CN115590879A - Platinum drug lipid derivative and application thereof - Google Patents
Platinum drug lipid derivative and application thereof Download PDFInfo
- Publication number
- CN115590879A CN115590879A CN202110717375.XA CN202110717375A CN115590879A CN 115590879 A CN115590879 A CN 115590879A CN 202110717375 A CN202110717375 A CN 202110717375A CN 115590879 A CN115590879 A CN 115590879A
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- Prior art keywords
- derivative
- platinum
- lipid derivative
- lipid
- nanoparticles
- Prior art date
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- 239000003814 drug Substances 0.000 title claims abstract description 60
- 229940079593 drug Drugs 0.000 title claims abstract description 57
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 30
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 39
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- A61K47/54—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 an organic compound
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Abstract
The invention belongs to the technical field of medicines, and relates to a platinum-based medicine lipid derivative and application thereof. The derivative is a self-stabilizing nano assembly material, and a platinum active drug group and a hydrophobic lipid long chain are bridged through different connecting bonds to form a micromolecular tetravalent platinum-lipid derivative. Under the assistance of a small amount of stabilizer, the derivative can be spontaneously assembled into nanoparticles in aqueous solution, and long circulation in vivo after administration is realized. Along with the extension of the hydrophobic carbon chain of the derivative, the assembly efficiency of the self-stabilizing nanoparticles is improved, the particle size is smaller, the stability is improved, and the antitumor effect of the drug is stronger.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a platinum-based medicine lipid derivative and application thereof.
Background
Chemotherapy is one of the most common strategies in cancer treatment, especially for tumors that cannot be surgically resected and metastasized. However, most chemotherapeutic drugs are cytotoxic drugs and have the disadvantages of poor stability, narrow therapeutic window, poor pharmacokinetic properties, and the like. And the existing preparation strategy has low delivery efficiency and poor tumor targeting, so that the chemotherapy clinical effect is poor and the toxic and side effects are serious. For example, oxaliplatin (Oxa) is widely used clinically as a first-line chemotherapeutic drug for colorectal cancer, ovarian cancer, and the like. However, because of the nonspecific cytotoxic effect of oxaliplatin, the solution sold in the market can cause serious toxic and side effects, the incidence rate of peripheral neuropathy after administration is high, and the clinical application of the oxaliplatin is greatly limited. Therefore, how to improve the adverse properties of chemotherapeutic drugs and increase the delivery efficiency is a clinically urgent problem to be solved.
In recent years, the wide application of chemical structure modification and nanotechnology in the field of drug delivery greatly enriches the delivery strategies of antitumor drugs, and a plurality of preparations such as irinotecan liposome, paclitaxel albumin nanoparticle, adriamycin liposome and the like have been successfully marketed. The derivatization strategy can improve the adverse properties of the chemotherapeutic drug through ingenious structural modification, including poor stability, great toxic and side effects and the like. In addition, a novel nano drug delivery system constructed based on the nano technology can obviously improve the pharmacokinetic property of the drug, prolong the in vivo circulation time of the chemotherapeutic drug, improve the accumulation of the drug at a tumor part through active targeting or passive targeting, increase the cellular uptake of the drug, control the release speed of the drug, further improve the anti-tumor effect and reduce the toxic and side effects.
On the basis, the self-stabilization type nano-drug delivery system based on the derivatization of the small-molecule drug combines the advantages of the derivatization strategy and the nano-technology together, and becomes a hot spot of chemotherapy drug delivery research in recent years due to the advantages of high drug loading capacity, good stability, low toxic and side effects and the like.
Self-assembled nanoparticles, such as polymeric micelles, lipid nanoparticles or nanoemulsions, are widely used as delivery vehicles for poorly soluble drugs. These carriers that can achieve controlled drug release usually wrap or adsorb the chemotherapeutic drug in the hydrophobic core of the particle, however, most self-assembled structure carriers interact with endogenous components, and there are problems of poor stability of drug loading, for example, many protein components in blood can competitively bind with the drug, resulting in high leakage rate and low drug loading in vivo of the nano carrier. Therefore, an in-vivo understanding of the "drug-carrier" binding stability and dissociation kinetics helps to improve the drug delivery efficiency and thus the therapeutic effect.
The self-stabilizing lipid derivative can be self-assembled into nanoparticles, and the chemical structure of the self-stabilizing lipid derivative has decisive influence on the assembly stability, the in-vivo fate and even the anti-tumor effect of the nanoparticles. The interaction between the self-stabilizing nanoparticles and endogenous biological components such as proteins, phospholipid bilayers, nucleic acids, organelles and the like influences the treatment condition of organisms on the drugs. The chemical structure of the derivative is reasonably designed, so that the derivative is assembled into a nano preparation with good stability and surface properties (particle size, potential, shape and the like), and the nano preparation has important significance for improving the drug delivery efficiency and playing the drug effect.
Disclosure of Invention
The invention aims to provide a tetravalent platinum-lipid derivative, and the derivative is used for preparing self-stabilizing nanoparticles, so that the application of high drug loading capacity, high stability, low toxicity and specific rapid drug release in tumor cells is realized.
In order to achieve the purpose, the invention adopts the technical scheme that:
a platinum drug lipid derivative is composed of platinum drug and hydrophobic lipid long chain as shown in general formula 1 or 2,
in the general formula 1, A is a platinum drug, O in the platinum drug is a non-leaving group, and a square is a leaving group; x is S, S-S, se, se-Se; r is a long hydrophobic lipid chain; n = an integer of 1-3;
in the general formula 2, A is a platinum drug, O in the platinum drug is a non-leaving group, and a square is a leaving group; r is a long hydrophobic lipid chain; n is a radical of an alkyl radical 1 An integer of 1-4.
The platinum drugs in the general formula 1 and the general formula 1 are cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin or episulfide platinum; r is C18-C36 fatty alcohol.
