, 1.2mmol EDCHCl, 1.2mmol NHS is dissolved in the 15mL dry DMF, stirring at normal temperature 24h under nitrogen protection.Then above-mentioned reactant liquor is dropwise splashed in the anhydrous DMF solution of 8mmol ethylenediamine stirring at normal temperature 48h under nitrogen protection.After reaction finishes, dialysis (MWCO1KDa), lyophilizing obtains the PzLL-SS-NH2 powder;
(5) PzLL
5The preparation of-SS-NC-mPEG: with 0.5mmol PzLL
5-SS-NH
2With 0.6mmol methoxy poly (ethylene glycol) aldehyde mPEG-CHO, be dissolved among the anhydrous 10mL DMF, evacuation leads to nitrogen, stirring reaction 24h under the room temperature, dialysis (MWCO3.5KDa), lyophilizing obtains containing the PzLL of disulfide bond and carbon-to-nitrogen double bon
5-SS-NC-mPEG block copolymer.
Embodiment 2
The preparation of amphipathic nature block polymer
(1) preparation of Z-Lys NCA: with 3g; the lysine of 23mmol benzyloxycarbonyl group protection is suspended in the 50mL anhydrous tetrahydro furan (THF); with 2.7g, the triphosgene of 9mmol is dissolved in the anhydrous THF of 20mL and dropwise adds in the above-mentioned suspension under argon shield, is stirred and heated to 50 ℃.Stopped reaction and natural cooling when treating the solution clarification, and usefulness normal hexane/oxolane (5: 1, v: v) recrystallization is 2~3 times, sucking filtration, the room temperature vacuum drying obtains product Z-LysNCA powder;
(2) PzLL
10Preparation: the ethylamine hydrochloride of 2mmol and the Z-Lys NCA of 20mmol are dissolved in the anhydrous N of 20mL; in the dinethylformamide (DMF); under argon shield, carry out ring-opening polymerization; react 5h under elder generation's ice bath; continue reaction 72h then under the room temperature; reaction solution is moved into bag filter (MWCO1KDa) dialysis, and lyophilizing obtains polylysine PzLL
10
(3) PzLL
10The preparation of-SS-COOH: with the acid of 16mmol dithio dipropyl; 12mmol1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl); 12mmol N-hydroxy-succinamide (NHS) is dissolved in the 10mL dry DMF, stirs 24h under the room temperature under nitrogen protection.With 2mmol PzLL
10Be dissolved in the dry DMF of 30mL, and dropwise splash in the above-mentioned reactant liquor, stirring at normal temperature reaction 48h.After reaction finishes, dialysis (MWCO1KDa), lyophilizing obtains PzLL
10-SS-COOH powder;
(4) PzLL
10-SS-NH
2Preparation: with 1mmol PzLL
10-SS-COOH, 1.2mmol EDCHCl, 1.2mmol NHS is dissolved in the 30mL dry DMF, stirring at normal temperature 24h under nitrogen protection.Then above-mentioned reactant liquor is dropwise splashed in the anhydrous DMF solution of 8mmol ethylenediamine stirring at normal temperature 48h under nitrogen protection.After reaction finishes, dialysis (MWCO1KDa), lyophilizing obtains PzLL
10-SS-NH
2Powder;
(5) PzLL
10The preparation of-SS-NC-mPEG: with 0.5mmol PzLL
10-SS-NH
2With 0.6mmol methoxy poly (ethylene glycol) aldehyde mPEG-CHO, be dissolved among the anhydrous 20mL DMF, evacuation leads to nitrogen, stirring reaction 24h under the room temperature, dialysis (MWCO3.5KDa), lyophilizing obtains containing the PzLL of disulfide bond and carbon-to-nitrogen double bon
10-SS-NC-mPEG block copolymer.
