CN110812490A - Rod-shaped prodrug self-delivery system and preparation method and application thereof - Google Patents
Rod-shaped prodrug self-delivery system and preparation method and application thereof Download PDFInfo
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- CN110812490A CN110812490A CN201911131891.3A CN201911131891A CN110812490A CN 110812490 A CN110812490 A CN 110812490A CN 201911131891 A CN201911131891 A CN 201911131891A CN 110812490 A CN110812490 A CN 110812490A
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
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- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
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- A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
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Abstract
The invention provides a preparation method of a rod-shaped prodrug self-delivery system, which is characterized in that the rod-shaped prodrug self-delivery system is formed by inducing the self-assembly of prodrugs; the structural unit of the self-delivery system is a prodrug of peptide dendrimer and drug coupling. The prodrug is induced to self-assemble into a rod-shaped nanoscale material, so that the rod-shaped nanoscale material has better pharmacokinetic property, EPR effect and cell-entering effect. Meanwhile, the self-delivery system is modified by proper targeting molecules, so that the pharmacokinetic performance and the target site delivery effect of the chemotherapeutic drug can be effectively improved, the bioavailability is improved, and the anti-tumor effect is remarkably enhanced. The obtained rod-shaped prodrug self-delivery system can shield inactive drugs in blood circulation and overcome the defects of poor solubility of chemotherapeutic drugs and the like. The medicine is activated and released under the special stimulation of the target site, the toxic and side effects of the medicine on healthy tissues are reduced, and the biocompatibility of the medicine is improved.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a rod-shaped prodrug self-delivery system, and a preparation method and application thereof.
Background
Most of the traditional antitumor drugs have the defects of poor water solubility, rapid in-vivo metabolic clearance, low tumor selectivity, large side effect on healthy tissues and the like. The prodrug endows the antitumor drug with excellent physicochemical property by modifying the antitumor drug, improves the water solubility and the stability, and simultaneously can passivate the antitumor drug, thereby having better biocompatibility. Meanwhile, through reasonable design, the prodrug can show better targeting property, is activated at a target position and fully exerts pharmacological action.
The prodrug self-delivery system (prodrug self-delivery system) has a nano scale, does not need an additional carrier compared with the traditional drug delivery system, can be used for self-delivering by inducing the self-assembly of the prodrug into the nanoparticle, effectively prolonging the circulation time of the drug in blood, passively targeting to tumor tissues through the high permeability and retention effect (EPR effect) of solid tumors, enhancing the cell-entering effect and effectively realizing the self-delivery of the prodrug. The special particle shape (such as a rod shape) has great effects on optimizing the pharmacokinetics and improving the cell entering effect. Therefore, the targeting modified rodlike prodrug self-delivery system can greatly improve the bioavailability of the prodrug and enhance the anti-tumor effect.
Disclosure of Invention
The invention aims to provide a rod-shaped self-delivery system for inducing self-assembly of a prodrug into a nano scale, and through appropriate targeted modification, enrichment of a medicament in a tumor part is increased, bioavailability of the medicament is effectively improved, and an anti-tumor effect is enhanced.
The invention is realized by the following technical scheme:
the invention provides a rod-shaped prodrug self-delivery system, which is prepared by the following preparation method: self-delivery system of rod-shaped prodrug by inducing self-assembly of prodrug into nanoscale; the structural unit of the self-delivery system is a prodrug of peptide dendrimer and drug coupling.
Alternatively, the rod-shaped prodrug self-delivery system can be constructed in one of hydrophilic-hydrophobic self-assembly, rod-shaped inorganic material-induced self-assembly and covalent bond coupling of the prodrug.
Wherein, the rod-shaped inorganic material can be one of carbon nano tube, gold rod and ZnO fiber.
The carbon nano tube and the gold rod can generate a large amount of heat under the condition of near-infrared illumination. The heat can: expanding blood vessels at the tumor part and promoting tumor penetration; the fluidity of cell membranes is increased, and the material is promoted to enter cells; overheating perturbs various physiological processes within the cell, causing apoptosis or necrosis.
Wherein the prodrug from the structural unit of the delivery system: the core is a hydrophobic anti-tumor drug coupled by dynamic sensitive chemical bonds; the outer end of the peptide dendrimer of the prodrug can be modified by functional groups to increase the effect of the prodrug, and the functional groups can be further protected and passivated, so that the prodrug can be activated only at a tumor part, the blood circulation time is prolonged, and the bioavailability is increased.
