CN115590879B - Platinum drug lipid derivative and application thereof - Google Patents
Platinum drug lipid derivative and application thereof Download PDFInfo
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- CN115590879B CN115590879B CN202110717375.XA CN202110717375A CN115590879B CN 115590879 B CN115590879 B CN 115590879B CN 202110717375 A CN202110717375 A CN 202110717375A CN 115590879 B CN115590879 B CN 115590879B
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- derivative
- lipid derivative
- platinum
- lipid
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- 150000002632 lipids Chemical class 0.000 title claims abstract description 75
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 59
- 239000003814 drug Substances 0.000 title claims abstract description 50
- 229940079593 drug Drugs 0.000 title claims abstract description 48
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 26
- 239000002105 nanoparticle Substances 0.000 claims abstract description 121
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 21
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 17
- 239000003381 stabilizer Substances 0.000 claims abstract description 16
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 39
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 15
- 229960004562 carboplatin Drugs 0.000 claims description 14
- YAYRGNWWLMLWJE-UHFFFAOYSA-L carboplatin Chemical compound O=C1O[Pt](N)(N)OC(=O)C11CCC1 YAYRGNWWLMLWJE-UHFFFAOYSA-L 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- 239000000047 product Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000013067 intermediate product Substances 0.000 claims description 11
- -1 platinum lipid Chemical class 0.000 claims description 11
- 150000001718 carbodiimides Chemical class 0.000 claims description 10
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- 230000002146 bilateral effect Effects 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- KIDPOJWGQRZHFM-UHFFFAOYSA-N platinum;hydrate Chemical compound O.[Pt] KIDPOJWGQRZHFM-UHFFFAOYSA-N 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 239000006185 dispersion Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000012467 final product Substances 0.000 claims description 3
- 239000004094 surface-active agent Substances 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 150000003057 platinum Chemical class 0.000 claims description 2
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- 239000000203 mixture Substances 0.000 claims 1
- 239000002245 particle Substances 0.000 abstract description 24
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 14
- 230000004087 circulation Effects 0.000 abstract description 7
- 230000000857 drug effect Effects 0.000 abstract description 4
- 239000007864 aqueous solution Substances 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 45
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- DLLMHEDYJQACRM-UHFFFAOYSA-N 2-(carboxymethyldisulfanyl)acetic acid Chemical compound OC(=O)CSSCC(O)=O DLLMHEDYJQACRM-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
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- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 5
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- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
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- IKYKEVDKGZYRMQ-PDBXOOCHSA-N (9Z,12Z,15Z)-octadecatrien-1-ol Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCCO IKYKEVDKGZYRMQ-PDBXOOCHSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- JPSKCQCQZUGWNM-UHFFFAOYSA-N 2,7-Oxepanedione Chemical compound O=C1CCCCC(=O)O1 JPSKCQCQZUGWNM-UHFFFAOYSA-N 0.000 description 1
- AXJLEYVRLPNPGF-UHFFFAOYSA-N 3-(2-carboxyethyldiselanyl)propanoic acid Chemical compound OC(=O)CC[Se][Se]CCC(O)=O AXJLEYVRLPNPGF-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
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- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
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- 229930012538 Paclitaxel Natural products 0.000 description 1
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- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- GTDPSWPPOUPBNX-UHFFFAOYSA-N ac1mqpva Chemical compound CC12C(=O)OC(=O)C1(C)C1(C)C2(C)C(=O)OC1=O GTDPSWPPOUPBNX-UHFFFAOYSA-N 0.000 description 1
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- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- GRHLMSBCOPRFNA-UHFFFAOYSA-M azanide 2-oxidoacetate platinum(4+) Chemical compound N[Pt]1(N)OCC(=O)O1 GRHLMSBCOPRFNA-UHFFFAOYSA-M 0.000 description 1
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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- 229940042317 doxorubicin liposome Drugs 0.000 description 1
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- 210000004185 liver Anatomy 0.000 description 1
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- 229950007221 nedaplatin Drugs 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
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- 150000007523 nucleic acids Chemical class 0.000 description 1
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- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physics & Mathematics (AREA)
- Biomedical Technology (AREA)
- Nanotechnology (AREA)
- Optics & Photonics (AREA)
- Inorganic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the technical field of medicines, and relates to a platinum drug lipid derivative and application thereof. The derivative is a self-stable nano-assembly material, and a platinum active drug group and a hydrophobic lipid long chain are bridged through different connecting bonds to form a tetravalent platinum-lipid derivative of a small molecule. With the help of a small amount of stabilizer, the derivative can spontaneously assemble into nano particles in an aqueous solution, so that long circulation in a body after administration is realized. Along with the extension of the hydrophobic carbon chain of the derivative, the assembly efficiency of the self-stabilizing nanoparticle is improved, the particle size is smaller, the stability is improved, and the antitumor drug effect of the drug is stronger.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a platinum drug lipid derivative and application thereof.