The fatty alcohol may be a linear or branched hydrophobic long lipid chain, such as n-octadecanol, oleyl alcohol, linolenyl alcohol, n-nonadecanol, n-eicosanol, n-docosanol, docosahexanol, n-tetracosanol, etc., preferably n-octadecanol, n-docosanol, n-tetracosanol.
The longer the hydrophobic lipid carbon chain of the self-stabilizing lipid derivative is, the smaller the particle size of the self-stabilizing nanoparticle formed by the self-stabilizing lipid derivative is, the better the colloidal stability is, and the stronger the antitumor effect is.
The preparation method of the platinum drug lipid derivative comprises the steps of firstly oxidizing a divalent platinum compound into tetravalent platinum with bilateral axial hydroxyl groups, then using acid anhydride to enable the bilateral hydroxyl groups of the tetravalent platinum to form esters to obtain an intermediate product containing bilateral carboxyl groups, and finally enabling the carboxyl groups to form esters with fatty alcohol to obtain the tetravalent platinum derivative with the bilateral lipid long-chain connection shown in a general formula 1 or a general formula 2.
Dissolving diacid in acetic anhydride, stirring for 1-2 hours at room temperature, dissolving the obtained product in N, N-dimethylformamide, adding oxidized tetravalent hydroxyl platinum and 4-dimethylamino pyridine, and stirring for 12-48 hours at 30-45 ℃ to obtain an intermediate product; dissolving the intermediate product and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide in N, N-dimethylformamide, stirring for 1-2 hours in an ice bath, then adding 4-dimethylaminopyridine and fatty alcohol, stirring for 12-48 hours at room temperature to obtain a final product, and carrying out all the reactions in a dark place under the protection of nitrogen to obtain the derivative shown in the general formula 1 or the general formula 2;
wherein, the mole ratio of dianhydride to the oxidized quadrivalent hydroxyl platinum is 0.6 to 1.5, and the mole ratio of the oxidized quadrivalent hydroxyl platinum to the 4-dimethylamino pyridine is 0.5 to 4; the molar ratio of the intermediate product to 1-ethyl-3 (3-dimethylpropylamine) carbodiimide is 1-4; the mol ratio of the intermediate product to the 4-dimethylamino pyridine is 0.5-4; the mol ratio of the 4-dimethylamino pyridine to the fatty alcohol is 0.5-4.
Wherein the diacid is malonic acid, succinic acid, glutaric acid, adipic acid, 2,2 '-thiodiacetic acid, 2,2' -selenodiacetic acid, 2,2 '-dithiodiacetic acid, 2,2' -diselenodiacetic acid, 3,3 '-dithiodipropionic acid or 3,3' -diselenodipropionic acid.
The method further comprises the following steps:
according to the invention, carboplatin and fatty alcohols with different chain lengths are selected as model drugs, and the carboplatin is oxidized and then is respectively connected with n-hexanol (a), n-dodecanol (b) and n-octadecanol (c) through disulfide bonds to prepare the self-stabilizing lipid derivative, wherein the structural formula of the self-stabilizing lipid derivative is shown as the following formula:
specifically, the invention provides a preparation method of a series of carboplatin-n-octadecanol derivatives, which comprises the following steps:
adipic acid or 2,2' -dithiodiacetic acid is dissolved in acetic anhydride, stirred for 1-2 hours at room temperature, the obtained product is dissolved in N, N-dimethylformamide, oxidized tetravalent hydroxycarbaplatin and 4-dimethylaminopyridine are added, and stirred for 12-48 hours at 35 ℃ to obtain an intermediate product. Dissolving the intermediate product and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide in N, N-dimethylformamide, stirring for 1-2 hours in an ice bath, then adding 4-dimethylaminopyridine and N-octadecanol, stirring for 12-48 hours at room temperature to obtain a final product, and carrying out all the reactions in a dark place under the protection of nitrogen.
An application of the derivative shown in the general formula 1 or the general formula 2 in preparing antitumor drugs.
A self-stabilizing lipid derivative nanoparticle, the composition of the nanoparticle comprising the self-stabilizing lipid derivative of claim 1 and a stabilizer; the mass ratio of the lipid derivative to the stabilizer is 99-70.
The stabilizer is one or more of a surfactant and/or a steric stabilizer which are commonly used in pharmacy.
The stabilizer is DSPE-PEG 2000 And the like surfactants or steric stabilizers which are commonly used in pharmacy.
The preparation method of the self-stabilizing lipid derivative nanoparticle comprises the steps of dissolving and dispersing the lipid derivative and a stabilizing agent into an organic solvent to obtain a dispersion system, slowly and dropwise adding the dispersion system into water or using a microfluidic cross-flow micromixing method and the like to assemble the derivative into the stable nanoparticle, and then removing the organic solvent to obtain the self-stabilizing lipid derivative nanoparticle.
Further, the lipid derivative and the stabilizer are dissolved and dispersed in an organic solvent, the organic solvent solution is slowly dripped into water dropwise or by using methods such as ultrasound, cross-flow micromixing and the like, so that the derivative is stably assembled into nanoparticles, and finally, the organic solvent in the nanoparticles is removed by adopting methods such as reduced pressure evaporation, dialysis or ultrafiltration, and the like, so as to obtain the nano colloidal solution without any organic solvent.
A pharmaceutical composition comprising said self-stabilizing lipid derivative.
An application of the self-stabilizing lipid derivative nanoparticle or the pharmaceutical composition in preparing an anti-tumor drug.
The administration mode of the antitumor drug is injection administration, oral administration or local administration.
The invention has the advantages that:
the synthetic lipid derivative is obtained by designing different long chain lengths of hydrophobic lipid, different connecting bonds and different side chain positions, and is used for preparing self-stabilizing nanoparticles, so that the influences of the assembling capacity, stability, reduction responsiveness, cytotoxicity, pharmacokinetics, tissue distribution and pharmacodynamics of the nanoparticles are improved; the method specifically comprises the following steps:
1) The synthetic method of the series of lipid derivatives is simple and easy to implement;
2) The lipid derivative prepared by the invention is used for preparing uniform derivative self-stabilization type nanoparticles, and the preparation method is simple and easy to implement, good in stability, low in stabilizer usage amount and high in drug loading.