The peptide dendrimer of the prodrug is a fan-shaped dendrimer with periphery hydrophilic functional modification and inner core capable of being connected with hydrophobic antitumor drugs, and can be second generation and third generation dendrimers.
The schematic of the prodrug molecule is as follows:
wherein M represents an outer shielding shell selected from polyethylene glycol, 2, 3-dimethylmaleic anhydride or 2,2,3,3, -tetramethylmaleic anhydride;
R2cleavable polypeptides or sensitive bonds representing a tumor microenvironment response selected from the group consisting of MMP-2 responsive polypeptides (GPQGIWGQ, GPLGLAG or GPLGIAGD), acid sensitive ester bonds, and the like;
R1represents a cleavable sensitive bond within the tumor cell selected from GSH-sensitive (disulfide or diselenide bond), ester bond, cathepsin-sensitive polypeptide (GFLG), or a hydrazone bond cleavable under lysosomal acidic conditions;
drug stands for an antitumor chemotherapeutic Drug, via the sensitive bond R1Coupled to the root of the dendrimer.
The rod-shaped prodrug self-delivery system is used for chemotherapy drug delivery.
The rod-shaped prodrug delivery system provided by the invention can be selectively connected with a targeting molecule, and is one of RGD, biotin, folic acid, transferrin and phenylboronic acid.
Through reasonable design, the prodrug can be disassembled and assembled at a designated position, and then the antitumor activity of the drug is fully exerted. Alternatively, the site of disassembly may be one or more of the tumor microenvironment, tumor cytoplasm, tumor lysosomes.
The invention has the beneficial effects that:
(1) the rod-shaped prodrug self-delivery system provided by the invention can shield passivation drugs in blood circulation and overcome the defects of poor solubility of chemotherapeutic drugs and the like. The negative electricity shielding layer can prevent protein adsorption in blood circulation and prolong blood circulation time. The medicine is activated and released under the special stimulation of a target part (such as tumor acid condition), so that the toxic and side effects of the medicine on healthy tissues are reduced, and the biocompatibility of the medicine is improved.
(2) The invention also provides a preparation method of the rod-shaped prodrug self-delivery system, which induces the self-assembly of the prodrug to form a rod-shaped nanoscale material, so that the rod-shaped nanoscale material has better pharmacokinetic property, EPR effect and cell-entering effect. Meanwhile, the self-delivery system is modified by proper targeting molecules, so that the pharmacokinetic performance and the target site delivery effect of the chemotherapeutic drug can be effectively improved, the bioavailability is improved, and the anti-tumor effect is remarkably enhanced.
(3) The invention also provides the application of the rod-shaped prodrug self-delivery system, and the prodrug is disassembled and assembled at the designated position through reasonable design, so that the chemotherapeutic drug can better exert the antitumor activity.
Description of the drawings:
FIG. 1 is a schematic representation of the tumor site delivery of a rod-shaped prodrug of the present invention from a delivery system.
FIG. 2 is a mass spectrum characterization of Compound 1 in the examples.
FIG. 3 is a mass spectrum characterization of Compound 2 in the examples.
FIG. 4 is a mass spectrum characterization of Compound 3 in the examples.
FIG. 5 is a mass spectrum characterization of Compound 4 in the examples.
FIG. 6 is a mass spectrometric characterization of Compound 5 in the examples.
FIG. 7 is a photograph of the lens described in example 3.
FIG. 8 shows the ultraviolet absorption spectrum and the fluorescence emission spectrum described in example 4.
FIG. 9 is a Zeta potential characterization as described in example 5.
Figure 10 is a DOX release profile under different conditions described in example 5.
FIG. 11 is a quantification of cellular uptake as described in example 6.
FIG. 12 is a confocal photograph of cell-mediated laser ablation as described in example 7
FIG. 13 is a confocal laser photograph of the effect of chemotherapy drug on nuclear delivery as described in example 8.
Figure 14 is an in vitro cytotoxicity test of the self-delivery system described in example 9 for 48 hours.
Figure 15 is a pharmacokinetic profile over 24 hours of in vivo injection in mice with self-delivery system as described in example 10.
FIG. 16 is the distribution of tumors and major organs after 24 hours of in vivo injection in mice with self-delivery system described in example 11.
FIG. 17 is a confocal laser photograph of a cryo-section of the tumor described in example 12, after staining of the blood vessels showing the distribution of the self-delivery system at the tumor site.
FIG. 18 is a photograph of an in vivo image as described in example 13.
FIG. 19 tumor volume changes in tumor-bearing mice described in example 14.
