CN115368436A - Peptidyl platinum self-assembly nano prodrug and preparation method and application thereof - Google Patents

Peptidyl platinum self-assembly nano prodrug and preparation method and application thereof Download PDF

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CN115368436A
CN115368436A CN202211005108.0A CN202211005108A CN115368436A CN 115368436 A CN115368436 A CN 115368436A CN 202211005108 A CN202211005108 A CN 202211005108A CN 115368436 A CN115368436 A CN 115368436A
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platinum
prodrug
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石凯
毕洪书
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Nankai University
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Priority to CN202311062814.3A priority patent/CN117599013A/en
Priority to PCT/CN2023/114266 priority patent/WO2024041535A1/en
Priority to PCT/CN2023/114257 priority patent/WO2024041532A1/en
Priority to CN202311061666.3A priority patent/CN117603299A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0819—Tripeptides with the first amino acid being acidic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Abstract

The invention discloses a peptidyl platinum self-assembly nano prodrug and a preparation method and application thereof; the prodrug is a tetravalent platinum complex containing tryptophan dipeptide in axial ligand, and can self-assemble in an aqueous medium to form a nano structure; the invention also provides a preparation method of the platinum nano prodrug, which has mild preparation conditions and simple operation and is suitable for industrial production. The nano prodrug has tumor microenvironment responsiveness, can promote selective accumulation of platinum drugs on tumor tissues and controllable release in tumor cells when used for tumor treatment, is one of essential amino acids for human bodies, participates in protein synthesis and metabolic regulation of organisms, is degraded into human endogenous substances, can improve the inhibition effect on tumor growth when applied to tumor treatment, and obviously reduces the toxic and side effects of the platinum drugs.

Description

Peptidyl platinum self-assembly nano prodrug and preparation method and application thereof
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a peptidyl platinum self-assembly nano prodrug and a preparation method and application thereof.
Background
Bivalent platinum drugs (such as cisplatin, carboplatin and oxaliplatin) have strong broad-spectrum anticancer activity, mainly play an antitumor role by destroying DNA of tumor cells, inhibiting replication and inducing apoptosis, and are widely used for clinical treatment of various malignant tumors at present. However, the drugs have the physicochemical characteristics of low solubility and poor stability, lack selectivity on tumor tissues, are very easy to cause serious side effects such as renal toxicity, neurotoxicity, bone marrow suppression and the like, and influence of innate and acquired drug resistance, and seriously limit the clinical curative effect and application of the drugs.
In recent years, the prodrug technology provides a new solution for improving the physicochemical properties of platinum drugs, reducing toxic and side effects and the like. Compared with bivalent platinum complex Pt (II), tetravalent platinum precursor complex Pt (IV) formed by adding two axial ligands has lower reaction activity and toxic and side effects, and after entering tumor cells, the dropped axial ligands can be converted into Pt (II) structures with cytotoxicity under the action of intracellular reducing media such as ascorbic acid, methionine, glutathione and the like, so that the cell killing effect is generated. However, the platinum small molecule prodrug also has the limitations of high metabolic rate, poor focal site accumulation capability, easy drug resistance and the like in a human body.
The nano drug delivery system constructed based on various carrier materials has great potential application value and development prospect in the aspect of realizing the effective transportation of chemotherapeutic drugs in vivo. The medicine can be carried to overcome physiological and pathological barriers, realize effective enrichment of tumor tissues and cells, complete continuous, controllable and targeted delivery, and further achieve the purposes of enhancing the treatment effect and reducing adverse reactions. However, the platinum micromolecules belong to metal drugs which are insoluble in oil and water, the affinity of the platinum micromolecules to most drug carriers is weak, and the effective load capacity is limited. Therefore, the existing platinum drugs need to be structurally modified to develop novel multifunctional platinum prodrugs with high antitumor activity, small toxic and side effects, strong selectivity to tumor tissues and controllable release, so as to improve the clinical application potential of the drugs.
Disclosure of Invention
In order to solve the technical problems, the invention provides a peptidyl platinum self-assembly nano prodrug and a preparation method and application thereof.