Background
Chemotherapy is one of the most common strategies in cancer treatment, especially for those tumors that cannot be resected by surgery and spread by metastasis. Most of the chemotherapeutics are cytotoxic drugs, and have the defects of poor stability, narrow treatment window, poor pharmacokinetic properties and the like. And the existing preparation strategy has low delivery efficiency and poor tumor targeting, so that the clinical effect of chemotherapy is poor and the toxic and side effects are serious. For example, oxaliplatin (Oxa) is widely used clinically as a first-line chemotherapeutic agent for the treatment of colorectal cancer, ovarian cancer, and the like. However, due to the nonspecific cytotoxic effect of oxaliplatin, the commercial solutions cause serious toxic and side effects, and the incidence of peripheral neuropathy after administration is high, which greatly limits the clinical application of oxaliplatin. Therefore, how to improve the adverse properties of chemotherapeutic drugs and to increase the delivery efficiency is a clinical challenge to be addressed.
In recent years, chemical structure modification and the wide application of nanotechnology in the field of drug delivery greatly enrich the delivery strategies of antitumor drugs, and a plurality of preparations such as irinotecan liposome, paclitaxel albumin nanoparticle, doxorubicin liposome and the like have been successfully marketed. Derivatization strategies can improve adverse properties of chemotherapeutic drugs through ingenious structural modification, including poor stability, large toxic and side effects and the like. In addition, the novel nano drug delivery system constructed based on the nano technology can remarkably improve the pharmacokinetic property of the drug, prolong the in vivo circulation time of the chemotherapeutic drug, improve the accumulation of the drug at the 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-stabilizing nano-drug delivery system based on derivatization of small-molecule drugs combines the advantages of derivatization strategies and nano-technology, and has become a hot spot for chemotherapy drug delivery research in recent years due to the advantages of high drug loading, 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 capable of achieving controlled drug release generally encapsulate or adsorb chemotherapeutic drugs on the hydrophobic core of the particles, however, most self-assembled structural carriers interact with endogenous components, and have problems such as poor drug loading stability, for example, many protein components in blood can be competitively combined with drugs, resulting in high leakage rate and low drug loading in the nanocarrier. Thus, an in-depth understanding of the in-vivo "drug-carrier" binding stability and dissociation kinetics helps to increase drug delivery efficiency and thus therapeutic efficacy.
The self-stabilizing lipid derivative can be self-assembled into nano particles, and the chemical structure of the self-stabilizing lipid derivative has decisive influence on the assembly stability, in-vivo fate and even anti-tumor effect of the nano particles. Interaction between self-stabilizing nanoparticles and endogenous biological components such as proteins, phospholipid bilayer, nucleic acid and organelles affects the handling of drugs by the body. The chemical structure of the derivative is reasonably designed, so that the derivative is assembled into a nano preparation with good stability and good surface properties (particle size, potential, shape and the like), and the nano preparation has important significance for improving the drug delivery efficiency and exerting the drug effect.
Disclosure of Invention
The technical problem to be solved by the invention is 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, high stability, low toxicity and specific quick release in tumor cells is realized.
In order to achieve the above purpose, the invention adopts the technical scheme that:
a platinum lipid derivative is composed of platinum and hydrophobic lipid long chain as shown in formula 1 or formula 2,
in the general formula 1, A is a platinum drug, O in the platinum drug is a non-leaving group, and square is a leaving group; x is S, S-S, se, se-Se; r is a hydrophobic lipid long chain; n=an integer from 1 to 3;
in the general formula 2, A is a platinum drug, O in the platinum drug is a non-leaving group, and square is a leaving group; r is a hydrophobic lipid long chain; n is n 1 =an integer of 1 to 4.
The platinum drugs in the general formulas 1 and 1 are cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin or cyclothioplatin; r is a C18-C36 fatty alcohol.
The fatty alcohol may be a long chain of a linear or branched hydrophobic lipid, such as n-stearyl alcohol, oleyl alcohol, linolenyl alcohol, n-nonadecyl alcohol, n-eicosyl alcohol, docosahexaenoic alcohol, n-tetracosyl alcohol, etc., preferably n-stearyl alcohol, n-eicosyl alcohol, n-tetracosyl alcohol.
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 colloid stability is, and the stronger the anti-tumor drug effect is.
The preparation method of the platinum drug lipid derivative comprises the steps of firstly oxidizing a bivalent platinum compound into tetravalent platinum with bilateral axial hydroxyl groups, then using anhydride to enable the bilateral hydroxyl groups of the tetravalent platinum to form ester to obtain an intermediate product containing bilateral carboxyl groups, and finally enabling the carboxyl groups to form ester with fatty alcohol to obtain the tetravalent platinum derivative with 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 hydroxyplatinum 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 a derivative shown in a general formula 1 or a general formula 2;
wherein, the mole ratio of dianhydride to oxidized tetravalent hydroxy platinum is 0.6-1.5, and the mole ratio of oxidized tetravalent hydroxy platinum to 4-dimethylaminopyridine is 0.5-4; the molar ratio of the intermediate product to the 1-ethyl-3 (3-dimethylpropylamine) carbodiimide is 1-4; the molar ratio of the intermediate product to the 4-dimethylaminopyridine is 0.5-4; the molar ratio of the 4-dimethylaminopyridine to the fatty alcohol is 0.5-4.
