CN108126212B - Preparation and application of reduction-sensitive tetravalent platinum nano-composite - Google Patents
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Abstract
The invention discloses a preparation method and application of a reduction-sensitive tetravalent platinum nano-composite. In vitro and in vivo test results show that the compound has reduction sensitivity in tumor cells, has higher antitumor activity and simultaneously obviously reduces the toxic and side effects of cisplatin in vivo.
Description
Technical Field
The invention relates to a preparation method and application of a reduction-sensitive tetravalent platinum nano-composite.
Background
Cisplatin, after having been discovered by Rosenberg et al in 1965, is rapidly becoming the most widely used first-line anticancer drug in clinic for treating various malignant tumors (including testicular cancer, ovarian cancer, breast cancer, bladder cancer, liver cancer, lung cancer, neck cancer and non-small cell lung cancer). Cisplatin acts through its covalent binding to adenine and guanine bases of DNA, causing interchain and intrachain cross-linking of DNA, inhibiting DNA synthesis and killing cells. Cisplatin has no specificity to each phase of a cell cycle, and the drug effect presents dose dependence, but the accompanying toxic and side effects such as nephrotoxicity, irreversible peripheral neuropathy and ototoxicity severely limit the clinical application of cisplatin. The advent of inert tetravalent platinum prodrug compounds has received considerable attention from researchers in order to reduce toxic side effects while retaining the antitumor activity of cisplatin.
The tetravalent platinum prodrug compound has an inert structure of octahedron coordination, and is considered to have wide application prospect in the research field of platinum anti-cancer drugs. The compound keeps the inertia of substitution dynamics with protein and other biological macromolecules in blood circulation, can reach tumor cells more stably, and is reduced into bivalent platinum active substances under the high reducing condition in the tumor cells, thereby exerting the anti-tumor activity. It is reported in the literature that axial ligands play an important role in the reduction of tetravalent platinum prodrug compounds, and that their redox electrode potentials change with changes in the axial ligands when the equatorial ligands of the tetravalent platinum compounds are the same, according to the following pattern: OH group-＜OAc-＜Cl-. In addition, if the axial ligand is OAc-, the oxidation-reduction electrode potential of the tetravalent platinum compound most meets the design requirement of the tetravalent platinum anti-cancer drug, and the tetravalent platinum anti-cancer drug does not have serious toxic and side effects caused by too fast reduction and does not inactivate the drug in vivo caused by too slow reduction. Thus, a series of tetravalent platinum drugs are emerging in succession, such as satraplatin (the first to enter clinical validation of oral tetravalent platinum drugs), omaplatin and iproplatin, among others. However, the tetravalent platinum drugs still have a plurality of problems in clinic, such as the failure to reduce the toxic and side effects of cisplatin, the weakening of the antitumor activity of cisplatin, and the like. In view of the challenges faced by the current tetravalent platinum prodrugs, finding an effective drug delivery system is a key measure to solve the problems with tetravalent platinum prodrugs.
The polymeric delivery system can overcome the drawbacks of the presence of tetravalent platinum prodrugs through an Enhanced Permeability and Retention (EPR) effect in tumor tissue. The importance of polymer delivery systems in oncology has been a great concern over the past decade with the advent of biodegradable polymers. A good polymeric carrier plays a crucial role for the delivery of anticancer drugs in vivo, it can successfully load the drug into a delivery system and release it at a specific tumor site. Furthermore, the polymeric carrier must be safe, non-antigenic and suitable for multiple administrations. Poly (glutamic acid) (PGA), N- (2-hydroxypropyl methacrylamide) (HPMA) and poly (ethylene glycol) (PEG) are reported to be the most widely used water-soluble polymers of hydrophobic drugs in clinical therapy. Poly (glutamic acid) PGA is the first choice for polymeric carriers due to its biocompatibility and biodegradability.