The technical scheme adopted by the invention is as follows: a peptidyl platinum self-assembly nano prodrug is characterized in that an axial ligand contains a tetravalent platinum complex of tryptophan dipeptide.
Preferably, the structure is as shown in formula 1:
Figure BDA0003808760680000021
wherein R is 1 、R 2 、R 3 、R 4 Individually and/or in combination selected from: cl, NH 3 、
Figure BDA0003808760680000022
Preferably, the self-assembled nano prodrug has a structure shown in any one of formulas II-IV;
Figure BDA0003808760680000023
Figure BDA0003808760680000024
Figure BDA0003808760680000025
preferably, the prodrugs are capable of self-assembling into nanostructures of particle size in the range of 10-1000nm, preferably 20-200nm, in aqueous media.
The preparation method of the peptidyl platinum prodrug comprises the following steps: oxidizing bivalent platinum complex Pt (II) into hydroxyl tetravalent platinum complex Pt (IV) by using chlorosuccinimide, and then condensing with oligopeptide containing tryptophan dipeptide motif under the catalysis of TBTU and triethylamine to obtain the peptidyl platinum prodrug.
The method for preparing the self-assembly nano prodrug comprises the steps of dissolving a peptidyl platinum prodrug in a first solvent to obtain an organic phase A; mixing the organic phase A and the water phase B to obtain a mixed solution C; and removing the first solvent in the mixed solution C to obtain the monodisperse nano prodrug.
The first solvent is one or a mixture of at least two of acetone, ethanol, methanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N, N-dimethylformamide; preferably, the first solvent is acetone and/or ethanol;
the water phase B is purified water, water for injection, HEPES buffer solution, tris buffer solution or PBS buffer solution; preferably, the water phase B is water for injection or HEPES buffer solution; preferably, the pH of the aqueous phase B is adjusted to a value of 7.0 to 7.8.
Preferably, the volume ratio of the aqueous phase B to the organic phase a is 1 to 100, preferably 1 to 40.
Preferably, the solvent in the mixed solution C is removed by a reduced-pressure evaporation method, a high-speed centrifugation method, a dialysis method or an ultrafiltration method; preferably, the solvent in the mixed solution C is removed by evaporation under reduced pressure.
Application of peptidyl platinum self-assembly nano prodrug in preparing antitumor drugs.
The invention has the advantages and positive effects that: the peptidyl self-assembly nano prodrug has tumor microenvironment responsiveness, and can promote the selective accumulation of platinum drugs on tumor tissues and the controllable release in tumor cells when being used for treating tumors, thereby improving the inhibition effect on the growth of drug-resistant tumors; meanwhile, premature release of the active bivalent platinum complex in blood circulation can be avoided, so that toxic and side effects are reduced; in addition, the composite peptide has good biocompatibility and safety, the assembled basic tryptophan is one of essential amino acids for human bodies, participates in synthesis and metabolic regulation of proteins of the organisms, and degradation products are all human endogenous substances, so that the toxic and side effects of platinum drugs can be obviously reduced when the composite peptide is applied to tumor treatment; the preparation condition of the nano prodrug is mild, the operation is simple, and the production process does not involve harmful solvents and the like, so that the nano prodrug is suitable for industrial production.
Drawings
FIG. 1 is a TEM morphology of the nano-prodrug prepared in example 4 of the present invention;
FIG. 2 is a graph showing the particle size distribution of the nano-prodrug prepared in example 4 of the present invention;
FIG. 3 is a graph showing the particle size distribution of the nano-prodrug prepared in example 5 of the present invention;
FIG. 4 is a graph of the particle size distribution of the nano-prodrug prepared in example 6 of the present invention;
FIG. 5 is a graph showing the release profile of the active ingredient of the nano-prodrug prepared in example 4 of the present invention;
FIG. 6 shows the evaluation of the in vivo antitumor activity of the nano-prodrug prepared in example 4 of the present invention;
fig. 7 is a body weight change for in vivo safety evaluation of the nano prodrug prepared in example 4 of the present invention;
fig. 8 is H & E staining of tissue sections for in vivo safety evaluation of the nano-prodrug prepared in example 4 of the present invention.
