CN116473940A - CAF-targeted drug-loaded lipid nanoparticle and preparation method thereof - Google Patents
CAF-targeted drug-loaded lipid nanoparticle and preparation method thereof Download PDFInfo
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- CN116473940A CN116473940A CN202310550404.7A CN202310550404A CN116473940A CN 116473940 A CN116473940 A CN 116473940A CN 202310550404 A CN202310550404 A CN 202310550404A CN 116473940 A CN116473940 A CN 116473940A
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- 239000002105 nanoparticle Substances 0.000 title claims abstract description 73
- 150000002632 lipids Chemical class 0.000 title claims abstract description 61
- 239000003814 drug Substances 0.000 title claims abstract description 59
- 229940079593 drug Drugs 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 230000004888 barrier function Effects 0.000 claims abstract description 24
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 20
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 20
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 18
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 18
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 16
- 230000008685 targeting Effects 0.000 claims abstract description 14
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 12
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 claims description 36
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 claims description 15
- 229940106189 ceramide Drugs 0.000 claims description 15
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 claims description 15
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 claims description 15
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 14
- 229940083466 soybean lecithin Drugs 0.000 claims description 14
- YDNKGFDKKRUKPY-TURZORIXSA-N N-hexadecanoylsphingosine Chemical compound CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)\C=C\CCCCCCCCCCCCC YDNKGFDKKRUKPY-TURZORIXSA-N 0.000 claims description 13
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- 239000000243 solution Substances 0.000 claims description 13
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- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 claims description 8
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims description 8
- VODZWWMEJITOND-NXCSZAMKSA-N N-octadecanoylsphingosine Chemical compound CCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)\C=C\CCCCCCCCCCCCC VODZWWMEJITOND-NXCSZAMKSA-N 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 claims description 6
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 claims description 5
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 5
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- 239000004698 Polyethylene Substances 0.000 claims description 5
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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 claims description 5
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims description 4
- 239000005537 C09CA07 - Telmisartan Substances 0.000 claims description 4
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 4
- NPRJSFWNFTXXQC-QFWQFVLDSA-N N-(hexanoyl)sphing-4-enine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@H](CO)NC(=O)CCCCC NPRJSFWNFTXXQC-QFWQFVLDSA-N 0.000 claims description 4
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims description 4
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 4
- FRKBLBQTSTUKOV-UHFFFAOYSA-N diphosphatidyl glycerol Natural products OP(O)(=O)OCC(OP(O)(O)=O)COP(O)(O)=O FRKBLBQTSTUKOV-UHFFFAOYSA-N 0.000 claims description 4
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 4
- 150000003905 phosphatidylinositols Chemical class 0.000 claims description 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 4
- 229960005187 telmisartan Drugs 0.000 claims description 4
- 108010072611 beta-cyclohexylalanyl-phenylalanyl-seryl-arginyl-tyrosyl-leucyl-tryptophyl-serine Proteins 0.000 claims description 3
- 210000002950 fibroblast Anatomy 0.000 claims description 3
- 239000000644 isotonic solution Substances 0.000 claims description 3
- 230000004913 activation Effects 0.000 claims description 2
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- 108090000623 proteins and genes Proteins 0.000 claims description 2
- 102000004169 proteins and genes Human genes 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 45
- 230000000694 effects Effects 0.000 abstract description 16
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- 230000000259 anti-tumor effect Effects 0.000 abstract description 8
- 238000012377 drug delivery Methods 0.000 abstract description 4
- 239000000890 drug combination Substances 0.000 abstract description 3
- 229920000371 poly(diallyldimethylammonium chloride) polymer Polymers 0.000 abstract description 3
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
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- VBVAVBCYMYWNOU-UHFFFAOYSA-N coumarin 6 Chemical compound C1=CC=C2SC(C3=CC4=CC=C(C=C4OC3=O)N(CC)CC)=NC2=C1 VBVAVBCYMYWNOU-UHFFFAOYSA-N 0.000 description 5
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- 239000000203 mixture Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
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- 239000002504 physiological saline solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
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- 108010019160 Pancreatin Proteins 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
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- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
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Classifications
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- 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
- A61K9/5192—Processes
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention provides a CAF targeted drug-loaded lipid nanoparticle, a preparation method and application thereof in pancreatic cancer, and belongs to the technical field of pharmaceutical preparations. The present invention is directed to the osmotic barrier effect of CAF in PDAC therapy and designs and prepares drug delivery systems and drug combinations for overcoming the CAF barrier of pancreatic cancer. The drug-loaded lipid nanoparticle capable of targeting the CAF barrier can induce the CAF barrier to generate exosomes loaded with anti-tumor drugs, promote the drug to be discharged to overcome the BSB effect of the CAF on the drugs, increase the arrival of the drugs at deep tumor sites and improve the anti-tumor effect.