FIG. 20H & E stained sections of the major organs of mice 21 days after receiving anti-tumor treatment as described in example 14.
The specific implementation mode is as follows:
the above summary of the present invention is described in further detail below with reference to specific embodiments, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples. Any modification made without departing from the spirit and principle of the present invention and equivalent replacement or improvement made only by conventional means according to the ordinary skill in the art should be included in the protection scope of the present invention.
The self-delivery peptide dendrimer prodrug is prepared by a dispersion method, and the structural formula is as follows:
lysine is selected as the framework of the peptide tree-shaped prodrug, and as an optional mode, the branching unit in the peptide tree-shaped macromolecule framework can be one of lysine and glutamic acid.
Wherein the functional group of the arginine dendrimer prodrug can be one of arginine, histidine, lysine and aspartic acid as an optional mode.
Wherein M represents a shielding layer for the "passivation" of the functional groups of the prodrug, the shielding layer optionally being
One kind of (1).
Wherein R is2Representing sensitization of the tumor microenvironmentThe chemical bond, optionally, may be one of acidity-sensitive tumor microenvironment, metalloproteinase-sensitive GPQGIWGQ, GPLGLAG, or GPLGIAGD.
Wherein drug represents hydrophobic antineoplastic drug, and can be one of adriamycin, paclitaxel, camptothecin, cisplatin, oxaliplatin or gemcitabine as an optional mode.
Wherein R is1Represents an intracellular sensitive chemical bond connecting the dendrimer and the chemotherapeutic drug, and can be one of tumor cell lysosome acidity sensitivity, glutathione sensitivity and cathepsin sensitivity as an optional mode.
The invention also provides a construction mode of the rod-shaped prodrug self-delivery system, which effectively improves the bioavailability of the antitumor drug and comprises the following specific steps:
(1) preparing the peptide dendrimer prodrug.
(2) Mixing single-walled carbon nano-tubes in a dilute nitric acid solution for oxidation, promoting the breakage of the carbon nano-tubes under the ultrasonic condition, and fully oxidizing and breaking the carbon nano-tubes. And (3) removing redundant acid and small segments of carbon nano tubes by using a filtering deionized water washing method, collecting filter residues and dissolving the filter residues in a dimethyl sulfoxide solvent. After the large-fragment carbon nano tube is removed by centrifugation, the oxidized carbon nano tube with uniform length is obtained.
(3) Taking the carbon oxide nanotube and a condensing agent (4n equivalent), adding polyoxyethylene diamine (M.W 2000, 1n equivalent) into a solvent for reaction under the protection of nitrogen; the reaction was carried out at room temperature for 24 hours, and the solvent and unreacted reagents were removed by ultrafiltration.
(4) The modified carbon nanotubes and thiolated Arg-Gly-Asp (5n equivalents) were placed together in 10M sodium ethanesulfonate phosphate buffer (pH 7.4) and reacted overnight.
And (3) taking the peptide dendrimer prodrug (5n equivalent) in the step (1) and the target modified single-wall carbon nanotube (1n equivalent) in the step (4), dissolving the peptide dendrimer prodrug and the target modified single-wall carbon nanotube in a good solvent together, dripping deionized water under the ultrasonic condition, and assembling the single-wall carbon nanotube induced dendrimer prodrug into a rod-shaped prodrug self-delivery system through hydrophilic-hydrophobic self-assembly and pi-pi stacking.
Alternatively, the peptide dendrimers of step (1) may be prepared by a convergent, divergent or combined convergent-divergent process.
Alternatively, the peptide dendritic prodrug molecule in the step (1) is prepared by a divergent method, and the specific preparation method comprises the following steps:
a) protecting amino acid with Boc (tert-butyloxycarbonyl), Pbf;
b) protecting carboxyl of amino acid with methyl ester;
c) preparing a second generation of dendrimer: weighing methyl ester protected lysine, lysine (2n equivalent), a condensing agent (3n equivalent), a catalyst (3n equivalent) and organic base (12n equivalent) according to a ratio, adding a solvent at 0 ℃ under the protection of nitrogen, reacting at room temperature for 48 hours, washing, drying and concentrating the obtained solution, and separating and purifying by column chromatography to obtain the second-generation dendrimer.
d) Deprotection: accurately weighing the second-generation dendritic peptide macromolecules, injecting redistilled dichloromethane under nitrogen atmosphere to fully dissolve the second-generation dendritic peptide macromolecules, slowly dropwise adding a deprotection reagent (12n equivalent), stirring and reacting for 12 hours under ice bath and nitrogen protection, removing protection, decompressing and concentrating, adding diethyl ether, keeping out of the sun, stirring overnight, standing, and removing supernate, and then spin-drying the residual diethyl ether to obtain the second-generation deprotected dendritic molecules.