Embodiment 3
Preparation with Lazer's sense disintegratable formula nano vesicle pharmaceutical carrier preparation
Take by weighing 3~10 parts of PzLL
5-SS-NC-mPEG block copolymer is dissolved among 3~10 parts of THF, use peristaltic pump in above-mentioned solution, dropwise to splash into 9~30 parts of deionized waters, taking by weighing 3~10 parts of methotrexates is dissolved among 1~3 part of THF, taking by weighing 3~10 parts of doxorubicin hydrochlorides is dissolved in 1~3 part of deionized water, add respectively in the water oil mixed solution of above-mentioned polymer, stir 5~8h, then above-mentioned preparation solution liquid is moved into bag filter (MWCO3.5KDa) and carry out the lucifuge dialysis, repeatedly changing water removes organic solvent and is not written into medicine, after dialysis finished, lyophilizing formed the pharmaceutical carrier powder formulation.
The dynamic mechanical light scattering diagram (particle diameter and distribution) of the Lazer sense disintegratable formula nano vesicle pharmaceutical carrier preparation aqueous solution of preparation as shown in Figure 1, the transmission electron microscope picture of Lazer's sense disintegratable formula nano vesicle pharmaceutical carrier preparation is as shown in Figure 2.
Embodiment 4
Preparation with Lazer's sense disintegratable formula nano vesicle pharmaceutical carrier preparation
Take by weighing 3~10 parts of PzLL
10-SS-NC-mPEG block copolymer is dissolved among 3~10 parts of THF, use peristaltic pump in above-mentioned solution, dropwise to splash into 9~30 parts of deionized waters, taking by weighing 3~10 parts of camptothecines is dissolved among 1~3 part of THF, taking by weighing 3~10 parts of gemcitabine hydrochlorates is dissolved in 1~3 part of deionized water, add respectively in the water oil mixed solution of above-mentioned polymer, stir 5~8h, then above-mentioned preparation solution liquid is moved into bag filter (MWCO3.5KDa) and carry out the lucifuge dialysis, repeatedly changing water removes organic solvent and is not written into medicine, after dialysis finished, lyophilizing formed the pharmaceutical carrier powder formulation.
A kind of Lazer sense disintegratable formula nano vesicle pharmaceutical carrier preparation, this carrier formulation is the nanometer sphere-like vesicle with hollow of hydrophobic bimolecular film and hydrophilic inner chamber; Utilize the solvent exchange method to form by the hydrophobic interaction self assembly by Lazer's sense amphipathic nature block polymer.Hydrophobic bimolecular film load dewatering medicament, hydrophilic inner chamber load hydrophilic drugs.Lazer sense amphipathic nature block polymer is formed by the responsive disulfide bond of reduction and the carbon-to-nitrogen double bon bridging hydrophilic polyglycol of pH sensitivity and the polylysine of hydrophobicity benzyloxycarbonyl group protection; The reduction sensitivity is glutathion (GSH) sensitivity.Reduction is responsive to realize that by disulfide bond the pH sensitivity is realized by carbon-to-nitrogen double bon.The dosage form of carrier formulation is lyophilized injectable powder, and the particle size range of carrier formulation is the 100-500 nanometer.