Wherein the diacid is malonic acid, succinic acid, glutaric acid, adipic acid, 2 '-thiodiacetic acid, 2' -selenodiacetic acid, 2 '-dithiodiacetic acid, 2' -diselenodiacetic acid, 3 '-dithiodipropionic acid or 3,3' -diselenodipropionic acid.
The method is characterized by further comprising the following steps:
according to the invention, carboplatin and fatty alcohols with different chain lengths are selected as model medicines, and the carboplatin is respectively connected with n-hexanol (a), n-dodecanol (b) and n-octadecanol (c) through disulfide bonds after being oxidized 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:
adipic acid or 2,2' -dithiodiacetic acid is dissolved in acetic anhydride, stirred for 1 to 2 hours at room temperature, the obtained product is dissolved in N, N-dimethylformamide, oxidized tetravalent hydroxycaprotinin and 4-dimethylaminopyridine are added, and stirred for 12 to 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, and stirring for 12-48 hours at room temperature to obtain a final product, wherein all the reactions are carried out in a dark place under the protection of nitrogen.
The application of the derivative is that the derivative shown in the general formula 1 or the general formula 2 is applied to the preparation of antitumor drugs.
A self-stabilizing lipid derivative nanoparticle comprising the self-stabilizing lipid derivative of claim 1 and a stabilizing agent; the mass ratio of the lipid derivative to the stabilizer is 99:1-70:30.
The stabilizer is one or more of surfactants and/or steric stabilizers commonly used in pharmacy.
The stabilizer is DSPE-PEG 2000 And surfactants or steric stabilizers 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 dropwise adding the obtained dispersion system into water or using microfluidic cross-flow micro-mixing and other methods to assemble the derivative into the stable nanoparticle, and 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 and dropwise added into water or the derivative is stably assembled into nano particles by using methods such as ultrasonic and cross-flow micro-mixing, and finally, the organic solvent in the nano particles is removed by adopting methods such as reduced pressure evaporation, dialysis or ultrafiltration, so as to obtain the nano colloid 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 antitumor drugs.
The anti-tumor drug is administered by injection, orally or topically.
The invention has the advantages that:
the synthetic lipid derivative is designed and obtained from different hydrophobic lipid long chain lengths, 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 obtained nanoparticles are improved; the method comprises the following steps:
1) The synthetic method of the serial lipid derivatives is simple and feasible;
2) The lipid derivative prepared by the invention is used for preparing uniform self-stabilizing nanoparticles of the derivative, the preparation method is simple and easy to implement, the stability is good, the usage amount of the stabilizer is small, and the drug loading amount is high.
3) The lipid derivative obtained by different lipid carbon chain lengths has the advantages that the nanometer assembly capacity of the lipid derivative is enhanced along with the carbon chain extension, 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, the medicine distribution at the tumor part is more, the anti-tumor curative effect of the nanoparticle is obviously improved, and the lipid derivative has important significance on reasonable structural design of the derivative and high-efficiency delivery of active medicines and has wide prospect in the field of disease treatment.
Drawings
FIG. 1 shows a disulfide bridge Lian Kabo-n-hexanol derivative (CSS 6) of example 1 of the invention 1 HMR spectra and mass spectra.
FIG. 2 shows a disulfide bridge Lian Kabo-n-dodecanol derivative (CSS 12) of example 2 of the invention 1 HMR spectra and mass spectra.
FIG. 3 shows a disulfide bridge Lian Kabo-n-octadecanol derivative (CSS 18) of example 3 of the invention 1 HMR spectra and mass spectra.
FIG. 4 is a diagram of an adipic acid ester bridge Lian Kabo-n-octadecanol derivative (C-18) of example 4 of the present invention 1 HMR spectra and mass spectra.
FIG. 5 is a disulfide bridge of the one-sided carboplatin-n-octadecanol derivative (mCSS 18) of example 5 of the invention 1 HMR spectra and mass spectra.
FIG. 6 is a synthetic route of carboplatin-lipid derivative of example 6 of the present invention, an external view transmission electron microscope, a particle size distribution map and a tyndall phenomenon external view of the carboplatin-lipid derivative nanoparticle of the present invention, wherein A is a synthetic route map of the carboplatin-lipid derivative, B is a transmission electron microscope of the carboplatin-lipid derivative nanoparticle of the present invention, C is an external view of the carboplatin-lipid derivative nanoparticle of the present invention, D is a particle size distribution map of the carboplatin-lipid derivative nanoparticle of the present invention, E is a tyndall phenomenon external view of the carboplatin-lipid derivative nanoparticle of the present invention.
FIG. 7 is a graph of particle size versus storage time for DSPE-PEG modified carboplatin-lipid derivative nanoparticles of example 7 of the invention, wherein A is the graph of particle size versus storage time for DSPE-PEG modified carboplatin-lipid derivative nanoparticles in PBS 7.4 and B is the graph of particle size versus storage time for DSPE-PEG modified carboplatin-lipid derivative nanoparticles in 10% FBS.