e) Preparing a third generation dendrimer: precisely weighing deprotected second-generation dendrimer, boc and pbf protected arginine (4n equivalent) condensing agent (6n equivalent), catalyst (6n equivalent) and organic base (24n equivalent), adding solvent at 0 ℃ under the protection of nitrogen, reacting at room temperature for 48 hours, washing, drying and concentrating the obtained solution, and separating and purifying by column chromatography to obtain third-generation dendrimer.
f) Protection by demethylation: accurately weighing the third generation dendrimer, adding 0.5M NaOH/MeOH (NaOH is 10n equivalent), reacting at room temperature overnight, spinning off methanol under reduced pressure, pumping out completely with oil pump, adding chloroform for dissolving, adjusting pH to 5-6 with 1M HCl, separating organic phase, and adding anhydrous MgSO4Drying, and spin-drying chloroform under reduced pressure to obtain white powder, i.e. the deprotected third-generation dendrimer.
g) Modification by hydrazine hydrate: precisely weighing the deprotected third generation dendrimer, adding 1.5n equivalents of Boc-NHNH2Condensing agent (3n isAmount), catalyst (3n equivalent), organic base (12n equivalent), adding solvent at 0 deg.C under the protection of nitrogen, reacting at room temperature for 48 hr, washing, drying, concentrating, and purifying by column chromatography to obtain hydrazine hydrate modified dendrimer.
h) Coupling the antitumor drugs: accurately weighing hydrazine hydrate modified dendrimer, adding 10n equivalent of DOX.HCl and a catalyst (catalytic amount of glacial acetic acid), and reacting in dimethyl sulfoxide solution under nitrogen atmosphere for 24 hours. The solvent and unreacted reagents were removed by dialysis.
i) The outer layer of the fan-shaped peptide dendrimer is modified with a negatively charged shell: accurately weighing the dendritic molecules coupled with the antitumor drugs, adding 20n equivalent of 2, 3-dimethylmaleic anhydride, reacting in a mixed solvent (volume ratio is 1:1:1) of dimethyl sulfoxide, pyridine and triethylamine for 24 hours under nitrogen atmosphere, placing the obtained solution in a dialysis bag, dialyzing with deionized water to remove the organic solvent and unreacted reagents, and freeze-drying to obtain dark red powder, namely the peptide dendritic molecule prodrug.
Preparation of a rod-shaped prodrug self-delivery system:
the peptide dendrimer prodrug and an inorganic core for inducing the self-assembly of the prodrug are taken to be co-dissolved in a good solvent (dimethyl sulfoxide). And dropping the solution into deionized water under ultrasonic condition to self-assemble to form a nano-scale rod-shaped drug delivery system. Dialysis (MWCO 100KDa) removes the organic solvent, yielding a suspension of the rod-shaped self-delivery system.
The rod-shaped prodrug is delivered from the tumor site of the delivery system, as shown in figure 1.
Example 1: the preparation of the peptide dendrimer prodrug has the following synthetic route:
FIGS. 2-6 are mass spectrometric characterizations of Compounds 1-5 in the examples, respectively.
Preparation of the second generation dendrimer: 3.0g of lysine, 11.13g of Boc-protected lysine, 9.87g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl) and 3.83g of 1-Hydroxybenzotriazole (HOBT) were weighed accurately into a single vial with a manifold, dissolved under nitrogen with Dichloromethane (DCM) and added with 21.33mL of N, N-Diisopropylethylamine (DIPEA) under an ice-water bath. After reacting for 24 hours at room temperature, washing, drying and concentrating the reaction solution, and purifying and separating by column chromatography.
Protection by tert-butyloxycarbonyl (Boc): 3.0g of the second generation dendrimer was weighed out accurately into a branched single vial, after DCM was dissolved under nitrogen, 11.83mL of trifluoroacetic acid (TFA) was added. After the reaction at room temperature for 12 hours, the resulting solution was concentrated, ice-cold anhydrous ether was added and stirred overnight in the dark, and the mixture was allowed to stand, and after the supernatant was decanted, the remaining ether was spin-dried to obtain Compound 1.