Description
Technical Field
The invention relates to a CAF-targeted drug-loaded lipid nanoparticle, a preparation method thereof and application thereof in pancreatic cancer, and belongs to the technical field of pharmaceutical preparations.
Background
Pancreatic cancer is one of the worst prognostic malignancies. Pancreatic Ductal Adenocarcinoma (PDAC) is the most common type of pancreatic cancer (more than 80%), even after treatment with the standard first-line chemotherapeutic drug gemcitabine, the 5-year survival rate of PDAC is less than 10%. The formation of drug delivery barriers (CAF barriers) from a large number of tumor-associated fibroblasts (CAFs) is the most critical factor limiting PDAC efficacy.
CAFs account for 90% of the stromal cells in late PDACs and are the primary producers of ECM in the CAF barrier. Since CAFs are preferentially located near blood vessels, they have a strong binding site barrier (Binding site barrier, BSB) to drugs and nanoparticles that enter the core of the tumor. CAFs preferentially ingest most of the drug that should be delivered to tumor cells, resulting in little drug reaching deep tumor sites. The BSB effect caused by CAFs in PDACs impedes penetration of drugs or nanoparticles into the deep tumor, thereby inhibiting the effects of chemotherapy. Thus, strategies to overcome CAF barriers, increase drug penetration, and improve pancreatic tumor treatment efficiency are urgently needed.
Currently, to overcome CAF barriers to improve therapeutic efficacy, elimination of CAF barriers by genetic engineering, chemical killing, etc. seems to be the most straightforward approach. In this way, the CAF barrier can be cleared directly, providing the possibility for effective infiltration of the drug. However, over-clearance of CAFs in the PDAC model induces strong immunosuppression and accelerates tumor progression and reduces survival. In addition, strategies such as particle size reduction are applied to assist drug permeation across the CAF barrier, but their efficacy is still limited by the BSB effect of CAF.
Disclosure of Invention
The present invention is directed to the barrier effect of CAF drug delivery in PDAC therapy and designs and prepares drug-loaded lipid nanoparticles and drug combinations for overcoming the CAF barrier of pancreatic cancer. The drug-loaded lipid nanoparticle provided by the invention targets CAF and is ingested, and ceramide with exosome induction effect in the drug-loaded lipid nanoparticle induces a large amount of secretion of CAF exosome, so that the anti-tumor drug is released from the CAF in an exosome form and delivered to tumor cells, the CAF barrier is overcome, and the treatment effect of the chemotherapeutic drug is improved. Compared with the existing nano preparation, the preparation method has the advantages that the ceramide with exosome induction effect is added by the novel component, on one hand, the ceramide is used as lipid, and the preparation and drug loading of lipid nanoparticles are not influenced; on the other hand, the CAF barrier is effectively overcome in vivo, the anti-tumor drug can be delivered across CAF in an exocrine and exocrine mode, the treatment effect is improved, the unexpected effect is achieved, a novel drug preparation is provided for pancreatic cancer, and the novel drug preparation has obvious creativity.
In one aspect, the invention provides a CAF-targeted drug-loaded lipid nanoparticle comprising a phospholipid, distearoyl phosphatidylethanolamine-polyethylene glycol-targeting molecule (DSPE-PEG-targeting molecule), a ceramide with exosome induction and a hydrophobic antitumor drug.
Further, the phospholipid is one or more of soybean lecithin, egg yolk lecithin, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine and sphingomyelin.
Further, the targeting molecule is one or more of an amine acetoanisoamide (AEAA), a Telmisartan, FH peptide, an AE105 peptide, and a Fibroblast Activation Protein (FAP) antibody.
Further, the ceramide with exosome induction function is one or more of C18 ceramide, C16 ceramide and C6 ceramide.
Further, the hydrophobic antitumor drug is one or more of CP4126, paclitaxel, doxorubicin and sorafenib.
Further, the mass ratio of the phospholipid and the DSPE-PEG-targeting molecule is 1:1-1:0.05.
Further, the mass ratio of the phospholipid to the DSPE-PEG-targeting molecule to the antitumor drug to the ceramide is 10-20:1-10:1-5:0.1-5.