3) According to the lipid derivative obtained by different lipid carbon chain lengths, along with the extension of the carbon chain, the nano assembly capacity of the lipid derivative is enhanced, the particle size of the lipid derivative self-stabilizing nanoparticle is reduced, the stability is increased, the cytotoxicity is stronger, the in-vivo long circulation effect is better, more drugs are distributed on tumor parts, the anti-tumor curative effect of the nanoparticle is obviously improved, the lipid derivative has important significance on reasonable structure design of the derivative and efficient delivery of active drugs, and the lipid derivative has a wide prospect in the field of disease treatment.
Drawings
FIG. 1 is a drawing showing the disulfide-bonded bridged carboplatin-n-hexanol derivative (CSS 6) of example 1 of the present invention 1 HMR spectra and mass spectra.
FIG. 2 is a drawing showing the disulfide-bond bridged carboplatin-n-dodecanol derivative (CSS 12) of example 2 of the present invention 1 HMR spectra and mass spectra.
FIG. 3 is a schematic representation of the disulfide-bridged carboplatin-n-octadecanol derivative (CSS 18) of example 3 of the present invention 1 HMR spectra and mass spectra.
FIG. 4 is a drawing showing an adipate bond bridged carboplatin-n-octadecanol derivative (C-18) according to example 4 of the present invention 1 HMR spectra and mass spectra.
FIG. 5 is a drawing of a disulfide-bridged unilateral carboplatin-n-octadecanol derivative (mCSS 18) of example 5 of the invention 1 HMR spectrum and mass spectrum.
Fig. 6 is a synthesis route of a carboplatin-lipid derivative of example 6 of the present invention, and is a transmission electron microscope image, a particle size distribution diagram, and a tyndall phenomenon appearance diagram of a DSPE-PEG modified carboplatin-lipid derivative nanoparticle, wherein a is a synthesis route diagram of a carboplatin-lipid derivative, B is a transmission electron microscope image of a DSPE-PEG modified carboplatin-lipid derivative nanoparticle, C is an appearance diagram of a DSPE-PEG modified carboplatin-lipid derivative nanoparticle, D is a particle size distribution diagram of a DSPE-PEG modified carboplatin-lipid derivative nanoparticle, E is an appearance diagram of a DSPE-PEG modified carboplatin-lipid derivative nanoparticle, and F is a tyndall phenomenon diagram of a DSPE-PEG modified carboplatin-lipid derivative nanoparticle.
Fig. 7 is a graph of particle size-storage time for DSPE-PEG modified carboplatin-lipid derivative nanoparticles of example 7 of the invention, where a is the graph of particle size-storage time for DSPE-PEG modified carboplatin-lipid derivative nanoparticles in PBS 7.4 and B is the graph of particle size-storage time for DSPE-PEG modified carboplatin-lipid derivative nanoparticles in 10-percent fbs.
Fig. 8 is a drug release profile of DSPE-PEG modified carboplatin lipid derivative nanoparticles of example 8 of this invention, where a is the drug release profile of DSPE-PEG modified carboplatin lipid derivative nanoparticles in 0mM GSH, B is the drug release profile of DSPE-PEG modified carboplatin lipid derivative nanoparticles in 1mM GSH, and C is the drug release profile of DSPE-PEG modified carboplatin lipid derivative nanoparticles in 10mM GSH.
Fig. 9 is a graph of blood concentration-time profile and drug in vivo tissue distribution of DSPE-PEG modified carboplatin lipid derivative nanoparticles of example 10 of the present invention, wherein a is a graph of DNA-Pt adduct content of DSPE-PEG modified carboplatin lipid derivative nanoparticles, B is a graph of blood concentration-time profile of DSPE-PEG modified carboplatin lipid derivative nanoparticles, C is a graph of blood concentration-time profile of 4-hour DSPE-PEG modified carboplatin lipid derivative nanoparticles, and D is a graph of blood concentration-time profile of 12-hour DSPE-PEG modified carboplatin lipid derivative nanoparticles.
Fig. 10 is a graph showing the in vivo antitumor activity of DSPE-PEG modified carboplatin lipid derivative nanoparticles of example 11 of the present invention, wherein a is the graph of the antitumor activity tumor volume of the DSPE-PEG modified carboplatin lipid derivative nanoparticles per 4T1 tumor-bearing mouse, B is the graph of the antitumor activity tumor volume of the DSPE-PEG modified carboplatin lipid derivative nanoparticles of 4T1 tumor-bearing mouse, C is the graph of the antitumor activity tumor weight of the DSPE-PEG modified carboplatin lipid derivative nanoparticles of 4T1 tumor-bearing mouse, and D is the graph of the change in body weight of 4T1 tumor-bearing mouse after administration.
FIG. 11 is a graph showing the in vivo antitumor effect of DSPE-PEG modified carboplatin-lipid derivative nanoparticles of example 11 of the present invention, wherein A is the plot of antitumor effect tumor volume of DSPE-PEG modified carboplatin-lipid derivative nanoparticles per B16-F10 tumor-bearing mouse, B is the plot of antitumor effect tumor volume of DSPE-PEG modified carboplatin-lipid derivative nanoparticles per B16-F10 tumor-bearing mouse, C is the plot of antitumor effect tumor weight of DSPE-PEG modified carboplatin-lipid derivative nanoparticles per B16-F10 tumor-bearing mouse, and D is the plot of body weight change of B16-F10 tumor-bearing mouse after administration.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto.