Disclosure of Invention
The invention aims to provide a novel reduction-sensitive tetravalent platinum nano-composite;
another objective of the present invention is to provide a preparation method of a reduction-sensitive tetravalent platinum nanocomposite;
still another object of the present invention is to provide the above-mentioned reduction-sensitive tetravalent platinum nanocomposite having an anti-tumor effect.
Therefore, the invention provides a sensitive tetravalent platinum nano-composite, which is characterized in that: cisplatin is used as a raw material, oxidized by an oxidant and modified by succinate to become tetravalent platinum prodrug micromolecules which are suitable for reducing and playing the activity in tumor cells, and then the tetravalent platinum prodrug is skillfully connected with a polyamino acid carrier through a coordination bond to form a tetravalent platinum nano-composite with reduction response in the tumor cells.
Wherein the polyamino acid carrier comprises Polyaspartic Acid (PASP), gamma-polyglutamic acid (gamma-PGA), alpha-polyglutamic acid (alpha-PGA), Polyarginine (PAA), polylysine (epsilon-PL)), and polyamino acid ester modified by hydroxyl-containing small-molecule polyhydroxycarboxylic acid, wherein the small-molecule polyhydroxycarboxylic acid comprises: lactic acid, citric acid, tricarballylic acid, aminomalonic acid, etc., preferably gamma-polyglutamic acid (gamma-PGA), alpha-polyglutamic acid (alpha-PGA), citric acid modified gamma-polyglutamic acid ester, and the structural formula is as follows:
the reduction-sensitive tetravalent platinum complex provided by the invention is formed by combining a polyamino acid carrier and oxidized and modified tetravalent platinum through coordination bonds, wherein the combination mode of the tetravalent platinum and the polyamino acid carrier is various, and the structure of the complex can be shown as follows by combining citric acid modified gamma-polyglutamic acid and tetravalent platinum as an example, but is not limited to the structure.
The preparation process of the reduction-sensitive tetravalent platinum nano composite provided by the invention is as follows:
(1) cisplatin oxidation: weighing a certain amount of cisplatin, adding a proper amount of ultrapure water and an oxidizing agent, and stirring for 12-36 h at room temperature in a dark place. Reduced pressure
(2) Modification of succinic acid: weighing a certain amount of bright yellow powder, dissolving the bright yellow powder in DMSO (dimethyl sulfoxide), adding succinic anhydride according to a molar ratio of 2: 1-1: 5, stirring in a water bath at 50-80 ℃ for overnight reaction to obtain a light yellow solution, vacuumizing to reduce the volume of the solution to 0.5ml, adding a proper volume of glacial acetone to obtain a light white precipitate, centrifuging at 3000r for 5-15 min, and drying in vacuum to obtain a light yellow solid.
(3) Preparing a compound: taking a certain amount of polyglutamic acid carrier powder, adding a proper amount of ultrapure water, stirring and dissolving, adding the synthesized tetravalent platinum prodrug micromolecules according to the molar ratio of 0.1: 1-1: 0.3, stirring at room temperature until the synthesized tetravalent platinum prodrug micromolecules are dissolved, continuously reacting for 24-72 hours, and freeze-drying to obtain the reduction-sensitive tetravalent platinum nano-composite.
The oxidant of step (1) for preparing the tetravalent platinum nanocomposite of the present invention may be MnO2，H2O2Preferably 30% H2O2Preparing an oxidant; stirring for 12-36 h in a dark place, and preferably for 24 h. The reaction molar ratio of the polyamino acid carrier and succinic anhydride adopted in the step (2) is 2: 1-1: 5, and the optimal molar ratio is 1: 1; the heating condition of the water bath is 50-80 ℃, and the optimal temperature is 70 ℃; the centrifugation time is 2-10 min, preferably 5 min. The reaction solvent of step (3) may be an inert organic solvent: such as DMF, DMSO, cyclohexane or pure water, preferably pure water as a reaction solvent; the reaction molar ratio of the tetravalent platinum prodrug micromolecules to the polyamino acid carrier is 0.1: 1-1: 0.3, and preferably 1: 0.2; the reaction time is 24-72 h, preferably 48 h; the drying method is vacuum drying or freeze drying, preferably freeze drying.