Preparing a third generation dendrimer: 3.0g of the second generation dendrimer, 11.62g of Boc and pbf protected arginine, 11.46g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl) and 2.98g of 1-Hydroxybenzotriazole (HOBT) were weighed accurately into a single vial with a manifold, dissolved under nitrogen with Dichloromethane (DCM) and added 12.14mL of N, N-Diisopropylethylamine (DIPEA) under ice-water bath. After reacting for 24 hours at room temperature, washing, drying and concentrating the reaction solution, and purifying and separating by column chromatography.
Protection by removing tertiary methyl ester: 1.0g of the third generation dendrimer was accurately weighed into a single vial with a manifold, and 4.0mL of a 0.5M NaOH/MeOH solution was added. The reaction was carried out at room temperature for 12 hours, methanol was dried by spinning, and after pumping with an oil pump, chloroform was added to dissolve the methanol. Adjusting pH to 5-6 with HCl, separating organic phase, drying, and spin drying to obtain compound 2.
Modification by hydrazine hydrate: 0.99g of the compound 2, 70.15mg of tert-butyloxycarbonyl-hydrazine (Boc-NHNH) are weighed out accurately2) 276.22mg PyBop and 71.71mg 1-Hydroxybenzotriazole (HOBT) were dissolved in a single vial with a manifold under nitrogen, Dichloromethane (DCM) was added and 0.34mL N, N-Diisopropylethylamine (DIPEA) was added under ice-water bath. After reacting for 24 hours at room temperature, washing, drying and concentrating the reaction solution, and purifying and separating by column chromatography.
de-Boc and pbf protection: 200mg of the second-generation dendrimer was weighed out accurately and placed in a branched single-neck flask, after DCM was dissolved under nitrogen, 0.52mL of trifluoroacetic acid (TFA) was added. Reacting at room temperature for 12 hours, concentrating the obtained solution, adding ice-cold anhydrous ether, stirring overnight in dark, standing, decanting the supernatant, and spin-drying the rest ether to obtain compound 3.
Coupling the antitumor drugs: 270.01mg of compound 3, 306.2mg of doxorubicin hydrochloride are weighed out accurately, dissolved in DMSO under nitrogen protection, and a catalytic amount of glacial acetic acid is added. After 72 hours of reaction at room temperature, the solvent was evaporated under reduced pressure, the solution was dialyzed in a dialysis bag with a cut-off of 1500Da, and the resulting aqueous solution was freeze-dried to obtain Compound 4.
And (3) modifying the shielding layer: accurately weighing 6.0mg of compound 4, 57.95mg of 2, 3-dimethylmaleic anhydride, reacting in a mixed solvent of dimethyl sulfoxide, pyridine and triethylamine (volume ratio is 1:1:1) for 24 hours under nitrogen atmosphere, placing the obtained solution in a dialysis bag with cut-off volume of 2000Da, dialyzing with deionized water to remove an organic solvent and unreacted reagents, and freeze-drying to obtain a dark red powdery compound 5, namely the peptide dendrimer prodrug.
Example 2: preparation of target modified carbon nano-tube
And (3) mixing single-walled carbon nano (20mg) in 100mL of 2.5M nitric acid solution, carrying out condensation reflux for 36h, carrying out ultrasonic treatment in an ultrasonic cleaner for 30 min, continuing to carry out condensation reflux for 36h, and fully oxidizing to break the carbon nano tube. And filtering and washing with deionized water by using a membrane with the pore diameter of 200nm, removing redundant acid and small segments of carbon nano tubes, collecting filter residues, and dissolving in a dimethyl sulfoxide solvent. After the large-fragment carbon nano-tube is removed by centrifugation at 1000rpm, the oxidized carbon nano-tube with uniform length is obtained, and the concentration is adjusted to 0.1 mg/mL.
Polyoxyethylene diamine (M.W 2000, 500mg) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl,49.3mg) and 1-hydroxybenzotriazole (HOBT,34.1mg) were charged in a single vial with a manifold under nitrogen atmosphere to a solution of oxidized carbon nanotubes (20mL) and 1.7. mu. L N, N-Diisopropylethylamine (DIPEA) was added under an ice-water bath. After 24 hours of reaction at room temperature, the residue was washed by ultrafiltration (cut-off 100kDa) and then resuspended.
Placing the modified carbon nano tube and thiolated Arg-Gly-Asp (100mg) into 10M sodium ethanesulfonate phosphate buffer solution (pH 7.4) together, reacting overnight, performing ultrafiltration (cut-off amount of 100KDa) to wash filter residue, and then performing heavy suspension in dimethyl sulfoxide solvent to obtain the target modified carbon nano tube.