The preparation method of a kind of Lazer sense disintegratable formula nano vesicle pharmaceutical carrier preparation may further comprise the steps:
(1) preparation of Z-Lys NCA: triphosgene (two (trichloromethyl) carbonic ester) is dissolved in the anhydrous tetrahydro furan (THF), under argon shield, dropwise join then in the anhydrous tetrahydro furan suspension of lysine monomer, be stirred and heated to 50 ℃, treating solution when clarification stopped reaction and natural cooling, is 5: 1 normal hexane/oxolane recrystallization 2 times with volume ratio, sucking filtration, the room temperature vacuum drying, obtain Z-Lys NCA powder, wherein, the lysine monomer is the lysine of benzyloxycarbonyl group protection;
(2) ring-opening polymerisation of Z-Lys NCA: be to be dissolved in anhydrous N at 1: 5 in molar ratio with ethylamine hydrochloride and Z-Lys NCA, in the dinethylformamide (DMF), under argon shield, carry out ring-opening polymerization; react 5h under elder generation's ice bath; continue reaction 72h then under the room temperature, dialysis, lyophilizing obtains PzLL
n
(3) PzLL
nThe preparation of-SS-COOH: dithio dipropyl acid, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl) and N-hydroxy-succinamide (NHS) are dissolved in anhydrous N; in the dinethylformamide (DMF); under nitrogen protection, stir 24h under the room temperature; obtain reactant liquor, will be dissolved in anhydrous N, the polylysine in the dinethylformamide dropwise splashes in the above-mentioned reactant liquor; stirring at normal temperature reaction 48h; after reaction finishes, dialysis, lyophilizing obtains PzLL
n-SS-COOH powder, wherein, the mol ratio of polylysine, dithio dipropyl acid, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide is 1: 8: 10: 10;
(4) PzLL
n-SS-NH
2Preparation: with PzLL
n-SS-COOH, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide are dissolved in anhydrous N; in the dinethylformamide; stirring at normal temperature 24h under nitrogen protection; obtain reactant liquor, then above-mentioned reactant liquor is dropwise splashed into the anhydrous N of excessive ethylenediamine, in the dinethylformamide solution; stirring at normal temperature 48h under nitrogen protection; after reaction finishes, dialysis, lyophilizing obtains PzLL
n-SS-NH
2Powder, wherein, PzLL
nThe mol ratio of-SS-COOH, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide and ethylenediamine is 1: 1.2: 1.2: 8;
(5) PzLL
nThe preparation of-SS-NC-mPEG: with PzLL
n-SS-NH
2Powder and methoxy poly (ethylene glycol) aldehyde (mPEG-CHO) are dissolved in anhydrous N, in the dinethylformamide, wherein, PzLL
n-SS-NH
2With the mol ratio of methoxy poly (ethylene glycol) aldehyde be 1: 1.2, evacuation leads to nitrogen, stirring reaction 24h under the room temperature, the dialysis, lyophilizing obtains containing the PzLL of disulfide bond and carbon-to-nitrogen double bon
n-SS-NC-mPEG block copolymer;
(6) with oxolane and deionized water dissolving PzLL
n-SS-NC-mPEG obtains PzLL
n-SS-NC-mPEG oil-water mixture; With oxolane solubilizing hydrophobic drug methotrexate, obtain the dewatering medicament oil solution; With deionized water dissolving hydrophilic drugs doxorubicin hydrochloride, obtain the hydrophilic drugs aqueous solution; Dewatering medicament oil solution and hydrophilic drugs aqueous solution are joined PzLL respectively
nIn-SS-NC-mPEG the oil-water mixture, stir 5~8h, and the immigration bag filter carries out the lucifuge dialysis, repeatedly change hydrophilic drugs or dewatering medicament that water is removed oxolane and is not written into, after dialysis finishes, lyophilizing forms the pharmaceutical carrier powder formulation, is Lazer's sense disintegratable formula nano vesicle pharmaceutical carrier preparation; Wherein, PzLL
nThe ratio of the weight portion of-SS-NC-mPEG, dewatering medicament and hydrophilic drugs is 3: 3: 3; PzLL
nIn-SS-NC-mPEG the oil-water mixture, PzLL
nThe ratio of the weight portion of-SS-NC-mPEG, oxolane and deionized water is 3: 3: 9; In the dewatering medicament oil solution, dewatering medicament is 3: 1 with the ratio of the weight portion of oxolane; In the hydrophilic drugs aqueous solution, hydrophilic drugs is 3: 1 with the ratio of the weight portion of deionized water.
Wherein, dialysis is all carried out in specification is the bag filter of MWCO1KDa in step (2), step (3) and the step (4); Dialysis is carried out in specification is the bag filter of MWCO3.5Kda in step (5) and the step (6).Wherein, MwCO namely stays the minimum molecular weight of the biomacromolecule in the bag filter, and Kda represents the mass fraction of molecular weight.The molecular weight of methoxy poly (ethylene glycol) aldehyde is 2000 in the step (5).