Detailed Description
Embodiments of the present invention will be described below with reference to the accompanying drawings.
The invention provides a peptidyl platinum self-assembly nano prodrug and a preparation method and application thereof. The peptidyl platinum prodrug axial ligand contains a tetravalent platinum complex of tryptophan dipeptide, the structure of the tetravalent platinum complex is shown as a formula 1,
Figure BDA0003808760680000041
wherein R is 1 、R 2 、R 3 、R 4 Individually and/or in combination selected from: cl, NH 3 、
Figure BDA0003808760680000042
The peptidyl platinum self-assembly nano prodrug has a structure shown in any one of formulas II-IV;
Figure BDA0003808760680000043
Figure BDA0003808760680000044
Figure BDA0003808760680000045
tryptophan dipeptide motif in the prodrug molecular structure can provide aromatic indole ring as assembly motif, and pi-pi stacking effect drives platinum complex to self-assemble in aqueous medium to form stable monodisperse nanometer structure.
The preparation method of the peptidyl platinum prodrug is characterized by comprising the following steps: oxidizing bivalent platinum complex Pt (II) into hydroxyl tetravalent platinum complex Pt (IV) by using chlorosuccinimide, and then condensing with oligopeptide containing tryptophan dipeptide motif under the catalysis of TBTU and triethylamine to obtain the peptidyl platinum prodrug.
The prepared peptidyl platinum prodrug is self-assembled into a nano structure; the prodrugs are capable of self-assembling into nanostructures of particle size in the range of 10-1000nm, preferably 20-200nm, in an aqueous medium. The self-assembly method comprises the following steps:
dissolving the prepared peptidyl platinum prodrug in a first solvent to obtain an organic phase A; the first solvent is one or a mixture of at least two of acetone, ethanol, methanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N, N-dimethylformamide; preferably, the first solvent is acetone and/or ethanol;
mixing the organic phase A and the water phase B to obtain a mixed solution C; the water phase B is purified water, water for injection, HEPES buffer solution, tris buffer solution or PBS buffer solution; preferably, the water phase B is water for injection or HEPES buffer solution; preferably, the pH value of the water phase B is adjusted to be 7.0-7.8; the volume ratio of the water phase B to the organic phase A is 1-100, preferably 1-40.
Removing the first solvent in the mixed solution C by a reduced pressure evaporation method, a high-speed centrifugation method, a dialysis method or an ultrafiltration method; preferably, the solvent in the mixed solution C is removed by reduced pressure evaporation, and the monodisperse nano prodrug is obtained after the solvent is removed;
the peptidyl platinum self-assembly nano prodrug can be used for preparing antitumor drugs, the drugs in the nano form have good stability, and the premature release of an active bivalent platinum complex in blood circulation can be avoided, so that the toxic and side effects are reduced, the selective accumulation of the platinum drugs on tumor tissues and the controllable release in tumor cells are promoted, and the inhibition effect on the growth of the drug-resistant tumors is improved. Degradation products of the assembly elements in the prodrug are all human endogenous amino acids, and the toxic and side effects of the platinum drugs can be obviously reduced when the prodrug is applied to tumor treatment.
The following describes the scheme of the present invention with reference to the accompanying drawings, wherein experimental methods without specific description of operation steps are all performed according to corresponding commercial specifications, and instruments, reagents and consumables used in the examples can be purchased from commercial companies without specific description.