FIG. 8 is a graph showing the drug release of the DSPE-PEG modified carboplatin-lipid derivative nanoparticle of example 8 of the present invention, wherein A is the drug release of the DSPE-PEG modified carboplatin-lipid derivative nanoparticle in 0mM GSH, B is the drug release of the DSPE-PEG modified carboplatin-lipid derivative nanoparticle in 1mM GSH, and C is the drug release of the DSPE-PEG modified carboplatin-lipid derivative nanoparticle in 10mM GSH.
FIG. 9 is a graph of blood concentration versus time for DSPE-PEG modified carboplatin-lipid derivative nanoparticles and a graph of tissue in vivo for a drug of example 10 of the present invention, wherein A is a graph of DNA-Pt adduct content for DSPE-PEG modified carboplatin-lipid derivative nanoparticles, B is a graph of blood concentration versus time for DSPE-PEG modified carboplatin-lipid derivative nanoparticles, C is a graph of blood concentration versus time for 4 hours DSPE-PEG modified carboplatin-lipid derivative nanoparticles, and D is a graph of blood concentration versus time for 12 hours DSPE-PEG modified carboplatin-lipid derivative nanoparticles.
FIG. 10 is an in vivo antitumor drug efficacy graph of the DSPE-PEG modified carboplatin-lipid derivative nanoparticle of example 11 of the present invention, wherein A is an antitumor drug efficacy tumor volume graph of the DSPE-PEG modified carboplatin-lipid derivative nanoparticle of each 4T1 tumor-bearing mouse, B is an antitumor drug efficacy tumor volume graph of the DSPE-PEG modified carboplatin-lipid derivative nanoparticle of the 4T1 tumor-bearing mouse, C is an antitumor drug efficacy tumor weight graph of the DSPE-PEG modified carboplatin-lipid derivative nanoparticle of the 4T1 tumor-bearing mouse, and D is a weight change graph of the 4T1 tumor-bearing mouse after administration.
FIG. 11 is an in vivo antitumor drug efficacy graph of the DSPE-PEG modified carboplatin-lipid derivative nanoparticle of example 11 of the present invention, wherein A is an antitumor drug efficacy tumor volume graph of the DSPE-PEG modified carboplatin-lipid derivative nanoparticle of each B16-F10 tumor-bearing mouse, B is an antitumor drug efficacy tumor volume graph of the DSPE-PEG modified carboplatin-lipid derivative nanoparticle of the B16-F10 tumor-bearing mouse, C is an antitumor drug efficacy tumor weight graph of the DSPE-PEG modified carboplatin-lipid derivative nanoparticle of the B16-F10 tumor-bearing mouse, and D is a weight change graph of the B16-F10 tumor-bearing mouse after administration.
Detailed Description
The invention is further illustrated by way of examples which follow, but are not thereby limited to the scope of the examples described.
The derivative is a self-stable nano-assembly material, and a platinum active drug group and a hydrophobic lipid long chain are bridged through different connecting bonds to form a tetravalent platinum-lipid derivative of a small molecule. With the help of a small amount of stabilizer, the derivative can spontaneously assemble into nano particles in an aqueous solution, so that long circulation in a body after administration is realized. Along with the extension of the hydrophobic carbon chain of the derivative, the assembly efficiency of the self-stabilizing nanoparticle is improved, the particle size is smaller, the stability is improved, and the antitumor drug effect of the drug is stronger.
Example 1: synthesis of disulfide bridge Lian Kabo-n-hexanol derivative (CSS 6)
600mg of carboplatin was dissolved in 20mL of deionized water, and after clarification, 2mL of 30% H was added thereto 2 O 2 And stirred continuously at 50 ℃ for 6 hours under the protection of nitrogen in dark. And (3) standing the reaction solution at 4 ℃ overnight for recrystallization, centrifuging for 6000 r 15min, collecting precipitate, washing with pre-cooled ethanol and diethyl ether for 3 times in sequence, 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. 6mL of toluene is added into the reaction solution to be uniformly mixed, toluene and unreacted acetic anhydride are removed by reduced pressure distillation, and the process is repeated three times to obtain the product 2,2' -dithiodiacetic anhydride. 0.5mmol of tetravalent hydroxycaprotinin was dispersed in 20mL DMF, 1.2mmol of 2,2' -dithiodiacetic anhydride and 0.2mmol of 4-dimethylaminopyridine were added with stirring at 35℃and the reaction was continued for 12 hours. Then 1mmol of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide was added to activate for 20 minutes, 1.5mmol of n-hexanol was added to the reaction mixture, and stirred overnight. The resulting solution was filtered, evaporated to about 2mL under reduced pressure using an oil pump, and the precipitate was collected by adding 50mL diethyl ether, washed three times with diethyl ether, and dried under vacuum to give the objective product. The whole reaction process is carried out in a dark place under the protection of nitrogen.