The derivative is a self-stabilizing nano assembly material, and a platinum active drug group and a hydrophobic lipid long chain are bridged through different connecting bonds to form a micromolecular tetravalent platinum-lipid derivative. Under the assistance of a small amount of stabilizer, the derivative can be spontaneously assembled into nanoparticles in aqueous solution, and long circulation in vivo after administration is realized. Along with the extension of the hydrophobic carbon chain of the derivative, the assembly efficiency of the self-stabilizing nanoparticles is improved, the particle size is smaller, the stability is improved, and the antitumor effect of the drug is stronger.
Example 1: synthesis of disulfide-bonded bridged carboplatin-n-hexanol derivative (CSS 6)
Dissolving 600mg of carboplatin in 20mL of deionized water, clarifying the solution, adding 2mL of 30% 2 O 2 And stirring was continued for 6 hours at 50 ℃ under nitrogen protection from light. And (3) placing the reaction solution at 4 ℃ overnight for recrystallization, carrying out 6000-turn 15min centrifugation, collecting precipitate, sequentially washing with ethanol and ether pre-cooled at-20 ℃ for 3 times respectively, and drying to obtain the oxidized tetravalent dihydroxycarboplatin. 5mmol of 2,2' -dithiodiacetic acid was dissolved in 8mL of acetic anhydride, and stirred at 25 ℃ for 2 hours. Adding 6mL of toluene into the reaction solution, uniformly mixing, distilling under reduced pressure to remove toluene and unreacted acetic anhydride, and repeating the process for three timesTo obtain 2,2' -dithiodiacetic anhydride. 0.5mmol of tetravalent hydroxycarbaplatin is dispersed in 20mL of DMF, 1.2mmol of 2,2' -dithiodiacetic anhydride and 0.2mmol of 4-dimethylaminopyridine are added with stirring at 35 ℃ and then the reaction is continued for 12 hours. Then, 1mmol of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide was added for activation for 20 minutes, and 1.5mmol of n-hexanol was added to the reaction mixture solution and stirred overnight. The resulting solution was filtered, evaporated to about 2mL using an oil pump under reduced pressure, and the precipitate was collected by addition of 50mL diethyl ether, washed three additional times with diethyl ether, and dried under vacuum to give the desired product. The whole reaction process is carried out under the protection of nitrogen and in the dark.
The structure of the derivative in the example is determined by mass spectrometry and nuclear magnetic resonance hydrogen spectrometry, the result and peak assignment are shown in fig. 1, the solvent selected for nuclear magnetic resonance is deuterated DMSO, and the spectrum analysis result is as follows:
ESI-MS(m/z):[C 26 H 46 N 2 O 12 PtS 4 ] - [M-H] - ＝901.02(calculated M:901.99)
example 2: synthesis of disulfide-bonded bridged carboplatin-n-dodecanol derivative (CSS 12)
Dissolving 600mg of carboplatin in 20mL of deionized water, clarifying the solution, adding 2mL of 30% 2 O 2 And stirring was continued for 6 hours at 50 ℃ under nitrogen protection from light. And (3) placing the reaction solution at 4 ℃ overnight for recrystallization, carrying out 6000-turn 15min centrifugation, collecting precipitate, sequentially washing with ethanol and ether pre-cooled at-20 ℃ for 3 times respectively, and drying to obtain oxidized tetravalent hydroxyl carboplatin. 5mmol of 2,2' -dithiodiacetic acid was dissolved in 8mL of acetic anhydride, and stirred at 25 ℃ for 2 hours. 6mL of toluene is added into the reaction solution and mixed evenly, the toluene and the unreacted acetic anhydride are removed by reduced pressure distillation, and the process is repeated for three times to obtain the product 2,2' -dithiodiacetic anhydride. 0.5mmol of tetravalent hydroxycarbaplatin is dispersed in 20mL of DMF, 1.2mmol of 2,2' -dithiodiacetic anhydride and 0.2mmol of 4-dimethylaminopyridine are added with stirring at 35 ℃ and then the reaction is continued for 12 hours. Then, 1mmol of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide was added thereto for activation for 20 minutes, and 1.5mmol of n-dodecanol was added to the reaction mixture solution, followed by stirring overnight. Filtering the resulting solution toEvaporate to about 2mL under reduced pressure with an oil pump and add 50mL ether to collect the precipitate, continue to wash with ether three times and dry under vacuum to give the desired product. The whole reaction process is carried out under the protection of nitrogen and in the dark.
The structures of the derivatives in the examples were determined by mass spectrometry and nuclear magnetic resonance hydrogen spectrometry, and the results and peak assignments are shown in fig. 2, the solvent used for nuclear magnetic resonance was deuterated DMSO, and the results of the spectroscopic analysis were as follows:
ESI-MS(m/z):[C 38 H 70 N 2 O 12 PtS 4 ] - [M-H] - ＝1069.25(calculated M:
1070.31)
example 3: synthesis of disulfide-bridged Carboplatin-n-Octadecanol derivative (CSS 18)
Dissolving 600mg of carboplatin in 20mL of deionized water, clarifying the solution, adding 2mL of 30% 2 O 2 And kept stirring for 6 hours at 50 ℃ under nitrogen protection in the dark. And (3) putting the reaction solution at 4 ℃ overnight for recrystallization, carrying out 6000-turn 15min centrifugation, collecting precipitate, sequentially washing with ethanol and ether precooled at-20 ℃ for 3 times respectively, and drying to obtain the oxidized tetravalent hydroxyl carboplatin. 5mmol of 2,2' -dithiodiacetic acid was dissolved in 8mL of acetic anhydride, and stirred at 25 ℃ for 2 hours. 6mL of toluene is added into the reaction solution and mixed evenly, the toluene and the unreacted acetic anhydride are removed by reduced pressure distillation, and the process is repeated for three times to obtain the product 2,2' -dithiodiacetic anhydride. 0.5mmol of tetravalent hydroxycarbaplatin is dispersed in 20mL of DMF, 1.2mmol of 2,2' -dithiodiacetic anhydride and 0.2mmol of 4-dimethylaminopyridine are added with stirring at 35 ℃ and then the reaction is continued for 12 hours. Then, 1mmol of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide was added thereto for activation for 20 minutes, and 1.5mmol of n-octadecanol was added to the reaction mixture solution, followed by stirring overnight. The resulting solution was filtered, evaporated to about 2mL using an oil pump under reduced pressure, and the precipitate was collected by addition of 50mL ether, washed three additional times with ether, and dried under vacuum to give the desired product. The whole reaction process is carried out under the protection of nitrogen and in the dark.