On the other hand, the invention provides a preparation method of CAF targeted drug-loaded lipid nanoparticles, which comprises the following steps:
(1) Adding a certain proportion of phospholipid, DSPE-PEG-targeting molecule, antitumor drug and ceramide into an organic solvent, and stirring to form a clear solution;
(2) Injecting the clarified solution into the isotonic solution at a constant rate at room temperature, and continuously stirring during injection;
(3) And (3) continuously stirring for 2 hours after the clear solution is completely injected to volatilize the organic solvent completely, so as to obtain the lipid nanoparticle aqueous solution with the CAF targeting function, which contains the active drug and the ceramide.
Further, the mass ratio of the phospholipid to the DSPE-PEG-targeting molecule to the antitumor drug to the ceramide is 10-20:1-10:1-5:0.1-5.
Further, the organic solvent is selected from one or more of ethanol, chloroform, diethyl ether and methanol.
Further, the isotonic solution is selected from one or more of phosphate buffer solution, 5% glucose solution and 0.9% physiological saline.
Further, the injection rate is 0.1 to 2mL/min, and the stirring rate is 100 to 3000rpm.
On the other hand, the invention provides an application of the CAF targeted drug-loaded lipid nanoparticle in preparing pancreatic cancer drugs.
Furthermore, the invention provides application of the CAF targeted drug-loaded lipid nanoparticle in preparation of a CAF barrier drug for overcoming pancreatic cancer.
Further, the pancreatic cancer is pancreatic ductal adenocarcinoma.
The beneficial effects are that:
1. according to the invention, the drug combination is loaded into the lipid nanoparticle and the CAF targeting molecule is modified, so that the drug can be effectively delivered to CAF in pancreatic cancer by modifying the targeting molecule, the accumulation of the drug in pancreatic cancer is obviously increased, and the anti-tumor effect of the drug can be improved.
2. The invention obviously improves the curative effect of pancreatic cancer. Ceramide delivered to CAF induces CAF to secrete exosomes in large amounts to deep tumor sites; hydrophobic chemotherapeutic agents delivered to CAF are loaded into the CAF exosomes during the formation of the CAF exosomes and secreted to the deep tumor sites as the CAF exosomes are secreted, a process that significantly increases the efficiency of the drug to reach the deep tumor sites. The antitumor effect shows that the tumor inhibition rate of a single chemotherapeutic drug on pancreatic cancer is 69.57 +/-2.12%, and after CAF targeting drug-loaded lipid nanoparticles are administered, the CAF drug delivery barrier is overcome, the deep penetration of the drug is increased, and the tumor inhibition rate is improved to 90.65+/-3.04%.
3. The proportion of the added medicine and the concentration of the phospholipid are optimized data designed for pancreatic cancer, and the curative effect is good. The raw materials used in the invention are simple, safe and reliable. The carrier material phospholipid is all endogenous substances of human body, is safe and nontoxic, is biodegradable, and has good biocompatibility.
4. The lipid nanoparticle prepared by the invention has the advantages of proper particle size (100-200 nm), stable process, simplicity and feasibility, and easy industrial production.
Drawings
FIG. 1 shows the encapsulation efficiency of CP4126 in lipid nanoparticles with different ratios of drug to lipid prepared in example 1 of the present invention;
FIG. 2 shows the uptake of lipid nanoparticles modified by DSPE-PEG-AEAA at different concentrations in CAF prepared according to example 2 of the present invention;
FIG. 3 is a graph showing particle size and electron microscope of lipid nanoparticle CC/L-A prepared in example 3 of the present invention
FIG. 4 shows the uptake of lipid nanoparticles prepared in Experimental example 1 in CAF according to the present invention;
FIG. 5 shows the tumor inhibition rate of the lipid nanoparticle prepared in Experimental example 2 of the present invention on pancreatic cancer;
Detailed Description
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail below with reference to specific examples and comparative examples.
Example 1
The effect of different drug-to-lipid ratios on drug encapsulation efficiency was examined. The mass ratio of the blank lipid nanoparticle to the DSPE-PEG-AEAA is controlled to be 4:1, the total mass of the blank lipid nanoparticle and the DSPE-PEG-AEAA is 20mg, 1mg of C18 ceramide is respectively weighed, 1mg, 2mg and 4mg of CP4126 medicine are respectively added into 1mL of ethanol, the mixture is stirred at room temperature to form a clear solution, the solution is injected into normal saline at the speed of 1mL/min, and the mixture is rapidly stirred at the speed of 1000rpm and continuously stirred for 2h in the injection process, so that the aqueous solution of the lipid nanoparticle containing the CP4126 and the C18 ceramide is obtained. The content of CP4126 in CC/L-A was measured by HPLC and the encapsulation efficiency was calculated. From the results in FIG. 1, it can be seen that CP4126 has an optimal encapsulation efficiency when the ratio of the drug to the lipid is 1:10. The optimal encapsulation efficiency is obtained, so that on one hand, the loss of the medicine in the preparation process is reduced, and most of the medicine is encapsulated in the paper nanoparticles; on the other hand, the preparation has optimal stability under the current formula, and is favorable for long-term storage.