The structure of the derivative in the examples was determined by mass spectrometry and nuclear magnetic resonance hydrogen spectrometry, the results and peak assignment are shown in fig. 1, the solvent used for nuclear magnetic resonance is deuterated DMSO, and the results of the spectroscopic analysis are 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 bridge Lian Kabo-n-dodecanol derivative (CSS 12)
600mg of carboplatin was dissolved in 20mL of deionized water, and after clarification, 2mL of 30% H was added thereto 2 O 2 And stirred continuously at 50 ℃ for 6 hours under the protection of nitrogen in dark. And (3) standing the reaction solution at 4 ℃ overnight for recrystallization, centrifuging for 6000 r 15min, collecting precipitate, washing with pre-cooled ethanol and diethyl ether for 3 times in sequence, and drying to obtain oxidized tetravalent hydroxycaprotinin. 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 to be uniformly mixed, toluene and unreacted acetic anhydride are removed by reduced pressure distillation, and the process is repeated three times to obtain the product 2,2' -dithiodiacetic anhydride. 0.5mmol of tetravalent hydroxycaprotinin was dispersed in 20mL DMF, 1.2mmol of 2,2' -dithiodiacetic anhydride and 0.2mmol of 4-dimethylaminopyridine were added with stirring at 35℃and the reaction was continued for 12 hours. Then 1mmol of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide was added to activate for 20 minutes, 1.5mmol of n-dodecanol was added to the reaction mixture, and stirred overnight. The resulting solution was filtered, evaporated to about 2mL under reduced pressure using an oil pump, and the precipitate was collected by adding 50mL diethyl ether, washed three more times with diethyl ether, and dried under vacuum to give the objective product. The whole reaction process is carried out in a dark place under the protection of nitrogen.
The structure of the derivative in the examples was determined by mass spectrometry and nuclear magnetic resonance hydrogen spectrometry, the results and peak assignment are shown in fig. 2, the solvent used for nuclear magnetic resonance is deuterated DMSO, and the results of the spectroscopic analysis are 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 bridge Lian Kabo-n-octadecanol derivative (CSS 18)
600mg of carboplatin was dissolved in 20mL of deionized water, and after clarification, 2mL of 30% H was added thereto 2 O 2 And stirred continuously at 50 ℃ for 6 hours under the protection of nitrogen in dark. And (3) standing the reaction solution at 4 ℃ overnight for recrystallization, centrifuging for 6000 r 15min, collecting precipitate, washing with pre-cooled ethanol and diethyl ether for 3 times in sequence, and drying to obtain oxidized tetravalent hydroxycaprotinin. 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 to be uniformly mixed, toluene and unreacted acetic anhydride are removed by reduced pressure distillation, and the process is repeated three times to obtain the product 2,2' -dithiodiacetic anhydride. 0.5mmol of tetravalent hydroxycaprotinin was dispersed in 20mL DMF, 1.2mmol of 2,2' -dithiodiacetic anhydride and 0.2mmol of 4-dimethylaminopyridine were added with stirring at 35℃and the reaction was continued for 12 hours. Then 1mmol of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide was added to activate for 20 minutes, 1.5mmol of n-stearyl alcohol was added to the reaction mixture, and stirred overnight. The resulting solution was filtered, evaporated to about 2mL under reduced pressure using an oil pump, and the precipitate was collected by adding 50mL diethyl ether, washed three more times with diethyl ether, and dried under vacuum to give the objective product. The whole reaction process is carried out in a dark place under the protection of nitrogen.
The structure of the derivative in the examples was determined by mass spectrometry and nuclear magnetic resonance hydrogen spectrometry, the results and peak assignment are shown in fig. 3, the solvent used for nuclear magnetic resonance is deuterated DMSO, and the results of the spectroscopic analysis are 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 adipic acid ester bridge Lian Kabo-n-octadecanol derivative (C-18)
600mg of carboplatin was dissolved in 20mL of deionized water, and after clarification, 2mL of 30% H was added thereto 2 O 2 And keep stirring continuously at 50deg.C under nitrogen protection in dark placeMix for 6 hours. And (3) standing the reaction solution at 4 ℃ overnight for recrystallization, centrifuging for 6000 r 15min, collecting precipitate, washing with pre-cooled ethanol and diethyl ether for 3 times in sequence, and drying to obtain oxidized tetravalent hydroxycaprotinin. 5mmol of hexamethylene diacetic acid was dissolved in 8mL of acetic anhydride and stirred at 25℃for 2 hours. 6mL of toluene is added into the reaction solution to be uniformly mixed, toluene and unreacted acetic anhydride are removed by reduced pressure distillation, and the process is repeated three times to obtain adipic anhydride product. 0.5mmol of tetravalent hydroxycaprotinin was dispersed in 20mL DMF, 1.2mmol of 2,2' -dithiodiacetic anhydride and 0.2mmol of 4-dimethylaminopyridine were added with stirring at 35℃and the reaction was continued for 12 hours. Then 1mmol of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide was added to activate for 20 minutes, 1.5mmol of n-stearyl alcohol was added to the reaction mixture, and stirred overnight. The resulting solution was filtered, evaporated to about 2mL under reduced pressure using an oil pump, and 50mL of diethyl ether was added to collect the precipitate, which was further washed three times with diethyl ether and dried under vacuum to give the objective product. The whole reaction process is carried out in a dark place under the protection of nitrogen.