Example 1:
the embodiment provides a preparation method of a peptidyl platinum prodrug with a structure shown as a formula (II), and the synthetic route is as follows:
Figure BDA0003808760680000061
specifically, cisplatin (300mg, 1mmol) and N-chlorosuccinimide (150mg, 1.1mmol) were suspended in 60mL of distilled water and reacted at room temperature for 12 hours with exclusion of light. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to precipitate a pale yellow precipitate. The precipitate was washed successively with acetone and diethyl ether to give a tetravalent platinum intermediate (yield 91.2%). Tetravalent platinum intermediate (176mg, 0.5 mmol), L-tryptophan-L-glutamic acid (0.55 mmol), TBTU (264mg, 0.82mmol) and triethylamine (84mg, 0.82mmol) are dissolved in dry dimethylformamide under the protection of nitrogen, and the mixture is reacted for 12 hours at room temperature in a dark place. After ether precipitation, washing, vacuum drying to obtain the product of formula (II) (yield 65%).
Of the product obtained 1 HNMR nuclear magnetic data are as follows: 1 HNMR(600MHz,DMSO-d6):δ10.22(s,1H),8.05(d,J＝6.7Hz,2H),7.62-7.58(m,2H),7.36(dd,J＝7.7,1.5Hz,2H),7.21-7.10(m,4H),7.05(d,J＝6.7Hz,1H),6.98-6.91(m,2H),6.76(d,J＝6.7Hz,1H),4.55-4.47(m,2H),3.53(p,J＝5.6Hz,1H),3.26(dd,J＝14.5,6.7Hz,1H),3.20(dd,J＝15.6,5.9Hz,1H),2.98(dd,J＝15.6,5.9Hz,1H),2.92(dd,J＝14.5,6.7Hz,1H),2.42(t,J＝7.5Hz,3H),2.37-2.28(m,1H),2.30-2.16(m,2H),1.96(p,J＝7.6Hz,2H),1.79(dtd,J＝15.3,8.4,5.0Hz,1H),1.68(d,J＝5.9Hz,2H),1.50(s,3H)。
example 2:
the embodiment provides a preparation method of a peptidyl platinum prodrug with a structure shown as a formula (III), and a synthetic route is as follows:
Figure BDA0003808760680000062
specifically, oxaliplatin (395mg, 1mmol) was reacted by the synthesis method in example 1 to obtain the product of the structural formula (III) (yield 71%). Of the product obtained 1 HNMR nuclear magnetic data are as follows:
1 HNMR(600MHz,DMSO-d6):δ10.22(s,1H),8.05(d,J＝6.7Hz,2H),7.60(dd,J＝7.2,1.2Hz,2H),7.36(dd,J＝7.7,1.5Hz,2H),7.21-7.10(m,4H),7.05(d,J＝6.7Hz,1H),6.98-6.91(m,2H),6.76(d,J＝6.7Hz,1H),4.55-4.47(m,2H),3.53(p,J＝5.5Hz,1H),3.26(dd,J＝14.5,6.7Hz,1H),3.20(dd,J＝15.6,5.9Hz,1H),2.98(dd,J＝15.6,5.9Hz,1H),2.92(dd,J＝14.5,6.7Hz,1H),2.56-2.48(m,2H),2.37-2.28(m,1H),2.30-2.16(m,2H),2.08-2.00(m,1H),1.84-1.66(m,7H),1.53-1.47(m,2H),1.38-1.30(m,1H),1.32-1.21(m,2H),1.15(dddd,J＝12.4,8.4,5.9,3.9Hz,1H).