Embodiment 6
A kind of Lazer sense disintegratable formula nano vesicle pharmaceutical carrier preparation, this carrier formulation is the nanometer sphere-like vesicle with hollow of hydrophobic bimolecular film and hydrophilic inner chamber; Utilize the solvent exchange method to form by the hydrophobic interaction self assembly by Lazer's sense amphipathic nature block polymer.Hydrophobic bimolecular film load dewatering medicament, hydrophilic inner chamber load hydrophilic drugs.Lazer sense amphipathic nature block polymer is formed by the responsive disulfide bond of reduction and the carbon-to-nitrogen double bon bridging hydrophilic polyglycol of pH sensitivity and the polylysine of hydrophobicity benzyloxycarbonyl group protection; The reduction sensitivity is glutathion (GSH) sensitivity.Reduction is responsive to realize that by disulfide bond the pH sensitivity is realized by carbon-to-nitrogen double bon.The dosage form of carrier formulation is lyophilized injectable powder, and the particle size range of carrier formulation is the 100-500 nanometer.
The preparation method of a kind of Lazer sense disintegratable formula nano vesicle pharmaceutical carrier preparation may further comprise the steps:
(1) preparation of Z-Lys NCA: triphosgene (two (trichloromethyl) carbonic ester) is dissolved in the anhydrous tetrahydro furan (THF), under argon shield, dropwise join then in the anhydrous tetrahydro furan suspension of lysine monomer, be stirred and heated to 50 ℃, treating solution when clarification stopped reaction and natural cooling, is 5 with volume ratio: the normal hexane of l/oxolane recrystallization 3 times, sucking filtration, the room temperature vacuum drying, obtain Z-Lys NCA powder, wherein, the lysine monomer is the lysine of benzyloxycarbonyl group protection;
(2) ring-opening polymerisation of Z-Lys NCA: be to be dissolved in anhydrous N at 1: 15 in molar ratio with ethylamine hydrochloride and Z-Lys NCA, in the dinethylformamide (DMF), under argon shield, carry out ring-opening polymerization; react 5h under elder generation's ice bath; continue reaction 72h then under the room temperature, dialysis, lyophilizing obtains PzLL
n
(3) PzLL
nThe preparation of-SS-COOH: dithio dipropyl acid, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl) and N-hydroxy-succinamide (NHS) are dissolved in anhydrous N; in the dinethylformamide (DMF); under nitrogen protection, stir 24h under the room temperature; obtain reactant liquor, will be dissolved in anhydrous N, the polylysine in the dinethylformamide dropwise splashes in the above-mentioned reactant liquor; stirring at normal temperature reaction 48h; after reaction finishes, dialysis, lyophilizing obtains PzLL
n-SS-COOH powder, wherein, the mol ratio of polylysine, dithio dipropyl acid, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide is 1: 8: 12: 12;
(4) PzLL
n-SS-NH
2Preparation: with PzLL
n-SS-COOH, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide are dissolved in anhydrous N; in the dinethylformamide; stirring at normal temperature 24h under nitrogen protection; obtain reactant liquor, then above-mentioned reactant liquor is dropwise splashed into the anhydrous N of excessive ethylenediamine, in the dinethylformamide solution; stirring at normal temperature 48h under nitrogen protection; after reaction finishes, dialysis, lyophilizing obtains PzLL
n-SS-NH
2Powder, wherein, PzLL