The structure of the derivative in the examples was determined by mass spectrometry and nuclear magnetic resonance hydrogen spectrometry, the results and peak assignment are shown in fig. 4, the solvent used for nuclear magnetic resonance is deuterated DMSO, and the results of the spectroscopic analysis are 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)
600mg of carboplatin was dissolved in 20mL of deionized water, and after clarification, 2mL of 30% H was added thereto 2 O 2 And stirred continuously at 50 ℃ for 6 hours under the protection of nitrogen in dark. And (3) standing the reaction solution at 4 ℃ overnight for recrystallization, centrifuging for 6000 r 15min, collecting precipitate, washing with pre-cooled ethanol and diethyl ether for 3 times in sequence, and drying to obtain oxidized tetravalent hydroxycaprotinin. 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, removing toluene and unreacted acetic anhydride by reduced pressure distillation, repeating the process for three times,the product 2,2' -dithiodiacetic anhydride is obtained. 0.5mmol of tetravalent hydroxycaprotinin was dispersed in 20mL of DMF, 0.6mmol of 2,2' -dithiodiacetic anhydride and 0.2mmol of 4-dimethylaminopyridine were added with stirring at 35℃and the reaction was continued for 12 hours. Then 1mmol of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide was added to activate for 20 minutes, 0.8mmol of n-stearyl alcohol was added to the reaction mixture, and stirred overnight. The resulting solution was filtered, evaporated to about 2mL under reduced pressure using an oil pump, and the precipitate was collected by adding 50mL diethyl ether, washed three more times with diethyl ether, and dried under vacuum to give the objective product. The whole reaction process is carried out in a dark place under the protection of nitrogen.
The structure of the derivative in the examples was determined by mass spectrometry and nuclear magnetic resonance hydrogen spectrometry, the results and peak assignment are shown in fig. 5, the solvent used for nuclear magnetic resonance is deuterated DMSO, and the results of the spectroscopic analysis are 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-stabilization nanoparticle
Precisely weighing 7mg DSPE-PEG 2000 Dissolved in 1mL of absolute ethanol to prepare 7mg/mL stock solution for later use. Precisely weighing 4mg of the derivative prepared in each of the above examples, and dissolving and dispersing in 0.2mL of DSPE-PEG 2000 And in the stock solution, dropwise adding the mixed solution into 2mL of deionized water by using a pipette, maintaining the stirring rotation speed at 600rpm, and stirring for 15min to obtain the lipid derivative self-stabilizing nanoparticles. The residual ethanol in all nanoparticles was then removed by rotary evaporation under reduced pressure at 30 ℃.
The particle diameter and morphology of the lipid derivative self-stabilizing nanoparticles prepared in example 6 were measured by transmission electron microscopy, and the result is shown in fig. 6B, which shows that the nanoparticles were uniformly spherical. As shown in tables 1 and 2, the particle size and polydispersity of the series of lipid derivative nanoparticles exhibited a clear correlation with the lipid chain length of the derivative: CSS 18-18 < CSS12< CSS6, i.e. the longer the chain length, the smaller the particle size of the nanoparticle and the more uniform the particle size distribution. Meanwhile, for carboplatin-lipid derivatives with the same carbon chain length, the double-side carbon chain grafted derivatives have smaller particle size and more uniform particle size distribution (CSS 18< mCSS 18) than the single-side carbon chain grafted derivatives. This correlation is more pronounced when the nanoparticle drug concentration is increased (1 mg Pt/mL and 1.5mg Pt/mL). Obvious precipitation occurs during the preparation of CSS6 and mCSS18 nanoparticles at a concentration of 1.5mg Pt/mL, while CSS18 nanoparticles still exhibit a uniform 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 for CSS6 nanoparticles that produced precipitation at the bottom of the bottle. The above results demonstrate that the short carbon chain lipid derivative CSS6 has poor assembly stability at high concentrations. Weak light beams are visible in supernatant of the mCSS18 nanoparticle, but precipitation exists, which indicates that the stability is poor and the assembly capability is weak. Among all nanoparticles, CSS18 had optimal physicochemical properties, even stabilized at 1.5mg Pt/mL, with a pale blue and clear appearance (FIG. 6C). These results indicate that the length and position of the aliphatic chain plays a critical role in the self-stabilizing assembly of carboplatin-lipid derivatives. The double-sided and long carbon chain derivatives have better assembly properties than the single-sided and short side chain derivatives.