The tetravalent platinum nano-composite prepared by the invention has uniform shape, the particle size is about 200nm, and the drug loading is 15%.
The accumulative release amount of the tetravalent platinum nano-composite prepared by the invention in a reduction condition and an acid environment in an in vitro release experiment for 48 hours is about 30 percent higher than that of a common blood environment.
The tetravalent platinum nano-composite prepared by the invention shows lower toxicity in-vitro cell experiments, but the antitumor activity is obviously enhanced after incubation under the reducing condition.
The tetravalent platinum nano-composite prepared by the invention has stronger tumor inhibition rate in-vivo efficacy experiments, obviously prolongs the life cycle of nude mice, and has better application prospect.
Drawings
FIG. 1 shows c, c, t- [ Pt (NH)3)2Cl2(OH)2Hydrogen spectrum of
FIG. 2 shows c, c, t- [ Pt (NH)3)2Cl2(OH)2In the infrared spectrum
FIG. 3 is a hydrogen spectrum of a tetravalent platinum prodrug small molecule
FIG. 4 is an infrared spectrum of tetravalent platinum prodrug small molecule
FIG. 5 is a hydrogen spectrum of tetravalent platinum nanocomposite
FIG. 6 is an infrared spectrum of tetravalent platinum nanocomposite
FIG. 7 is a TEM image of tetravalent platinum nanocomposite
FIG. 8 is a graph showing in vitro release of tetravalent platinum nanocomposites
FIG. 9 is a diagram of in vitro apoptosis of tetravalent platinum nanocomposites
FIG. 10 is an in vivo efficacy profile of tetravalent platinum nanocomposites
Detailed Description
The invention is further elucidated below.
Example 1
c，c，t-[Pt(NH3)2Cl2(OH)2]Synthesis and characterization of
(1)c，c，t-[Pt(NH3)2Cl2(OH)2]The synthesis of (2): weighing a certain amount of cisplatin, adding a proper amount of ultrapure water and 30% of hydrogen peroxide water, and stirring for 12-36 hours at room temperature in a dark place. Filtering under reduced pressure, washing with ultrapure water, ethanol and diethyl ether twice respectively, and removing residual solvent to obtain bright yellow solid.
(2)c，c，t-[Pt(NH3)2Cl2(OH)2Structural characterization
NMR analysis of c, c, t- [ Pt (NH)3)2Cl2(OH)2Drying, dissolving in DMSO-d6, and performing nuclear magnetic resonance H spectrum1HNMR) and the results are shown in fig. 1.
Infrared spectrum analysis for c, c, t- [ Pt (NH)3)2Cl2(OH)2And (3) drying a proper amount of pure product, grinding and tabletting with a small amount of KBr to prepare a sample, scanning at the room temperature within the range of 4000-500 cm < -1 >, and obtaining the resolution of 2cm < -1 >, wherein the result is shown in figure 2.
Example 2
c，c，t-[Pt(NH3)2Cl2(OH)(OOCCH2CH2COOH)]The synthesis and the structural characterization of (1):
(1)c，c，t-[Pt(NH3)2Cl2(OH)(OOCCH2CH2COOH)]the synthesis of (2): weighing a certain amount of the bright yellow powder in the example 1, dissolving the powder in a proper amount of DMSO, adding succinic anhydride according to a mol ratio of 2: 1-1: 3, stirring in a water bath at 50-80 ℃ overnight for reaction to obtain a light yellow solution, vacuumizing to reduce the volume of the solution to 0.5ml, adding a proper amount of glacial acetone to obtain a light white precipitate, centrifuging at 3000r for 5-15 min, and vacuum-drying to obtain a light yellow solid.