nThe mol ratio of-SS-COOH, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide and ethylenediamine is 1: 1.5: 1.5: 8;
(5) PzLL
nThe preparation of-SS-NC-mPEG: with PzLL
n-SS-NH
2Powder and methoxy poly (ethylene glycol) aldehyde (mPEG-CHO) are dissolved in anhydrous N, in the dinethylformamide, wherein, PzLL
n-SS-NH
2With the mol ratio of methoxy poly (ethylene glycol) aldehyde be 1: 1.2, evacuation leads to nitrogen, stirring reaction 24h under the room temperature, the dialysis, lyophilizing obtains containing the PzLL of disulfide bond and carbon-to-nitrogen double bon
n-SS-NC-mPEG block copolymer;
(6) with oxolane and deionized water dissolving PzLL
n-SS-NC-mPEG obtains PzLL
n-SS-NC-mPEG oil-water mixture; With oxolane solubilizing hydrophobic drug paclitaxel, obtain the dewatering medicament oil solution; With deionized water dissolving hydrophilic drugs gemcitabine hydrochlorate, obtain the hydrophilic drugs aqueous solution; Dewatering medicament oil solution and hydrophilic drugs aqueous solution are joined PzLL respectively
nIn-SS-NC-mPEG the oil-water mixture, stir 5~8h, and the immigration bag filter carries out the lucifuge dialysis, repeatedly change hydrophilic drugs or dewatering medicament that water is removed oxolane and is not written into, after dialysis finishes, lyophilizing forms the pharmaceutical carrier powder formulation, is Lazer's sense disintegratable formula nano vesicle pharmaceutical carrier preparation; Wherein, PzLL
nThe ratio of the weight portion of-SS-NC-mPEG, dewatering medicament and hydrophilic drugs is 10: 3: 10; PzLL
nIn-SS-NC-mPEG the oil-water mixture, PzLL
nThe ratio of the weight portion of-SS-NC-mPEG, oxolane and deionized water is 10: 3: 30; In the dewatering medicament oil solution, dewatering medicament is 10: 3 with the ratio of the weight portion of oxolane; In the hydrophilic drugs aqueous solution, hydrophilic drugs is 10: 3 with the ratio of the weight portion of deionized water.
Wherein, dialysis is all carried out in specification is the bag filter of MWCO1KDa in step (2), step (3) and the step (4); Dialysis is carried out in specification is the bag filter of MWCO3.5Kda in step (5) and the step (6).Wherein, MwCO namely stays the minimum molecular weight of the biomacromolecule in the bag filter, and Kda represents the mass fraction of molecular weight.The molecular weight of methoxy poly (ethylene glycol) aldehyde is 2000 in the step (5).
Embodiment 7
A kind of Lazer sense disintegratable formula nano vesicle pharmaceutical carrier preparation, this carrier formulation is the nanometer sphere-like vesicle with hollow of hydrophobic bimolecular film and hydrophilic inner chamber; Utilize the solvent exchange method to form by the hydrophobic interaction self assembly by Lazer's sense amphipathic nature block polymer.Hydrophobic bimolecular film load dewatering medicament, hydrophilic inner chamber load hydrophilic drugs.Lazer sense amphipathic nature block polymer is formed by the responsive disulfide bond of reduction and the carbon-to-nitrogen double bon bridging hydrophilic polyglycol of pH sensitivity and the polylysine of hydrophobicity benzyloxycarbonyl group protection; The reduction sensitivity is glutathion (GSH) sensitivity.Reduction is responsive to realize that by disulfide bond the pH sensitivity is realized by carbon-to-nitrogen double bon.The dosage form of carrier formulation is lyophilized injectable powder, and the particle size range of carrier formulation is the 100-500 nanometer.