example 3:
the embodiment provides a preparation method of a peptidyl platinum prodrug with a structure shown as a formula (IV), and a synthetic route is as follows:
Figure BDA0003808760680000071
specifically, carboplatin (371mg, 1mmol) was reacted by the synthesis method of example 1 to obtain the product of structural formula (IV) (yield 68%). Of the product obtained 1 HNMR nuclear magnetic data are as follows: 1 HNMR(600MHz,DMSO-d6):δ10.22(s,1H),8.05(d,J＝6.7Hz,2H),7.62-7.58(m,2H),7.36(dd,J＝7.7,1.5Hz,2H),7.21-7.10(m,4H),7.05(d,J＝6.7Hz,1H),6.98-6.91(m,2H),6.76(d,J＝6.7Hz,1H),4.55-4.47(m,2H),3.53(p,J＝5.6Hz,1H),3.26(dd,J＝14.5,6.7Hz,1H),3.20(dd,J＝15.6,5.9Hz,1H),2.98(dd,J＝15.6,5.9Hz,1H),2.92(dd,J＝14.5,6.7Hz,1H),2.42(t,J＝7.5Hz,3H),2.37-2.16(m,3H),1.96(p,J＝7.6Hz,2H),1.79(dtd,J＝15.3,8.4,5.0Hz,1H),1.68(d,J＝5.9Hz,2H)。
example 4:
the embodiment provides a nano self-assembly method of a peptidyl platinum prodrug with a structure shown as a formula (II). Specifically, the prodrug (10 mg) obtained in example 1 was dissolved in 100. Mu.L of an ethanol-acetone mixed solvent (1:1), the solution was poured into 20mLHEPES buffer (pH 7.4), stirring was continued for 30min after the addition, and the solvent was removed by evaporation under reduced pressure to obtain a nano colloidal solution. The obtained nano prodrug has the appearance of monodisperse spheres, as shown in figure 1, the particle size distribution is shown in figure 2, the average particle size is 118nm, and the PDI is 0.12.
Example 5:
the embodiment provides a nano self-assembly method of a peptidyl platinum prodrug with a structure shown as a formula (III). Specifically, the prodrug (10 mg) obtained in example 2 was self-assembled by the method in example 4. The particle size distribution of the obtained nano prodrug is shown in figure 3, the average particle size is 132nm, and the PDI is 0.18.
Example 6:
the embodiment provides a nano self-assembly method of a peptidyl platinum prodrug with a structure shown as a formula (IV). Specifically, the prodrug (10 mg) obtained in example 3 was self-assembled by the method in example 4. The particle size distribution of the obtained nano prodrug is shown in FIG. 4, the average particle size is 121nm, and the PDI is 0.09.
Example 7:
this example investigates the environmentally responsive release behavior of self-assembled nano-prodrugs. Taking the self-assembled nano prodrug prepared in example 4 as an example, the self-assembled nano prodrug is dispersed in 20mL of buffer solution (pH 7.4) containing different concentrations of reduced glutathione GSH, samples are taken at specific time points and centrifuged at high speed, the concentration of the active ingredient in the supernatant after centrifugation is measured, and a drug release curve is drawn, and the result is shown in FIG. 5. The nano prodrug is slowly released in a release medium without GSH, and the cumulative release rate in 48 hours is lower than 20 percent; the release of the active ingredient is accelerated significantly in a release medium containing a higher concentration of GSH (5 mM), and the cumulative release rate reaches 80% in 48 hours. The in vitro release result shows that the nano prodrug has tumor microenvironment responsiveness and can rapidly release active ingredients under the action of the reductive environment in tumor cells.
Example 8:
this example investigates the in vitro cytotoxicity of self-assembled nano-prodrugs. Using the self-assembled nano prodrug prepared in example 4 as an example, the CCK8 method was used to evaluate its cytotoxicity in vitro. The specific method comprises the following steps: tumor cells in logarithmic growth phase were seeded in 96-well plates (5X 10) 3 Hole), after the cells adhere to the wall, the culture solution is changed to contain the self-assembly nano prodrug, cisplatin solution is used as a control group, after incubation is carried out for 48 hours at 37 ℃, 10 mu LCCK8 reagent is added into each hole, and after incubation is carried out for 4 hours, the OD value of each hole is measured at the wavelength of 450 nm. Calculating cell survival rate to obtain half Inhibition Concentration (IC) of drug on cell growth 50 ). The in vitro toxicity results of the prepared self-assembled nano prodrug on tumor cells are shown in table 1.
TABLE 1 cytotoxic Activity of Nanopropiodrugs (II)
Figure BDA0003808760680000081
The results in table 1 show that half of the inhibitory concentration of the self-assembled nano prodrug after incubation for 48 hours with human ovarian cancer SKOV3 cells is equivalent to that of cisplatin solution, which indicates that the proliferation inhibitory capacity of cisplatin on tumor cells is not affected after self-assembly of cisplatin into nano prodrug; particularly, after incubation with a platinum drug-resistant cell line SKOV3/DDP, the half inhibition concentration of the self-assembled nano prodrug is obviously lower than that of a cisplatin solution, so that the nano prodrug has certain advantages in the aspect of relieving tumor drug resistance.