Example 2
The effect of DSPE-PEG-AEAA ratio on targeting was examined. An uptake experiment was performed with the fluorescent substance coumarin 6 (C6) instead of the drug to screen the optimum amount of DSPE-PEG-AEAA. Weighing C6 1mg, controlling the total mass of the blank lipid nanoparticle and DSPE-PEG-AEAA to be 20mg, and setting the mass ratio of soybean lecithin to DSPE-PEG-AEAA to be 18:2, 16:4 and 12:8. Weighing the medicines according to a proportion, adding the medicines into 1mL of ethanol, stirring at room temperature to form a clear solution, injecting the solution into physiological saline at a speed of 1mL/min, and rapidly stirring at a speed of 1000rpm in the injection process, and continuously stirring for 2 hours to obtain the aqueous solution of the CAF-targeted lipid nanoparticle containing coumarin 6.
Will be 5 x 10 4 NIH/3T3 was inoculated into 12-well plates and activated with 10ng/mL TGF-. Beta.1 for 24h to give CAF cells. To each well was added C6/L-A (C6 final concentration 200 ng/mL) at different ratios of DSPE-PEG-AEAA, and after incubation at 37℃for 0.5h, the cells were digested with pancreatin and resuspended in PBS for flow-fluorescence quantification. As can be seen from the results of FIG. 2, the nanoparticles had a ratio of soybean lecithin to DSPE-PEG-AEAA of 16:4The best CAF targeting, which helps the drug to accumulate more to the tumor target site, is important for improving the anti-tumor effect.
Example 3
AEAA modified co-supported CP4126 and C16 ceramide lipid nanoparticles (CC/L-A) were prepared. 16mg of soybean lecithin, 4mg of DSPE-PEG-AEAA, 2mg of CP4126 and 1mg of C16 ceramide are added into 1mL of ethanol, the mixture is stirred at room temperature to form a clear solution, the solution is injected into physiological saline at a speed of 1mL/min, and the mixture is rapidly stirred at a speed of 1000rpm and continuously stirred for 2 hours during the injection process, so that the aqueous solution of the CAF targeting lipid nanoparticle containing the CP4126 and the C18 ceramide is obtained.
The particle size of CC/L-A was measured by DLS and the surface morphology of CC/L-A was characterized by transmission electron microscopy. FIG. 3 is a particle size distribution diagram and a transmission electron microscope diagram of CC/L-A. The particle size of CC/L-A is 140.4+ -5.6 nm, the encapsulation efficiency of CP4126 is 92.3% + -1.57, and the morphology of CC/L-A is round. The lipid nanoparticle prepared in this example has the best AEAA modification ratio, and the best encapsulation efficiency is obtained, while also having a suitable particle size. The nanoparticle needs to pass through the tumor vascular gap (less than 200 nm) when reaching the tumor part, so the lipid nanoparticle prepared by the embodiment can effectively pass through the tumor vascular gap to reach the tumor part and accumulate for a long time, which is important for improving the anti-tumor effect.
Example 4
Preparation of FH peptide modified Co-carried CP4126 and C16 ceramide lipid nanoparticle (CC/L-FH), the preparation method was the same as in example 3. Wherein, soybean lecithin 16mg, DSPE-PEG-FH 4mg, CP41262mg and C16 ceramide 1mg.
The particle size of CC/L-FH was measured at 142.1.+ -. 4.0nm. The lipid nanoparticle prepared by the embodiment can effectively reach the tumor part through the tumor vascular gap.
Example 5
Telmisartan modified co-supported CP4126 and C16 ceramide lipid nanoparticle (CC/L-T) was prepared in the same manner as in example 3. Wherein, soybean lecithin 16mg, DSPE-PEG-Telmisartan 4mg, CP41262mg, C16 ceramide 1mg.
The particle size of CC/L-T was 139.2.+ -. 1.4nm. The lipid nanoparticle prepared by the embodiment can effectively reach the tumor part through the tumor vascular gap.