TABLE 1 particle size, particle size distribution and surface potential of DSPE-PEG modified low concentration (0.5 mg Pt/mL) carboplatin-lipid derivative 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 high concentration (1 mg Pt/mL, 1.5mg Pt/mL) of DSPE-PEG modified carboplatin-lipid derivative self-stabilizing nanoparticles
Example 7: colloidal stability test of DSPE-PEG modified lipid derivative self-stabilizing nanoparticles
Each DSPE-PEG modified lipid derivative prepared in example 6 was taken out of the stable nanoparticle by 1mL, added to 20mL of phosphate buffer (PBS, pH 7.4) (fig. 7A) for 7 days at 37 ℃ or added to phosphate buffer (PBS, pH 7.4) containing 10% fbs (fig. 7B) for 24 hours at 37 ℃ and its particle size change was determined by dynamic light scattering at a predetermined time point (see fig. 7). From the results of fig. 7A and B, the particle size and PDI of the remaining nanoparticles in 10mm PBS 7.4 were kept stable for one week except for the CSS6 NPs, and the particle size and PDI of the CSS6 NPs were significantly increased, indicating that the nanoparticle composed of the short chain lipid derivative was poor in stability. In 10% FBS, 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) with 0mM,1mM and 10mM GSH was used as release medium in the in vitro release test to simulate the non-reducing environment, the reducing environment in blood circulation and the reducing environment of tumor sites, respectively. Dialysis bags (molecular weight cut-off 1 kD) containing 1mL of free carboplatin solution (Car) and five lipid derivative nanoparticles (CSS 6, CSS12, CSS18, C-18 and mCSS18 nanoparticles) were immersed in 20mL of the corresponding release medium, placed at 37℃and shaken at constant temperature and constant speed at a speed of 100rpm, respectively. The released drug content was determined by taking 1mL of the free carboplatin solution and the release medium of the nanoparticle group of five lipid derivatives at time points 1, 2, 4, 8, 12 and 24 hours, respectively (see fig. 8).
As shown in fig. 8A, the cumulative drug release for each group of nanoparticles was less than 10% in 0mM GSH buffer. As shown in FIG. 8B, disulfide bond containing CSS6, CSS12, CSS18 and mCSS18 nanoparticles released slightly faster than C-18 nanoparticles in 1mM GSH release buffer. In contrast, as shown in FIG. 8C, in 10mM GSH release medium, the lipid derivative self-stabilizing nanoparticles (CSS 6, CSS12, CSS18 and mCSS18 nanoparticles) released more than 70% of the drug in 4 hours, more than 80% of the drug in 24 hours, and the release amount at any time point was significantly higher than that of the non-disulfide lipid derivative C-18 nanoparticles. It is demonstrated that carboplatin-lipid derivative nanoparticles containing disulfide bonds are more sensitive to GSH and more responsive than lipid derivative nanoparticles that are not disulfide bond intercalated. According to the nanoparticle characterization and stability experimental results described above, the lipid derivative CSS18 of the longest carbon chain has an optimal self-stabilizing assembly behavior and good colloidal stability, and the responsiveness to GSH is substantially equivalent to other disulfide derivatives. This suggests that enhancing the assembly and stability of lipid derivative nanoparticles by strategies of chemical structure tuning does not affect their specific responsiveness to intracellular GSH.
EXAMPLE 9 cytotoxicity of DSPE-PEG modified lipid derivatives from stable nanoparticles
The toxicity of DSPE-PEG modified lipid derivative self-stabilizing nanoparticles on three tumor cells, mouse prostate cancer (RM-1) cells, mouse breast cancer (4T 1) cells, human ovarian cancer cells (A2780) and human normal liver (L02) cells was examined by MTT method. Firstly, cells with good morphology are digested, the cells are diluted to 5000cells/mL by using a cell culture medium and uniformly blown, 100 mu L of cell suspension is added into each well of a 96-well plate, and the cells are incubated in an incubator for 24 hours to adhere to the cells. After the cells are attached, the lipid derivative nanoparticles prepared in example 6 are added. 100 μl of each well of test solution was added, 3 wells in parallel per concentration. The control group, i.e. without adding the liquid medicine to be detected, is singly supplemented with 100 mu L of culture solution, and is placed in an incubator for incubation with cells. 48 hours after dosing, the 96-well plate was taken out, 20. Mu.L of 5mg/mL MTT solution was added to each well, the plates were thrown out after incubation in an incubator for 4 hours, and after the 96-well plate was back-buckled on filter paper to sufficiently suck the residual liquid, 200. Mu.L of 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. Absorbance values after zeroing of each well were determined at 570nm using a microplate reader.
The cytotoxicity results are shown in Table 3. CSS6 nanoparticles have the least cytotoxic effect on all cell lines and even lower activity than derivative nanoparticles C-18NPs without disulfide bonds. Among 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, suggesting that GSH-responsive lipid derivative strategies are 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 of treatment with different lipid derivative solutions and nanoparticles 50 Value (mu 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 pharmacokinetic and tissue distribution StE-PEG modified lipid derivative self-stabilizing nanoparticles
SD rats weighing 200-250g were randomly grouped and fasted for 12 hours prior to dosing, and were given free water. Carboplatin solution and DSPE-PEG modified lipid derivative self-stabilizing nanoparticles prepared in example 6 were each intravenously injected. The dosage is 3mg/kg. The orbit was bled at the prescribed time points and plasma was isolated. Drug concentrations in plasma were determined by inductively coupled plasma mass spectrometry (see fig. 9 and table 4).