Example 9:
this example examined peptidyl platinum self-assembled nano-particles having the structure shown in formula (III)In vitro cytotoxicity of the prodrugs. Specifically, taking the self-assembled nano prodrug prepared in example 5 as an example and an oxaliplatin solution as a control group, the half Inhibitory Concentration (IC) of the self-assembled nano prodrug on human colon cancer HCT116 and a drug-resistant cell line HCT116/L-OHPD thereof was tested by the method in example 8 50 ). The in vitro toxicity results of the prepared self-assembled nano prodrug on tumor cells are shown in table 2.
TABLE 2 cytotoxic Activity of Nanopropiodrugs (III)
Figure BDA0003808760680000091
Example 10:
in this example, the in vitro cytotoxicity of the peptidyl platinum self-assembled nano prodrug with the structure shown in formula (IV) is examined. Specifically, using the self-assembled nano prodrug prepared in example 6 as an example and a carboplatin solution as a control group, the half Inhibitory Concentration (IC) of the self-assembled nano prodrug on human ovarian cancer SKOV3 and its platinum-resistant cell line SKOV3/DDP was tested in the same manner as in example 8 50 ). The in vitro toxicity results of the prepared self-assembled nano prodrug on tumor cells are shown in table 2.
TABLE 3 cytotoxic Activity of Nanopropiodrugs (IV)
Figure BDA0003808760680000092
Example 11:
this example evaluates the in vivo antitumor efficacy of self-assembled nano prodrugs. Specifically, a 150 μ LSKOV3/DDP tumor cell suspension (1X 10) 7 ) Inoculating to the ventral subcutaneous part of Balb/c nude mouse to make the tumor volume reach 100-150mm 3 In this case, tumor-bearing mice were randomly divided into three groups (5 mice per group), and the self-assembled nano-prodrug prepared in example 4 (2 mg/kg dose calculated as free cisplatin) was administered to the tail vein 1 time every 2 days for 5 consecutive times. The long and short diameters of the tumor were measured every other day and the tumor volume was calculated, the results are shown in fig. 6. During the treatment period, the tumor volume of the normal saline group continuously increasesNo inhibitory effect on tumor growth; the cisplatin solution group can not effectively inhibit the tumor growth of tumor-bearing mice, and the self-assembled nano prodrug group has a significantly stronger tumor growth inhibition effect than the cisplatin solution group.
Example 12:
this example evaluates the in vivo safety of self-assembled nano-prodrugs. Specifically, healthy KM mice (5-7 weeks) were taken, weighed 20-23g, and randomly divided into 3 groups (10 per group), and the physiological saline, cisplatin solution, and self-assembled nano-prodrug prepared in example 4 (dose 2mg/kg, calculated as free cisplatin) were administered into the tail vein, 1 time every 2 days, and 5 times were administered consecutively. After the administration, the mice were fed regularly, daily attention was paid to the survival conditions, and the body weights were measured, and the results are shown in fig. 7. Mice were sacrificed on day 14 post-dose, major organs (heart, liver, spleen, lung, kidney) were collected, fixed with 4% paraformaldehyde, and tissue sections H & E stained, with the results shown in figure 8.
As can be seen from the results in FIG. 7, the weight of the mice in the cisplatin solution group was significantly reduced after administration, and the weight was reduced by about 25% in 14 days, suggesting that the cisplatin solution group had a severe systemic toxicity. The body weight of the mice in the self-assembled nano prodrug group slightly rises, and is similar to the body weight change of the mice in the normal saline, so that the health condition of the mice is good, and the death phenomenon does not occur. H & E staining results of main organ tissue sections of mice show that obvious liver and kidney injuries are observed in a cisplatin solution group, and the organ tissue sections of a self-assembled nano prodrug group and a normal saline group have no obvious pathological changes, which shows that the toxicity of the original drug can be obviously reduced by the self-assembled nano prodrug, and the self-assembled nano prodrug has higher in-vivo safety when being applied to tumor treatment.