Example 3: preparation of rod-shaped prodrug self-delivery system
10mg of peptide dendrimer prodrug and 2mg of target-modified carbon nano tube are dissolved in 200 mu L of good solvent dimethyl sulfoxide. The solution was self-assembled by dropping 1800 μ L of deionized water under sonication, and the organic solvent was removed by dialysis (MWCO 100KDa) to give a suspension of a Rod-like self-delivery system, which is called R-DSDS (Rod-like drug-delivery system).
Example 4: characterization of a rod-shaped self-delivery System
And (3) morphology characterization: preparing 100 mu g/mL R-DSDS solution, dripping the solution on a through net, drying at room temperature, and observing the morphology of the solution by a projection electron microscope. As shown in fig. 7, the structure is a rod-shaped nanoparticle.
Ultraviolet and fluorescence spectrum characterization: 100 mu g/mL of R-DSDS solution is prepared and is respectively detected by an ultraviolet absorption spectrometer and a fluorescence spectrometer (excitation wavelength is 480 nm). As shown in FIG. 8, the left UV absorption spectrum shows a distinct doxorubicin absorption peak at 560nm based on the spectrum of the carbon nanotubes. The fluorescence spectrum on the right shows a clear quenching (due to the pi-pi conjugation of doxorubicin and carbon nanotubes).
Example 5: sensitivity characterization of rod-shaped systems
Acid-activatable barrier removal: 100 mug/mL of R-DSDS solution is prepared, the Zeta potential of the particle surface with the negative electricity shielding layer is measured to be-38.1 mV by using a dynamic light scattering method (DLS instrument), the Zeta potential of the particle surface is 12.8mV after the shielding layer is removed by acid activation (figure 9), and the exposure of positive charge arginine residues is beneficial to the adhesion of the particles to tumor cells and efficient cell entry.
Acid-activatable chemotherapeutic drug release: 200 mu g/mL of R-DSDS solution is respectively placed in a buffer solution with pH 7.4, and 1mL of the R-DSDS solution is placed in a dialysis bag with the throttling molecular weight of 1000 Da. The dialysis bag was placed in 15mL of the above buffer and incubated at 37 ℃ with shaking. Every 1 hour 1mL of external buffer was removed and 1mL of fresh buffer was replenished for the response. The dialysis bags were placed in the pH 6.5 buffer at hour 8 and in the pH 5.0 at hour 16, and the spotting measurements were continued until 48 hours (fig. 10).
Example 6: quantification of cellular uptake
Human colon cancer adriamycin resistant strain cell (LoVo/Adr) is cultured at 5 × 104Was inoculated in a 6-well plate and after 24 hours of culture, a 1640 medium solution of 2. mu.g/mL R-DSDS and an equivalent concentration of each control group was incubated with the cells for 2 hours. After washing three times with PBS, the cells were collected, lysed with lysis buffer, and 50. mu.L of 5M HCl was added to each well sample, incubated at 50 ℃ for 1.5 hours, and the hydrazone bond was cleaved sufficiently to release DOX. After cooling, 50. mu.L of 1M NaOH solution was added and vortex mixed. Add 1mL chloroform/isopropanol (volume ratio 4/1) and vortex to extract the doxorubicin. After separating the organic phase, the solvent was evaporated to dryness, 1mL of dimethyl sulfoxide was added for redissolution, and the amount of doxorubicin was quantified using a fluorescence spectrophotometer. The quantitative results are shown in FIG. 11.
Example 7: laser confocal images taken by cells
Human colon cancer adriamycin resistant strain cell (LoVo/Adr) is divided into 1 × 104Was inoculated in a glass-bottom dish and cultured for 24 hours, and then a 1640 medium solution of 2. mu.g/mL R-DSDS and an equivalent concentration of each control group was incubated with the cells for 2 hours. After staining the nuclei with the nuclear dye Hochst 33342, they were washed three times with PBS and observed for cellular uptake by laser confocal. The results are shown in FIG. 12.
Example 8: nuclear delivery of chemotherapeutic agents
Human colon cancer adriamycin resistant strain cell (LoVo/Adr) is divided into 1 × 104The cells were inoculated in a glass plate, and after 24 hours of culture, a 1640 medium solution of each control group of 1. mu.g/mL R-DSDS and an equivalent concentration was incubated with the cells for 24 hours. After staining the nuclei with the nuclear dye Hochst 33342, laser confocal observations were made of the nuclear delivery of chemotherapeutic agents. The results are shown in FIG. 13.