As shown in FIGS. 9A-B and Table 4, the improvement in AUC of CSS18 and C-18 nanoparticles was most pronounced, 36.11 mg.h.L-1, about 8-fold improvement over the solution. CSS6 nanoparticles were rapidly eliminated in plasma, AUC (2.2 fold) and t 1/2 Slightly increased. The AUC ordering of lipid derivative nanoparticles is: CSS 18-18>CSS12≈mCSS18>CSS6 shows that the long circulation characteristic of the nanoparticle is related to the carbon chain length of the derivative, i.e. the longer the carbon chain, the more stable the nanoparticle 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 FIGS. 9C and D, respectively, for intratumoral accumulation of lipid derivative nanoparticlesThe sequence is as follows: CSS 18-18>CSS12>mCSS18>CSS6 shows that the long circulation characteristic of the nanoparticle is related to the carbon chain length of the derivative, namely, the longer the carbon chain is, the more stable the nanoparticle is, the longer the body circulation time is, and the more accumulation is 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 pharmacodynamics 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. Until the tumor volume grows to 150mm 3 At this time, tumor-bearing mice were randomly divided into 7 groups of 5, 5% glucose control group, oxaliplatin solution group, CSS6 nanoparticle group, CSS12 nanoparticle group, CSS18 nanoparticle group, C-18 nanoparticle group, mCSS18 nanoparticle group, respectively. Dosing was performed every other day, 4 times in succession. The establishment of the B16-F10 tumor-bearing mouse model is consistent with the 4T1 model.
From the results of tumor growth inhibition of FIGS. 10 and 11, characterized by tumor volume, weight of two types of tumor model mice, FIGS. 10A and 11FIG. 11A shows tumor volume of each mouse, FIG. 10B shows FIG. 11B shows mean values, and in particular FIGS. 10A-D show FIGS. 11A-D, 5% glucose injection as control group tumor volume was maximum, day 14 up to 1200mm 3 CSS6 nanoparticles 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 400, 700 and 900mm on day 14, respectively) 3 ) Tumor growth rate of tumor-bearing mice treated with CSS18 nanoparticles was the lowest, and tumor volume was the smallest on day 14. The tumor growth inhibition rule of the B16-F10 tumor-bearing mice is basically consistent with that of the 4T1 tumor-bearing mice, 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 shows that the longer the carboplatin-lipid derivative carbon chain, the stronger the antitumor effect of the self-stabilizing nanoparticle.
Claims (9)
1. A platinum lipid derivative, which is characterized in that: the derivative is composed of platinum drugs and hydrophobic lipid long chains and is shown in a general formula 1,
in the general formula 1, A is a platinum drug, wherein the platinum drug is carboplatin, O in the platinum drug is a non-leaving group, and square is a leaving group; x is S-S; r is a hydrophobic lipid long chain; n=an integer from 1 to 3; r is a C18-C36 fatty alcohol.
2. The method for preparing a platinum lipid derivative according to claim 1, wherein: firstly, oxidizing a bivalent platinum compound into tetravalent platinum with bilateral axial hydroxyl groups, then using anhydride to enable the bilateral hydroxyl groups of the tetravalent platinum to form ester to obtain an intermediate product containing bilateral carboxyl groups, and finally enabling the carboxyl groups to form ester with fatty alcohol to obtain the tetravalent platinum derivative with bilateral lipid long chain connection shown in the general formula 1.
3. A method for preparing a platinum lipid derivative according to claim 2, 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 hydroxyplatinum 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 a derivative shown in a general formula 1;
wherein the mole ratio of the oxidized tetravalent hydroxyplatinum to the 4-dimethylaminopyridine is 0.5-4; the molar ratio of the intermediate product to the 1-ethyl-3 (3-dimethylpropylamine) carbodiimide is 1-4; the molar ratio of the 4-dimethylaminopyridine to the fatty alcohol is 0.5-4.
4. Use of a derivative according to claim 1, characterized in that: the derivative shown in the general formula 1 is applied to the preparation of antitumor drugs.
5. A self-stabilizing lipid derivative nanoparticle, characterized in that the composition of the nanoparticle comprises the self-stabilizing lipid derivative of claim 1 and a stabilizing agent; the mass ratio of the lipid derivative to the stabilizer is 99:1-70:30.
6. The self-stabilizing lipid derivative nanoparticle according to claim 5, wherein the stabilizing agent is one or more of a surfactant and/or a steric stabilizer commonly used in pharmacy.
7. The method for preparing self-stabilizing lipid derivative nanoparticles according to claim 5, wherein the lipid derivative of claim 1 and the stabilizer are dissolved and dispersed in an organic solvent to obtain a dispersion system, the obtained dispersion system is slowly and dropwise added into water or a microfluidic cross-flow micromixing method is used to assemble the derivative into stable nanoparticles, and then the organic solvent is removed to obtain the self-stabilizing lipid derivative nanoparticles.
8. A pharmaceutical composition characterized by: a lipid derivative comprising the platinum drug according to claim 1.
9. An application, characterized in that: use of the self-stabilizing lipid derivative nanoparticle according to claim 5 or the pharmaceutical composition according to claim 8 for the preparation of an antitumor drug.
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