The embodiments of the present invention have been described in detail, but the description is only for the preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention. All equivalent changes and modifications made within the scope of the present invention shall fall within the scope of the present invention.

Claims (10)

1. A peptidyl platinum self-assembled nano prodrug, which is characterized in that: the axial ligand contains a tetravalent platinum complex of tryptophan dipeptide.
2. Peptidyl platinum self-assembling nano-prodrugs according to claim 1, characterized in that: the structure is shown in formula I:
Figure FDA0003808760670000011
wherein R is 1 、R 2 、R 3 、R 4 Individually and/or in combination selected from: cl, NH 3 、
Figure FDA0003808760670000012
3. A peptidyl platinum self-assembling nano prodrug according to claim 2, characterized by having a structure represented by any one of formulae II to IV;
Figure FDA0003808760670000013
4. peptidyl platinum self-assembling nano-prodrug according to any one of claims 1 to 3, characterized in that: the prodrugs are capable of self-assembling into nanostructures of particle size in the range of 10-1000nm, preferably 20-200nm, in an aqueous medium.
5. A method of preparing a peptidyl platinum prodrug according to any one of claims 1 to 4, comprising the steps of: oxidizing bivalent platinum complex Pt (II) into hydroxyl tetravalent platinum complex Pt (IV) by using chlorosuccinimide, and then condensing with oligopeptide containing tryptophan dipeptide motif under the catalysis of TBTU and triethylamine to obtain the peptidyl platinum prodrug.
6. A method of preparing the peptidylplatine-based self-assembled nano prodrug according to any one of claims 1 to 4, characterized in that: dissolving the prepared peptidyl platinum prodrug in a first solvent to obtain an organic phase A; mixing the organic phase A and the water phase B to obtain a mixed solution C; and removing the first solvent in the mixed solution C to obtain the monodisperse nano prodrug.
7. The preparation method of peptidyl platinum self-assembled nano prodrug according to claim 5, wherein:
the first solvent is one or a mixture of at least two of acetone, ethanol, methanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide and N, N-dimethylformamide; preferably, the first solvent is acetone and/or ethanol; the water phase B is one or more of purified water, water for injection, HEPES buffer solution, tris buffer solution or PBS buffer solution; preferably, the water phase B is water for injection or HEPES buffer solution; preferably, the pH of the aqueous phase B is adjusted to a value of 7.0 to 7.8.
8. The preparation method of peptidyl platinum self-assembled nano prodrug according to claim 5 or 6, wherein: the volume ratio of the water phase B to the organic phase A is 1-100, preferably 1-40.
9. A method of preparing a peptidyl platinum prodrug according to claim 5, wherein: the solvent in the mixed solution C is removed by a reduced pressure evaporation method, a high-speed centrifugation method, a dialysis method or an ultrafiltration method; preferably, the solvent in the mixed solution C is removed by evaporation under reduced pressure.
10. Use of peptidyl platinum self-assembling nano prodrug as claimed in any one of claims 1 to 4 in the preparation of an anti-tumor drug.
CN202211005108.0A 2022-08-22 2022-08-22 Peptidyl platinum self-assembly nano prodrug and preparation method and application thereof Pending CN115368436A (en)

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Cited By (1)

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WO2024041532A1 (en) * 2022-08-22 2024-02-29 赣州和美药业股份有限公司 Tetravalent platinum-containing complex, prodrug, preparation method therefor, and use thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024041532A1 (en) * 2022-08-22 2024-02-29 赣州和美药业股份有限公司 Tetravalent platinum-containing complex, prodrug, preparation method therefor, and use thereof
WO2024041535A1 (en) * 2022-08-22 2024-02-29 赣州和美药业股份有限公司 Nano-composition, preparation method therefor, and use thereof

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