The structures of the derivatives in the examples were determined by mass spectrometry and nuclear magnetic resonance hydrogen spectrometry, and the results and peak assignments are shown in fig. 3, the solvent used for nuclear magnetic resonance was deuterated DMSO, and the results of the spectroscopic analysis were as follows:
ESI-MS(m/z):[C 50 H 94 N 2 O 12 PtS 4 ] - [M-H] - ＝1237.5(calculated M:1238.63)
example 4: synthesis of adipate bond bridged carboplatin-n-octadecanol derivative (C-18)
Dissolving 600mg of carboplatin in 20mL of deionized water, clarifying the solution, adding 2mL of 30% 2 O 2 And stirring was continued for 6 hours at 50 ℃ under nitrogen protection from light. And (3) putting the reaction solution at 4 ℃ overnight for recrystallization, carrying out 6000-turn 15min centrifugation, collecting precipitate, sequentially washing with ethanol and ether precooled at-20 ℃ for 3 times respectively, and drying to obtain the oxidized tetravalent hydroxyl carboplatin. 5mmol of adipic acid was dissolved in 8mL of acetic anhydride and stirred at 25 ℃ for 2 hours. Adding 6mL of toluene into the reaction solution, uniformly mixing, distilling under reduced pressure to remove the toluene and unreacted acetic anhydride, and repeating the process for three times to obtain the product adipic anhydride. 0.5mmol of tetravalent hydroxycarbaplatin is dispersed in 20mL of DMF, 1.2mmol of 2,2' -dithiodiacetic anhydride and 0.2mmol of 4-dimethylaminopyridine are added with stirring at 35 ℃ and then the reaction is continued for 12 hours. Then, 1mmol of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide was added thereto for activation for 20 minutes, and 1.5mmol of n-octadecanol was added to the reaction mixture solution, followed by stirring overnight. The resulting solution was filtered, evaporated to about 2mL using an oil pump under reduced pressure, and the precipitate was collected by the addition of 50mL of diethyl ether, washed three additional times with diethyl ether, and dried under vacuum to give the desired product. The whole reaction process is carried out under the protection of nitrogen and in the dark.
The structures of the derivatives in the examples were determined by mass spectrometry and nuclear magnetic resonance hydrogen spectrometry, and the results and peak assignments are shown in fig. 4, the solvent used for nuclear magnetic resonance was deuterated DMSO, and the results of the spectroscopic analysis were as follows:
ESI-MS(m/z):[C 54 H 102 N 2 O 12 PtS 4 ] - [M-H] - ＝1165.42(calculated M:
1166.47)
example 5: synthesis of disulfide-bridged unilateral carboplatin-n-octadecanol derivative (mCSS 18)
Dissolving 600mg of carboplatin in 20mL of deionized water, clarifying the solution, adding 2mL of 30% 2 O 2 And kept stirring for 6 hours at 50 ℃ under nitrogen protection in the dark. And (3) putting the reaction solution at 4 ℃ overnight for recrystallization, carrying out 6000-turn 15min centrifugation, collecting precipitate, sequentially washing with ethanol and ether precooled at-20 ℃ for 3 times respectively, and drying to obtain the oxidized tetravalent hydroxyl carboplatin. 5mmol of 2,2' -dithiodiacetic acid was dissolved in 8mL of acetic anhydride, and the mixture was stirred at 25 ℃ for 2 hours. 6mL of toluene is added into the reaction solution and mixed evenly, the toluene and the unreacted acetic anhydride are removed by reduced pressure distillation, and the process is repeated for three times to obtain the product 2,2' -dithiodiacetic anhydride. 0.5mmol of tetravalent hydroxycarbaplatin is dispersed in 20mL of DMF, 0.6mmol of 2,2' -dithiodiacetic anhydride and 0.2mmol of 4-dimethylaminopyridine are added with stirring at 35 ℃ and then the reaction is continued for 12 hours. Then, 1mmol of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide was added thereto for activation for 20 minutes, and 0.8mmol of n-octadecanol was added to the reaction mixture solution, followed by stirring overnight. The resulting solution was filtered, evaporated to about 2mL using an oil pump under reduced pressure, and the precipitate was collected by addition of 50mL ether, washed three additional times with ether, and dried under vacuum to give the desired product. The whole reaction process is carried out under the protection of nitrogen and in the dark.
The structures of the derivatives in the examples were determined by mass spectrometry and nuclear magnetic resonance hydrogen spectrometry, and the results and peak assignments are shown in fig. 5, the solvent used for nuclear magnetic resonance was deuterated DMSO, and the results of the spectroscopic analysis were as follows:
ESI-MS(m/z):[C 38 H 70 N 2 O 12 PtS 4 ] - [M-H] - ＝820.89(calculated M:
821.94)
example 6: preparation of DSPE-PEG modified lipid derivative self-stabilizing nanoparticle
Accurately weighing 7mg DSPE-PEG 2000 Dissolving in 1mL of absolute ethanol to prepare a stock solution of 7mg/mL for later use. Precisely weighing 4mg of the derivative prepared in each example, dissolving and dispersing in 0.2mL of DSPE-PEG 2000 In the stock solution, the mixed solution is dropwise added into 2mL of deionized water by a pipette, and the stirring rotating speed is maintainedStirring at 600rpm for 15min to obtain lipid derivative self-stabilizing nanoparticles. Then residual ethanol in all nanoparticles was removed by rotary evaporation under reduced pressure at 30 ℃.