The preparation method of a kind of Lazer sense disintegratable formula nano vesicle pharmaceutical carrier preparation may further comprise the steps:
(1) preparation of Z-Lys NCA: triphosgene (two (trichloromethyl) carbonic ester) is dissolved in the anhydrous tetrahydro furan (THF), under argon shield, dropwise join then in the anhydrous tetrahydro furan suspension of lysine monomer, be stirred and heated to 50 ℃, treating solution when clarification stopped reaction and natural cooling, is 5: 1 normal hexane/oxolane recrystallization 2~3 times with volume ratio, sucking filtration, the room temperature vacuum drying, obtain Z-Lys NCA powder, wherein, the lysine monomer is the lysine of benzyloxycarbonyl group protection;
(2) ring-opening polymerisation of Z-Lys NCA: be to be dissolved in anhydrous N at 1: 10 in molar ratio with ethylamine hydrochloride and Z-Lys NCA, in the dinethylformamide (DMF), under argon shield, carry out ring-opening polymerization; react 5h under elder generation's ice bath; continue reaction 72h then under the room temperature, dialysis, lyophilizing obtains PzLL
n
(3) PzLL
nThe preparation of-SS-COOH: dithio dipropyl acid, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl) and N-hydroxy-succinamide (NHS) are dissolved in anhydrous N; in the dinethylformamide (DMF); under nitrogen protection, stir 24h under the room temperature; obtain reactant liquor, will be dissolved in anhydrous N, the polylysine in the dinethylformamide dropwise splashes in the above-mentioned reactant liquor; stirring at normal temperature reaction 48h; after reaction finishes, dialysis, lyophilizing obtains PzLL
n-SS-COOH powder, wherein, the mol ratio of polylysine, dithio dipropyl acid, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide is 1: 8: 11: 11;
(4) PzLL
n-SS-NH
2Preparation: with PzLL
n-SS-COOH, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide are dissolved in anhydrous N; in the dinethylformamide; stirring at normal temperature 24h under nitrogen protection; obtain reactant liquor, then above-mentioned reactant liquor is dropwise splashed into the anhydrous N of excessive ethylenediamine, in the dinethylformamide solution; stirring at normal temperature 48h under nitrogen protection; after reaction finishes, dialysis, lyophilizing obtains PzLL
n-SS-NH
2Powder, wherein, PzLL
nThe mol ratio of-SS-COOH, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide and ethylenediamine is 1: 1.3: 1.3: 8;
(5) PzLL
nThe preparation of-SS-NC-mPEG: with PzLL
n-SS-NH
2Powder and methoxy poly (ethylene glycol) aldehyde (mPEG-CHO) are dissolved in anhydrous N, in the dinethylformamide, wherein, PzLL
n-SS-NH
2With the mol ratio of methoxy poly (ethylene glycol) aldehyde be 1: 1.2, evacuation leads to nitrogen, stirring reaction 24h under the room temperature, the dialysis, lyophilizing obtains containing the PzLL of disulfide bond and carbon-to-nitrogen double bon
n-SS-NC-mPEG block copolymer;
(6) with oxolane and deionized water dissolving PzLL
n-SS-NC-mPEG obtains PzLL
n-SS-NC-mPEG oil-water mixture; With oxolane solubilizing hydrophobic drug camptothecine, obtain the dewatering medicament oil solution; With deionized water dissolving hydrophilic drugs gemcitabine hydrochlorate, obtain the hydrophilic drugs aqueous solution; Dewatering medicament oil solution and hydrophilic drugs aqueous solution are joined PzLL respectively
nIn-SS-NC-mPEG the oil-water mixture, stir 5~8h, and the immigration bag filter carries out the lucifuge dialysis, repeatedly change hydrophilic drugs or dewatering medicament that water is removed oxolane and is not written into, after dialysis finishes, lyophilizing forms the pharmaceutical carrier powder formulation, is Lazer's sense disintegratable formula nano vesicle pharmaceutical carrier preparation; Wherein, PzLL
nThe ratio of the weight portion of-SS-NC-mPEG, dewatering medicament and hydrophilic drugs is 3: 10: 3; PzLL
nIn-SS-NC-mPEG the oil-water mixture, PzLL
nThe ratio of the weight portion of-SS-NC-mPEG, oxolane and deionized water is 3: 10: 20; In the dewatering medicament oil solution, dewatering medicament is 5: 2 with the ratio of the weight portion of oxolane; In the hydrophilic drugs aqueous solution, hydrophilic drugs is 5: 2 with the ratio of the weight portion of deionized water.