Example 9: in vitro antitumor effect
Human colon cancer adriamycin resistant strain cell (LoVo/Adr) is divided into 1 × 104Was inoculated in 96-well plates and after 24 hours of culture, R-DSDS (0, 0.001,0.01,0.5, 1,5,10,20, 50) was added at various concentrations100. mu.g/mL) and equivalent concentrations of each control group of 1640 medium solution were incubated with the cells for 24 hours, each group setting up 6 replicates. Cells were washed three times with PBS, added to serum-free medium containing 10% CCK-8, and incubated at 37 ℃ for 2 hours. The absorbance at 450nm was measured using a microplate reader. Cell viability was calculated using the following formula:
The relative cell viability(n＝6)was expressed as:(ODsample–ODbackground)/(ODcontrol–ODbackground)×100％.
the results are shown in fig. 14, where the activated rod-like self-delivery system has significant toxicity.
Example 10: pharmacokinetics of rod-shaped prodrug self-delivery systems
Animal feeding: all animals were kept at 25 ℃ and 55% humidity. Experimental procedures for all animals were as prescribed by the university of Sichuan related animal husbandry regulations.
BALB/c mice were randomly divided into two groups of 12 mice each, and were injected with DOX.HCl and R-DSDS via tail vein at a dose concentration of 10 mg/kg. At 0.05,0.5,1,6,12, and 24 hour time points of dosing, mouse blood was collected by eye bleeding and plasma was collected by centrifugation (3000r/5 min). To each sample suspension was added 50. mu.L of 5M HCl solution and incubated at 50 ℃ for 1.5 hours to sufficiently cleave the hydrazone bond to release DOX. After cooling, 50. mu.L of 1M NaOH solution was added and vortex mixed. Add 1mL chloroform/isopropanol (volume ratio 4/1) and vortex to extract the doxorubicin. After separating the organic phase, the solvent was evaporated to dryness, 1mL of dimethyl sulfoxide was added for redissolution, and the amount of doxorubicin was quantified using a fluorescence spectrophotometer. As shown in fig. 15, the rod-shaped self-delivery system significantly increased the blood circulation time of the drug, increasing bioavailability.
Example 11: tumor tissue and major organ distribution of rod-shaped prodrug self-delivery system
Establishing a LoVo tumor model: LoVo/Adr cells were cultured at 5X 106The amount of (A) was inoculated in the axilla of BALB/c nude mice. When the tumor grows to 100mm3In this case, DOX.HCl and R-DSDS were administered via tail vein at a concentration of 10 mg/kg. Mice were sacrificed 24 hours later and tumor tissue and heart, liver, spleen, lung and kidney were taken. Is organized inGrinding in liquid nitrogen, dissolving the tissue in KH at a concentration of 1g/10mL2PO4Solution (20mM, pH 2.8), sonicated for 10 min. 100 μ L of the tissue suspension was added to 50mL of 5M HCl solution and incubated at 50 ℃ for 1.5 hours to break the hydrazone bond sufficiently to release DOX. After cooling, 50mL of 1M NaOH solution was added and vortex mixed. Add 1mL chloroform/isopropanol (volume ratio 4/1) and vortex to extract the doxorubicin. Centrifuging (10000g,5min), separating organic phase, evaporating to remove solvent, adding 1mL dimethyl sulfoxide for redissolution, quantifying adriamycin amount with a fluorescence spectrophotometer, and calculating to obtain the percentage of the traditional Chinese medicine amount in each tissue in the injection dose. As shown in fig. 16, the rod-shaped self-delivery system significantly increased the enrichment of the drug in the tumor, increasing bioavailability.
Example 12: in vivo permeation effect of rod-shaped prodrug self-delivery system
LoVo/Adr cells were cultured at 5X 106The amount of (A) was inoculated in the axilla of BALB/c nude mice. When the tumor grows to 100mm3In this case, DOX.HCl and R-DSDS were administered via tail vein at a concentration of 10 mg/kg. Mice were sacrificed 24 hours later, tumor tissues were taken, sections were frozen, and sections were stained with FITC-labeled CD31 antibody. The enrichment of the material at the tumor site was observed by confocal laser, as shown in fig. 17, the prodrug self-delivery system could significantly enhance the enrichment of the drug at the tumor site, and could penetrate to reach a distance far from the blood vessel, greatly improving the bioavailability and increasing the anti-tumor effect.