The particle size and morphology of the lipid derivative self-stabilizing nanoparticles prepared in example 6 were measured by transmission electron microscopy, and the results are shown in fig. 6B, which is a transmission electron microscopy image showing that the nanoparticles are uniform spheres. As shown in tables 1 and 2, the particle size and polydispersity of the series of lipid derivative nanoparticles showed a clear correlation with the lipid chain length of the derivative: CSS18 ≈ C-18 yarn-woven CSS12 yarn-woven CSS6, namely the longer the chain length is, the smaller the particle size of the nanoparticles is, and the more uniform the particle size distribution is. Meanwhile, for the carboplatin-lipid derivative with the same carbon chain length, the particle size of the derivative grafted by the double-side carbon chain is smaller than that of the derivative grafted by the single-side carbon chain, and the particle size distribution is more uniform (CSS 18< mCSS 18). This correlation is more pronounced as the nanoparticle drug concentration is increased (1 mg Pt/mL and 1.5mg Pt/mL). The CSS6 and mCSS18 nanoparticles appeared to precipitate significantly during the preparation at a concentration of 1.5mg Pt/mL, while the CSS18 nanoparticles still exhibited a uniform and transparent appearance at concentrations as high as 6mg Pt/mL, as shown in fig. 6C. In FIG. 6E, the Tyndall effect was observed under the laser beam for all nanoparticles (1.5 mg Pt/mL) except CSS6 nanoparticles that precipitated on the bottom of the vial. The above results indicate that the short carbon chain lipid derivative CSS6 has poor assembly stability at high concentrations. The supernatant of the mCSS18 nanoparticles can see weak light beams, but precipitates still exist, which indicates that the stability of the mCSS18 nanoparticles is poor and the assembly capability of the mCSS18 nanoparticles is weak. Of all nanoparticles, CSS18 had the best physicochemical properties, even stabilized at 1.5mg Pt/mL, with a bluish and clear appearance (fig. 6C). These results indicate that the length and position of the aliphatic chain play a crucial role in the self-stabilizing assembly pattern of the carboplatin-lipid derivative. Compared with the derivatives with single-side carbon chains and short-side carbon chains, the derivatives with double sides and long carbon chains have better assembly performance.
TABLE 1 particle size, particle size distribution and surface potential of DSPE-PEG modified Low concentration (0.5 mg Pt/mL) carboplatin lipid derivatives self-stabilizing nanoparticles
| Pt(IV)NPs | Size(nm) | PDI | Zeta(mV) |
| CSS6 | 150.4±21.53 | 0.409±0.030 | -19.1±1.501 |
| CSS12 | 102.4±3.108 | 0.113±0.033 | -25.4±1.992 |
| CSS18 | 84.39±1.054 | 0.132±0.022 | -22.5±1.768 |
| C-18 | 87.53±4.805 | 0.193±0.032 | -29.7±2.326 |
| mCSS18 | 117.3±4.513 | 0.290±0.024 | -14.6±1.147 |
TABLE 2 particle size and particle size distribution of DSPE-PEG modified high concentration (1 mg Pt/mL, 1.5mg Pt/mL) carboplatin lipid derivatives self-stabilizing nanoparticles
Example 7: colloidal stability test of DSPE-PEG modified lipid derivative self-stabilized nanoparticles
Each of the DSPE-PEG modified lipid derivatives prepared in example 6 was taken out by 1mL from the stabilized nanoparticle, added to 20mL of phosphate buffer solution (PBS, pH 7.4) (FIG. 7A) and incubated at 37 ℃ for 7 days or added to phosphate buffer solution (PBS, pH 7.4) (FIG. 7B) containing 10% FBS and incubated at 37 ℃ for 24 hours, and the change in particle size was measured by dynamic light scattering at a predetermined time point (see FIG. 7). As shown by the results of fig. 7A and B, the particle size and PDI of the remaining nanoparticles in 10mM PBS 7.4, except for CSS6 NPs, remained stable for one week, and the particle size and PDI of CSS6 NPs increased significantly, indicating that the nanoparticles composed of short-chain lipid derivatives were poor in stability. In 10% FBS, the long-chain lipid derivative nanoparticles (C-18, CSS12 and CSS18 NPs) remained stable for 24 hours with no significant change in appearance and size.
Phosphate buffered saline (PBS, pH 7.4) at 0mM,1mM and 10mM GSH was used as release medium in the in vitro release assay to simulate a non-reducing environment, a reducing environment in the blood circulation and a reducing environment at the tumor site, respectively. Dialysis bags (cut-off molecular weight 1 kD) containing 1mL of free carboplatin solution (Car) and five lipid derivative nanoparticles (CSS 6, CSS12, CSS18, C-18 and mCSS18 nanoparticles), respectively, were immersed in 20mL of the corresponding release medium, placed at 37 ℃ and shaken at constant temperature and constant speed at 100 rpm. The amount of drug released was determined by taking 1mL of free carboplatin solution and release media from the five lipid derivative nanoparticle sets at time points 1, 2, 4, 8, 12, and 24 hours, respectively (see figure 8).
As shown in fig. 8A, the cumulative drug release amount of each group of nanoparticles was less than 10% in 0mM GSH buffer. As shown in FIG. 8B, in 1mM GSH release buffer, the release rate of the disulfide bond-containing CSS6, CSS12, CSS18 and mCSS18 nanoparticles is slightly higher than that of C-18 nanoparticles. As shown in fig. 8C, in a release medium of 10mM GSH, the drug release amount of the lipid derivative self-stabilizing nanoparticles (CSS 6, CSS12, CSS18, and mCSS18 nanoparticles) is greater than 70% in 4 hours, the drug release amount exceeds 80% in 24 hours, and the drug release amount at any time point is significantly greater than that of the non-disulfide-bond lipid derivative C-18 nanoparticles. The shows that the carboplatin-lipid derivative nanoparticle containing the disulfide bond is more sensitive to GSH and has stronger responsiveness than the lipid derivative nanoparticle inserted with the non-disulfide bond. According to the nanoparticle characteristics and the stability experiment results, the longest carbon chain lipid derivative CSS18 has the optimal self-stable assembly behavior and good colloidal stability, and the responsiveness to GSH is basically equivalent to that of other disulfide bond derivatives. This indicates that the strategy of chemical structure adjustment to enhance the assembly and stability of lipid derivative nanoparticles does not affect their specific responsiveness to intracellular GSH.