Wherein, dialysis is all carried out in specification is the bag filter of MWCO1KDa in step (2), step (3) and the step (4); Dialysis is carried out in specification is the bag filter of MWCO3.5Kda in step (5) and the step (6).Wherein, MwCO namely stays the minimum molecular weight of the biomacromolecule in the bag filter, and Kda represents the mass fraction of molecular weight.The molecular weight of methoxy poly (ethylene glycol) aldehyde is 2000 in the step (5).
Claims (10)
1. Lazer's sense disintegratable formula nano vesicle pharmaceutical carrier preparation is characterized in that this carrier formulation is the nanometer sphere-like vesicle with hollow of hydrophobic bimolecular film and hydrophilic inner chamber; Utilize the solvent exchange method to form by the hydrophobic interaction self assembly by Lazer's sense amphipathic nature block polymer.
2. disintegratable formula nano vesicle pharmaceutical carrier preparation is felt by a kind of Lazer according to claim 1, it is characterized in that described hydrophobic bimolecular film load dewatering medicament, described hydrophilic inner chamber load hydrophilic drugs.
3. disintegratable formula nano vesicle pharmaceutical carrier preparation is felt by a kind of Lazer according to claim 1, it is characterized in that described Lazer sense amphipathic nature block polymer is formed by the responsive disulfide bond of reduction and the carbon-to-nitrogen double bon bridging hydrophilic polyglycol of pH sensitivity and the polylysine of hydrophobicity benzyloxycarbonyl group protection; Described reduction sensitivity is the glutathion sensitivity.
4. disintegratable formula nano vesicle pharmaceutical carrier preparation is felt by a kind of Lazer according to claim 1, it is characterized in that the dosage form of described carrier formulation is lyophilized injectable powder, and the particle size range of described carrier formulation is the 100-500 nanometer.
5. preparation method as the arbitrary described Lazer of claim 1~4 sense disintegratable formula nano vesicle pharmaceutical carrier preparation is characterized in that this method may further comprise the steps:
(1) preparation of ε-benzyloxycarbonyl group protection lysine: triphosgene is dissolved in the anhydrous tetrahydro furan, under argon shield, dropwise join then in the anhydrous tetrahydro furan suspension of lysine monomer, be stirred and heated to 50 ℃, stopped reaction and natural cooling when treating the solution clarification, it is 5: 1 normal hexane/oxolane recrystallization 2~3 times with volume ratio, sucking filtration, the room temperature vacuum drying obtains ε-benzyloxycarbonyl group protection lysine powder;
(2) preparation of polylysine: ethylamine hydrochloride and ε-benzyloxycarbonyl group protection lysine are dissolved in anhydrous N, in the dinethylformamide, under argon shield, carry out ring-opening polymerization, react 5h under elder generation's ice bath, continue reaction 72h then under the room temperature, dialysis, lyophilizing obtains containing the polylysine of n chain link, wherein n 〉=1;
(3) contain the preparation of the end carboxyl polylysine of disulfide bond: dithio dipropyl acid, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide are dissolved in anhydrous N, in the dinethylformamide, under nitrogen protection, stir 24h under the room temperature, obtain reactant liquor, to be dissolved in anhydrous N, polylysine in the dinethylformamide dropwise splashes in the above-mentioned reactant liquor, stirring at normal temperature reaction 48h, after reaction finishes, dialysis, lyophilizing obtains containing the end carboxyl polylysine powder of disulfide bond;
(4) contain the preparation of the amino polylysine of end of disulfide bond: end carboxyl polylysine, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and the N-hydroxy-succinamide that will contain disulfide bond are dissolved in anhydrous N, in the dinethylformamide, stirring at normal temperature 24h under nitrogen protection, obtain reactant liquor, then above-mentioned reactant liquor is dropwise splashed into the anhydrous N of excessive ethylenediamine, in the dinethylformamide solution, stirring at normal temperature 48h under nitrogen protection, after reaction finishes, dialysis, lyophilizing obtain containing the amino polylysine powder of end of disulfide bond;