Example 13: tumor site enrichment effect of rod-shaped prodrug self-delivery system
LoVo/Adr cells were cultured at 5X 106The amount of (A) was inoculated in the axilla of BALB/c nude mice. When the tumor grows to 100mm3In this case, DOX.HCl and R-DSDS were administered via tail vein at a concentration of 10 mg/kg. Mice were anesthetized with intraperitoneal injections of chloral hydrate (0.1mg/mL) at 1,5,10 hour time points of administration, respectively. DOX distribution was observed with a CRi Maestro Living body imager with excitation and emission wavelengths of 455nm and 605nm, respectively. As shown in fig. 18, the prodrug self-delivery system can be enriched in a large amount at the tumor site to exert an antitumor effect sufficiently.
Example 14: in vivo antitumor Effect of rod-shaped prodrug self-delivery System
LoVo/Adr cells were cultured at 5X 106The amount of (A) was inoculated in the axilla of BALB/c nude mice. When the tumor grows to 100mm3In this case, DOX.HCl and R-DSDS were administered via tail vein at a concentration of 10 mg/kg. Mice were randomly divided into 3 groups of 6 mice each, and the tumor volume was measured by injecting physiological saline, dox.hcl and R-DSDS through the tail vein, once every three days, for a total of 4 times, respectively. As shown in fig. 19, compared to doxorubicin hydrochloride, the experimental group was able to effectively inhibit tumor growth and had an excellent anti-tumor effect, which fully demonstrates that the design can effectively improve the bioavailability of the prodrug and greatly increase the anti-tumor effect.
After the antitumor treatment is finished, the H & E staining result of the section of the main organ of the mouse is taken, and the result shows that the organ of the experimental group shown in figure 20 is healthy, and the rod-shaped self-delivery prodrug delivery system has good biocompatibility.
Claims (10)
1. A method for preparing a rod-shaped prodrug self-delivery system, which is characterized in that the rod-shaped prodrug self-delivery system is assembled into a nanoscale rod-shaped prodrug self-delivery system by inducing the self-assembly of the prodrug; the structural unit of the self-delivery system is a prodrug of peptide dendrimer and drug coupling.
2. The method for preparing a rod-shaped prodrug self-delivery system according to claim 1, wherein the method for inducing prodrug self-assembly is one of prodrug hydrophilic-hydrophobic self-assembly, rod-shaped inorganic material induced self-assembly and covalent bond coupling.
3. The method for preparing a rod-shaped prodrug self-delivery system according to claim 2, wherein the rod-shaped inorganic material is one of carbon nanotubes, gold rods and ZnO fibers.
4. The method for preparing a rod-shaped prodrug self-delivery system according to claim 1, wherein the core of the prodrug of the structural unit of the self-delivery system is a hydrophobic antitumor drug coupled with a dynamic sensitive chemical bond; the outer end of the peptide dendrimer of the prodrug is modified by functional groups.
5. The method for preparing a rod-shaped prodrug self-delivery system according to claim 4, wherein the functional group is protected and inactivated so that it can be activated only at the tumor site.
6. The method of claim 4, wherein the peptide dendrimer of the prodrug is a second or third generation dendrimer with a modified peripheral hydrophilic function and a core linked to a hydrophobic anti-tumor drug.
7. The method for preparing a rod-shaped prodrug self-delivery system according to claim 1, wherein the prodrug molecule is represented schematically as follows:
wherein M represents an outer shielding shell selected from polyethylene glycol, 2, 3-dimethylmaleic anhydride or 2,2,3,3, -tetramethylmaleic anhydride;
R2a cleavable polypeptide or sensitive bond representing a tumor microenvironment response selected from the group consisting of MMP-2 responsive polypeptide GPQGIWGQ, GPLGLAG or GPLGIAGD, acid sensitive ester bond;
R1represents a breakable sensitive bond in a tumor cell, and is selected from a GSH sensitive disulfide bond or a diselenide bond, an ester bond, a cathepsin sensitive polypeptide GFLG, or a hydrazone bond breakable under lysosome acidic conditions;
drug stands for an antitumor chemotherapeutic Drug, via the sensitive bond R1Coupled to the root of the dendrimer.
8. A rod-shaped prodrug self-delivery system, characterized in that it is prepared according to any one of claims 1 to 7.
9. Use of the rod-shaped prodrug self-delivery system according to claim 8 for the delivery of chemotherapeutic drugs.
10. The use of the rod-shaped prodrug self-delivery system according to claim 9, wherein the rod-shaped prodrug self-delivery system is conjugated to a targeting molecule selected from the group consisting of RGD, biotin, folic acid, transferrin, phenylboronic acid; the prodrug is disassembled at a designated position, and the disassembled position is one or more of a tumor microenvironment, a tumor cytoplasm and a tumor lysosome.
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