Example 9 cytotoxicity of DSPE-PEG modified lipid derivatives self-stabilized nanoparticles
The toxicity of the DSPE-PEG modified lipid derivative self-stabilizing nanoparticles on three tumor cells, namely mouse prostate cancer (RM-1) cells, mouse breast cancer (4T 1) cells, human ovarian cancer cells (A2780) and human normal liver (L02) cells is examined by adopting an MTT method. Firstly, digesting cells with good morphology, diluting the cells to 5000cells/mL by using a cell culture medium, uniformly blowing the cells, adding 100 mu L of cell suspension into each hole of a 96-hole plate, and placing the cells in an incubator for incubation for 24 hours to adhere to the walls. After the cells adhere to the wall, the lipid derivative nanoparticles prepared in example 6 were added. Test solution was added at 100. Mu.L per well, 3 parallel wells per concentration. In the control group, 100 mul of culture solution is singly supplemented without adding the liquid medicine to be detected, and the control group is placed in an incubator to be incubated with cells together. At 48 hours after dosing, the 96-well plate was removed, 20 μ L of 5mg/mL MTT solution was added to each well, the plate was spun off after incubation for 4 hours in an incubator, the 96-well plate was inverted on filter paper to completely blot the residual liquid, and 200 μ L DMSO was added to each well and shaken on a shaker for 10 minutes to dissolve the bluish violet crystals. A1 wells (containing only 200. Mu.L DMSO) were set as zeroed wells. The absorbance value after zeroing of each well was measured at 570nm using a microplate reader.
The cytotoxic results are shown in table 3. The CSS6 nanoparticles have the weakest cytotoxic effect on all cell lines, and the activity of the CSS6 nanoparticles is even lower than that of derivative nanoparticles C-18NPs without disulfide bonds. Of all self-stabilizing nanoparticles, CSS18 nanoparticles showed the strongest cytotoxicity in three cancer cell lines, even with IC of carboplatin solution 50 Close. After 48 hours of culture in L-02 cells, all derivative nanoparticles showed weaker cytotoxicity than free carboplatin, indicating that the GSH-responsive lipid derivative strategy is expected to achieve selective killing of tumors and low toxic side effects of normal tissues.
TABLE 3 IC of 4T1, B16, A2780 and L-02 cells after 48 hours treatment of different lipid derivative solutions and nanoparticles 50 Value (μ M)
| Sample | 4T1 | B16 | A2780 | L-02 |
| Car sol | 24.37 | 2.242 | 206.5 | 47.28 |
| CSS6 NPs | 818.1 | 155.6 | >1000 | 684.7 |
| CSS12NPs | 34.37 | 1.882 | 35.62 | 76.95 |
| CSS18NPs | 10.62 | 2.624 | 8.875 | 191.2 |
| C-18NPs | 115.9 | 47.28 | 403.2 | 439.4 |
| mCSS18NPs | 62.42 | 28.62 | 186.5 | 321.4 |
Example 10 pharmacokinetics and tissue distribution studies of DSPE-PEG modified lipid derivative self-stabilizing nanoparticles
SD rats weighing between 200-250g were randomly assigned to a group, fasted for 12 hours before administration, and allowed free access to water. The carboplatin solution and the DSPE-PEG modified lipid derivative self-stabilizing nanoparticles prepared in example 6 were injected intravenously, respectively. The dosage of the drug is 3mg/kg. Blood was collected from the orbit at the prescribed time points and separated to obtain plasma. The drug concentration in plasma was determined by inductively coupled plasma mass spectrometry (see fig. 9 and table 4).
The pharmacokinetic study results are shown in FIGS. 9A-B and Table 4, where the AUC improvement of CSS18 and C-18 nanoparticles is the most significant, 36.11 mg. H. L-1, which is about 8 times higher than that of the solution. CSS6 nanoparticles were rapidly eliminated in plasma, AUC (2.2 fold) and t 1/2 Slightly increased. The AUC of the lipid derivative nanoparticles was ranked as: CSS18 ≈ C-18>CSS12≈mCSS18>CSS6, indicates that the long circulation properties of the nanoparticles are related to the carbon chain length of the derivative, i.e. the longer the carbon chain, the more stable the nanoparticles and the longer the systemic circulation time. The results of in vivo distribution experiments at 4 hours and 12 hours after administration are shown in fig. 9C and D, respectively, and the intratumoral accumulation amounts of the lipid derivative nanoparticles are ranked as follows: CSS18 ≈ C-18>CSS12>mCSS18>CSS6 shows that the long circulation properties of the nanoparticles are related to the carbon chain length of the derivative, i.e. the longer the carbon chain, the more stable the nanoparticles are, the longer the systemic circulation time, the more accumulation at the tumor site.