(2)c，c，t-[Pt(NH3)2Cl2(OH)(OOCCH2CH2COOH)]Structural characterization
NMR analysis of c, c, t- [ Pt (NH)3)2Cl2(OH)(OOCCH2CH2COOH)]Drying, dissolving in DMSO-d6, and performing nuclear magnetic resonance H spectrum1HNMR) and the results are shown in fig. 3.
Infrared spectrum analysis for c, c, t- [ Pt (NH)3)2Cl2(OH)(OOCCH2CH2COOH)]Drying the pure product in proper amount, grinding and tabletting with a small amount of KBr to prepare a sample, scanning at the room temperature within the range of 4000-500 cm < -1 >, and obtaining the result shown in figure 4, wherein the resolution ratio is 2cm < -1 >.
Example 3
Preparation and characterization of tetravalent platinum nanocomposite:
preparation of tetravalent platinum nanocomposite: taking a certain amount of freeze-dried carrier powder, adding a proper amount of ultrapure water, stirring and dissolving, adding the synthesized tetravalent platinum prodrug micromolecules according to the molar ratio of 0.1: 1-1: 0.3, stirring and dissolving at room temperature, continuously reacting for 24-72 hours, and freeze-drying to obtain the reduction-sensitive tetravalent platinum nano-composite.
Structural characterization of tetravalent platinum nanocomposites:
taking a proper amount of dry and pure tetravalent platinum nano-composite by nuclear magnetic resonance analysis, dissolving in DMSO-d6, and performing nuclear magnetic resonance H spectrum (1HNMR) and the results are shown in fig. 5.
And (3) performing infrared spectrum analysis to obtain a proper amount of a tetravalent platinum nano-composite dry pure product, grinding and tabletting with a small amount of KBr to prepare a sample, scanning at the room temperature within the range of 4000-500 cm < -1 >, and performing resolution ratio of 2cm < -1 >, wherein the result is shown in figure 6.
TEM transmission electron microscope analysis to get proper amount of tetravalent platinum nanometer compound dry pure product, dissolving with ultrapure water and diluting to certain concentration, slowly dripping into coated copper net, absorbing excessive liquid with filter paper, drying under infrared lamp, observing under 80kV projection electron microscope, and finding out the result shown in FIG. 7.
Example 4
Drug loading measurement of tetravalent platinum nanocomposite
Precisely weighing a proper amount of tetravalent platinum nano-composite, dissolving in a certain amount of concentrated nitric acid, carrying out nitrolysis at 80 ℃ for 30min, cooling to room temperature, accurately transferring a volumetric flask with a pipette to a volume of 10ml, and metering the volume to a scale with ultrapure water. And (3) taking 20 mu L of the solution, measuring an absorbance A value by using a graphite furnace atomic absorption spectrophotometer, substituting the absorbance A value into a standard curve to obtain the concentration of the platinum solution, and calculating the platinum content in the tetravalent platinum nano composite. Three batches of the cisplatin are tested in parallel, the cisplatin drug-loading rate is about 15%, the cisplatin utilization rate is high, and the compound preparation cost is low.
Example 5
In vitro release study of tetravalent platinum nanocomposites
Four release media were formulated separately: PBS buffer solution of ph5.0, ph7.4, 0.1mM NaAsc and 5mM NaAsc, a certain amount of tetravalent platinum nanocomposite was accurately weighed, dissolved in a proper amount of the above-mentioned release medium, quickly placed in a sealed dialysis bag (MWCO 3500), immediately sealed, and then placed in five times the volume of the release medium. Different release systems were placed in constant temperature shaking chambers at 37 ℃ and 100rpm, respectively, and 1ml of release medium was aspirated at the corresponding time points for analysis, while 1ml of fresh release medium was rapidly replenished. And (3) measuring the platinum concentration in different release media by adopting a graphite furnace atomic absorption spectrophotometer method.