(5) preparation of Lazer's sense amphipathic nature block polymer: the amino polylysine powder of end and the methoxy poly (ethylene glycol) aldehyde that will contain disulfide bond are dissolved in anhydrous N, in the dinethylformamide, evacuation leads to nitrogen, stirring reaction 24h under the room temperature, dialysis, lyophilizing obtain containing Lazer's sense amphipathic nature block polymer of disulfide bond and carbon-to-nitrogen double bon;
(6) with oxolane and deionized water dissolving Lazer sense amphipathic nature block polymer, obtain Lazer's sense amphipathic nature block polymer oil-water mixture; Use the oxolane solubilizing hydrophobic drug, obtain the dewatering medicament oil solution; Use the deionized water dissolving hydrophilic drugs, obtain the hydrophilic drugs aqueous solution; Dewatering medicament oil solution and hydrophilic drugs aqueous solution are joined respectively in Lazer's sense amphipathic nature block polymer oil-water mixture, stir 5~8h, and the immigration bag filter carries out the lucifuge dialysis, repeatedly change hydrophilic drugs or dewatering medicament that water is removed oxolane and is not written into, after dialysis finishes, lyophilizing forms the pharmaceutical carrier powder formulation, is Lazer's sense disintegratable formula nano vesicle pharmaceutical carrier preparation.
6. the preparation method of disintegratable formula nano vesicle pharmaceutical carrier preparation is felt by a kind of Lazer according to claim 5, it is characterized in that, the lysine monomer described in the step (1) is the lysine of benzyloxycarbonyl group protection.
7. the preparation method of disintegratable formula nano vesicle pharmaceutical carrier preparation is felt by a kind of Lazer according to claim 5, it is characterized in that, the mol ratio of the ethylamine hydrochloride described in the step (2) and ε-benzyloxycarbonyl group protection lysine is 1: (5~15);
The mol ratio of the polylysine described in the step (3), dithio dipropyl acid, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide is 1: 8: (10~12): (10~12);
The mol ratio of the end carboxyl polylysine that contains disulfide bond described in the step (4), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide and ethylenediamine is 1: (1.2~1.5): (1.2~1.5): 8;
The mol ratio of the amino polylysine of the end that contains disulfide bond described in the step (5) and methoxy poly (ethylene glycol) aldehyde is 1: 1.2;
The ratio of the weight portion of Lazer sense amphipathic nature block polymer, dewatering medicament and the hydrophilic drugs described in the step (6) is (3~10): (3~10): (3~10); In the described Lazer sense amphipathic nature block polymer oil-water mixture, the ratio of the weight portion of Lazer sense amphipathic nature block polymer, oxolane and deionized water is (3~10): (3~10): (9~30); In the described dewatering medicament oil solution, dewatering medicament is (3~10) with the ratio of the weight portion of oxolane: (1~3); In the described hydrophilic drugs aqueous solution, hydrophilic drugs is (3~10) with the ratio of the weight portion of deionized water: (1~3).
8. the preparation method of a kind of Lazer according to claim 5 sense disintegratable formula nano vesicle pharmaceutical carrier preparation is characterized in that, the dialysis described in step (2), step (3) and the step (4) is all carried out in specification is the bag filter of MWCO1KDa; Dialysis described in step (5) and the step (6) is carried out in specification is the bag filter of MWCO3.5Kda.
9. the preparation method of disintegratable formula nano vesicle pharmaceutical carrier preparation is felt by a kind of Lazer according to claim 5, it is characterized in that the molecular weight of the methoxy poly (ethylene glycol) aldehyde described in the step (5) is 2000.
10. the preparation method of disintegratable formula nano vesicle pharmaceutical carrier preparation is felt by a kind of Lazer according to claim 5, it is characterized in that, hydrophilic drugs described in the step (6) is selected from doxorubicin hydrochloride or gemcitabine hydrochlorate, and dewatering medicament is selected from methotrexate, paclitaxel or camptothecine.
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