TABLE 4 pharmacokinetic parameters of lipid derivative self-stabilizing nanoparticles
| Sample | AUC 0-12h a) | t 1/2 b) | CL c) | V d) |
| Car | 4.236±2.143 | 4.635±4.602 | 1.669±1.281 | 15.83±2.633 |
| CSS6 NPs | 9.418±5.290 | 4.506±3.985 | 1.016±1.794 | 14.75±3.093 |
| CSS12NPs | 19.63±5.136 | 4.426±4.630 | 0.999±1.801 | 14.62±3.173 |
| CSS18NPs | 36.11±18.53 | 3.669±4.200 | 0.837±1.879 | 13.88±3.513 |
| C-18NPs | 33.99±21.55 | 3.802±4.120 | 0.847±1.875 | 13.93±3.493 |
| mCSS18NPs | 18.84±10.34 | 4.632±4.055 | 0.892±1.853 | 14.26±3.333 |
Example 11 pharmacodynamic study of DSPE-PEG modified lipid derivative self-stabilizing nanoparticles
The 4T1 cell suspension was inoculated subcutaneously on the right dorsal side of female Balb/c mice. When the tumor volume grows to 150mm 3 Then, tumor-bearing mice were randomly divided into 7 groups of 5 mice each, which were respectively a 5% glucose control group, an oxaliplatin solution group, a CSS6 nanoparticle group, a CSS12 nanoparticle group, a CSS18 nanoparticle group, a C-18 nanoparticle group, and an mCSS18 nanoparticle group. The administration is carried out every other day for 4 times. The establishment of the B16-F10 tumor-bearing mouse model is consistent with the 4T1 model.
The results of tumor growth inhibition in FIGS. 10 and 11, characterized by tumor volume and weight of two types of tumor model mice, FIGS. 10A and 11A are tumor volumes per mouse, FIG. 10B is mean value in FIG. 11B, FIGS. 10A-D are mean values, and in FIGS. 11A-D, 5% glucose injection is maximal as control tumor volume, and up to 1200mm on day 14 3 CSS6 and C-18 nanoparticles have limited tumor growth inhibition, probably due to poor stability and delayed release of the drug. The CSS18, CSS12 and mCSS18 nanoparticle groups showed significant tumor suppression (tumor volumes at day 14 of 400, 700 and 900mm, respectively 3 ) The tumor growth rate of the tumor-bearing mice treated by the CSS18 nanoparticles is lowest, and the tumor volume is smallest at day 14. The tumor growth inhibition rule of the B16-F10 tumor-bearing mouse is basically consistent with that of the 4T1 tumor-bearing mouse, and the relationship between the in-vivo anti-tumor effect of the derivative nanoparticles and the carbon chain length of the lipid derivative is as follows: CSS18>CSS12>mCSS18 (corresponding to "CSS 9")>CSS6, which shows that the longer the carbon chain of the carboplatin-lipid derivative is, the stronger the anti-tumor effect of the self-stabilizing nanoparticle is.
Claims (10)
1. A platinum drug lipid derivative is characterized in that: the derivative is formed by platinum drugs and a hydrophobic lipid long chain and is shown in a general formula 1 or a general formula 2,
in the general formula 1, A is a platinum drug, O in the platinum drug is a non-leaving group, and a square is a leaving group; x is S, S-S, se, se-Se; r is a long hydrophobic lipid chain; n = an integer of 1-3;
in the general formula 2, A is a platinum drug, O in the platinum drug is a non-leaving group, and a square is a leaving group; r is a long hydrophobic lipid chain; n is 1 An integer of 1-4.
2. The platinum-based drug lipid derivative of claim 1, wherein: the platinum drugs in the general formula 1 and the general formula 1 are cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin or episulfide platinum; r is C18-C36 fatty alcohol.
3. The method for preparing a lipid derivative of a platinum-based drug according to claim 1, wherein: firstly, oxidizing a divalent platinum compound into tetravalent platinum with bilateral axial hydroxyl groups, then using acid anhydride to enable the bilateral hydroxyl groups of the tetravalent platinum to form esters to obtain an intermediate product containing bilateral carboxyl groups, and finally enabling the carboxyl groups to form esters with fatty alcohol to obtain the tetravalent platinum derivative connected with the bilateral lipid long chain shown in the general formula 1 or the general formula 2.
4. The method for preparing a platinum-based drug lipid derivative according to claim 3, wherein: dissolving diacid in acetic anhydride, stirring for 1-2 hours at room temperature, dissolving the obtained product in N, N-dimethylformamide, adding oxidized tetravalent hydroxyl platinum and 4-dimethylaminopyridine, and stirring for 12-48 hours at 30-45 ℃ to obtain an intermediate product; dissolving the intermediate product and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide in N, N-dimethylformamide, stirring for 1-2 hours in an ice bath, then adding 4-dimethylaminopyridine and fatty alcohol, stirring for 12-48 hours at room temperature to obtain a final product, and carrying out all the reactions in a dark place under the protection of nitrogen to obtain the derivative shown in the general formula 1 or the general formula 2;
wherein, the mole ratio of the oxidized tetravalent hydroxyl platinum and the 4-dimethylamino pyridine is 0.5-4; the molar ratio of the intermediate product to 1-ethyl-3 (3-dimethylpropylamine) carbodiimide is 1-4; the mol ratio of the 4-dimethylamino pyridine to the fatty alcohol is 0.5-4.
5. Use of a derivative according to claim 1, wherein: the derivative shown in the general formula 1 or the general formula 2 is applied to preparation of antitumor drugs.
6. A self-stabilizing lipid derivative nanoparticle, wherein the composition of the nanoparticle comprises the self-stabilizing lipid derivative of claim 1 and a stabilizer; the mass ratio of the lipid derivative to the stabilizer is 99-70.
7. The self-stabilizing lipid derivative nanoparticle according to claim 6, wherein the stabilizer is one or more of a surfactant and/or a steric stabilizer commonly used in pharmacy.
8. The preparation method of the self-stabilizing lipid derivative nanoparticles as claimed in claim 6, wherein the lipid derivative as shown in claim 1 and a stabilizer are dissolved and dispersed in an organic solvent to obtain a dispersion system, the dispersion system is slowly and dropwise added into water or microfluidic cross-flow micromixing and other methods are used to assemble the derivative into stable nanoparticles, and then the organic solvent is removed to obtain the self-stabilizing lipid derivative nanoparticles.
9. A pharmaceutical composition characterized by: a self-stabilizing lipid derivative according to claim 1.
10. An application, characterized by: use of the self-stabilizing lipid derivative nanoparticle of claim 6 or the pharmaceutical composition of claim 9 for the preparation of an anti-tumor drug.
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