The experimental results are shown in fig. 8: in the tetravalent platinum nano-composite, the accumulative release amount of platinum in a simulated tumor environment (pH5.0) is obviously higher than that in a physiological environment (pH7.4), and the accumulative release amount of platinum in 48 hours is more than 30 percent. The release of tetravalent platinum nanocomplexes in the release medium of 5mM NaAsc showed significant reduction sensitivity, with the cumulative platinum release of tetravalent platinum nanocomplexes being only 20% in the release medium of 0.1mM NaAsc, while the cumulative platinum release of NaAsc at 5mM reached 58%, which was 38% higher.
Example 6
In vitro apoptosis study of tetravalent platinum nanocomposites
MCF-7 cells in logarithmic growth phase were seeded at 10 x 5/well in 6-well plates and incubated for 24 hours in a cell culture incubator with complete culture in RPMI 1640. Respectively setting a blank group (without adding drugs), a control group (free cisplatin), a drug administration group (tetravalent platinum nano-complex), a reduction group (tetravalent platinum nano-complex which is incubated for three hours by GSH in advance), preferably setting the adherent growth of cells to be 60-70%, discarding a culture medium, and then adding corresponding drugs according to the setting of each group to continue incubation. After the drug acts for 24 hours, the culture medium is removed, PBS is used for washing for three times, then 0.25% trypsin solution (without EDTA) is used for collecting cells, Binding Buffer is added for suspending the cells, Annexin V-FITC 5 muL is added, then Propidium Iodide 5 muL is added for mixing, stirring is carried out for 5-15 min in a dark place at room temperature, and the apoptosis condition is detected by a flow cytometer.
The apoptosis condition is shown in fig. 9, after free cisplatin is incubated for 24h, compared with the normal cells of the control group, the apoptosis ratio is 39%, the apoptosis rate of the tetravalent platinum nano-composite group is 15.57%, and the apoptosis rate of the reduction group (pre-incubated with glutathione for 3 hours) is obviously higher than that of the tetravalent platinum nano-composite group, and is 24.94%.
Example 7
In vivo efficacy study of tetravalent platinum nanocomposite
The nude mice of four weeks old are raised for one week, and are inoculated with human breast cancer cells MCF-7 to establish a human tumor model. About 7-10 days, when the tumor volume is 100mm3In the process, 30 tumor-bearing nude mice are taken, the weight of the tumor-bearing nude mice is 20-22 g, and the tumor-bearing nude mice are randomly divided into 5 groups: blank control group, free CDDP group, tetravalent platinum nanocomplex group (three doses), 6 per group. Fasting was performed for 12h before administration, and water was freely available. CDDP and each preparation freeze-dried powder are respectively diluted to appropriate concentration by adopting normal saline injection, tail vein injection administration is carried out, dosages of tetravalent platinum nano-complex groups are respectively 8mg/kg, 15mg/kg and 30mg/kg (both in terms of CDDP), normal saline injection is taken as a control, the administration volume of each nude mouse is 0.2ml, administration is carried out every other day, administration is carried out for four times, and the anti-tumor effect of the preparation is observed by measuring the tumor volume dynamic state. From the first administration, clinical symptoms of nude mice were observed every day, and the size of tumor was measured using a vernier caliper, and the body weight of nude mice was weighed. The tumor volume calculation formula is as follows:
tumor volume 0.5ab2(a is the longest diameter of the tumor; b is the shortest diameter of the tumor)
The in vivo efficacy results are shown in figure 10: compared with a normal saline control group, the cisplatin group and the tetravalent platinum nano-composite group with different doses both show obvious tumor inhibition effects, wherein the tumor inhibition effect of cisplatin is most obvious, when the dose of the tetravalent platinum nano-composite is 8mg/kg, the tumor inhibition rate is only 25% of that of cisplatin, when the dose is gradually increased, the tumor inhibition rate of the tetravalent platinum nano-composite on tumors is also enhanced, when the dose is increased to 15mg/kg, the tumor inhibition rate is increased to 60%, the dose is continuously increased, and when the dose is increased to 30mg/kg, the tumor inhibition rate of the tetravalent platinum nano-composite is consistent with that of cisplatin. It is noteworthy that the high dose of the drug did not cause significant toxic side effects in nude mice, and the body weight fluctuated smoothly within the normal range. The dose of the cisplatin is only 4mg/kg, the weight of the nude mice is obviously reduced, and the cisplatin shows stronger toxic and side effects. It can be seen from the plotted life cycle curve that the nude mice in the cisplatin group generally have poor quality of life, and the life cycle is significantly lower than that of the tetravalent platinum nanocomposite group, which also reflects that the tetravalent platinum nanocomposite can avoid the side effects caused by free cisplatin in addition to retaining strong tumor killing power of cisplatin.
Claims (3)
1. A reduction-sensitive tetravalent platinum nano-composite is characterized in that the tetravalent platinum nano-composite takes cisplatin as a raw material, is oxidized by an oxidant and modified by succinate to form tetravalent platinum prodrug micromolecules which are suitable for reducing and playing the activity in tumor cells, then the tetravalent platinum prodrug is skillfully connected with a polyamino acid carrier through a coordination bond, reaches the tumor part through an EPR effect, avoids the rapid metabolism of liver and kidney, and achieves the anti-tumor effects of targeted release and long-acting slow release,
the preparation method of the reduction-sensitive tetravalent platinum nano-composite comprises the following steps:
(1) cisplatin oxidation: weighing a certain amount of cisplatin, adding a proper amount of ultrapure water and an oxidant, stirring for 12-36 h at a dark room temperature, carrying out vacuum filtration, washing twice with ultrapure water, ethanol and diethyl ether respectively, and removing residual solvent to obtain a compound I;
(2) modification of succinic acid: weighing a certain amount of the compound I, dissolving the compound I in DMSO (dimethyl sulfoxide), adding succinic anhydride according to a molar ratio of 2: 1-1: 3, stirring in a water bath at 50-80 ℃ for overnight reaction to obtain a light yellow solution, vacuumizing to reduce the volume of the solution to 0.5ml, adding a proper amount of glacial acetone to obtain a light white precipitate, centrifuging at 3000r for 5-15 min, and drying in vacuum to obtain a tetravalent platinum prodrug micromolecule compound II;
(3) preparation of polymer: taking a certain amount of polyamino acid carrier powder, adding a proper amount of ultrapure water, stirring and dissolving, adding the synthesized tetravalent platinum prodrug micromolecule compound II according to the molar ratio of 0.1: 1-1: 0.3, stirring and dissolving at room temperature, continuously reacting for 24-72 h, and freeze-drying to obtain the reduction-sensitive tetravalent platinum nano-composite.
2. The reduction-sensitive tetravalent platinum nanocomposite of claim 1, wherein the oxidant of step (1) is MnO2Or H2O2(ii) a Stirring for 12-36 h in a dark place;
the reaction molar ratio of the compound I adopted in the step (2) to succinic anhydride is 2: 1-1: 5; heating the mixture in a water bath to 50-80 ℃; centrifuging for 2-10 min;
the reaction molar ratio of the tetravalent platinum prodrug micromolecule compound II to the polyamino acid carrier in the step (3) is 0.1: 1-1: 0.3; the reaction time is 24-72 h; the drying method is vacuum drying or freeze drying.
3. The reduction-sensitive tetravalent platinum nanocomposite of claim 1, wherein tetravalent platinum is bonded to the carboxyl groups in two ways, comprising:
(A) tetravalent platinum is coordinately bound to one carboxyl group; (B) tetravalent platinum coordinatively bound to two carboxyl groups
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