Example 6
Preparation of AE105 peptide modified Co-carried CP4126 and C16 ceramide lipid nanoparticles (CC/L-AE 105) were prepared in the same manner as in example 3. Wherein, soybean lecithin 16mg, DSPE-PEG-AE105 mg, CP41262mg and C16 ceramide 1mg.
The particle size of CC/L-AE105 was measured to be 142.8.+ -. 0.3nm. The lipid nanoparticle prepared by the embodiment can effectively reach the tumor part through the tumor vascular gap.
Example 7
Preparation of FAP mab peptide modified Co-carried CP4126 and C16 ceramide lipid nanoparticle (CC/L-FAP) the preparation method was the same as in example 3. Wherein, soybean lecithin 16mg, DSPE-PEG-FAP 4mg, CP41262mg, C16 ceramide 1mg.
The particle size of CC/L-FAP was measured to be 145.8.+ -. 3.5nm. The lipid nanoparticle prepared by the embodiment can effectively reach the tumor part through the tumor vascular gap.
Example 8
AEAA modified co-supported Paclitaxel (PTX) and C16 ceramide lipid nanoparticles (CP/L-A) were prepared in the same manner as in example 3. Wherein, soybean lecithin 16mg, DSPE-PEG-A4 mg, PTX 2mg and C16 ceramide 1mg.
The particle size of CP/L-A was found to be 141.8.+ -. 2.9nm. The lipid nanoparticle prepared by the embodiment can effectively reach the tumor part through the tumor vascular gap.
Example 9
AEAA modified co-supported Doxorubicin (DOX) and C16 ceramide lipid nanoparticles (CD/L-A) were prepared in the same manner as in example 3. Wherein, soybean lecithin 16mg, DSPE-PEG-A4 mg, DOX 2mg and C16 ceramide 1mg.
The particle size of CD/L-A was 142.4.+ -. 4.6nm. The lipid nanoparticle prepared by the embodiment can effectively reach the tumor part through the tumor vascular gap.
Example 10
AEAA modified co-supported Sorafenib (SF) and C16 ceramide lipid nanoparticles (CS/L-A) were prepared in the same manner as in example 3. Wherein, soybean lecithin 16mg, DSPE-PEG-A4 mg, SF 2mg and C16 ceramide 1mg.
The particle size of CS/L-A was measured to be 140.6.+ -. 7.2nm. The lipid nanoparticle prepared by the embodiment can effectively reach the tumor part through the tumor vascular gap.
Example 11
AEAA modified Co-supported CP4126 and C18 ceramide lipid nanoparticles (CC/L-A) were prepared in the same manner as in example 3. Wherein, soybean lecithin 16mg, DSPE-PEG-AEAA 4mg, CP41262mg and C18 ceramide 1mg.
The particle size of CS/L-A was determined to be 143.8.+ -. 3.7nm. The lipid nanoparticle prepared by the embodiment can effectively reach the tumor part through the tumor vascular gap.
Example 12
AEAA modified Co-supported CP4126 and C6 ceramide lipid nanoparticles (CC/L-A) were prepared in the same manner as in example 3. Wherein, soybean lecithin 16mg, DSPE-PEG-AEAA 4mg, CP41262mg and C6 ceramide 1mg.
The particle size of CS/L-A was determined to be 138.2.+ -. 2.4nm. The lipid nanoparticle prepared by the embodiment can effectively reach the tumor part through the tumor vascular gap.
Example 13
AEAA modified co-carried CP4126 and C6 ceramide lipid nanoparticle (CC/L-A) are prepared by taking egg yolk lecithin, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine and sphingomyelin as lipid materials respectively, and the preparation method is the same as that of example 3. Wherein, the egg yolk lecithin, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine and sphingomyelin are 16mg, DSPE-PEG-AEAA 4mg, CP4126 mg and C6 ceramide 1mg.
The particle diameters of CC/L-A were determined to be 139.4.+ -. 5.7nm, 140.3.+ -. 2.8nm, 141.2.+ -. 6.9nm, 139.9.+ -. 4.2nm, 140.5.+ -. 1.3nm, 140.6.+ -. 2.9nm, 141.5.+ -. 3.2nm and 137.5.+ -. 3.4nm, respectively. The lipid nanoparticle prepared by the embodiment can effectively reach the tumor part through the tumor vascular gap.
Experimental example 1
Preparation of AEAA-modified coumarin 6 (C6) -loaded lipid nanoparticles (C6/L-A) and AEAA-free C6-loaded lipid nanoparticles (C6/L-A) were prepared in the same manner as in example 3. Will be 5 x 10 4 NIH/3T3 was inoculated into 12-well plates and activated with 10ng/mL TGF-. Beta.1 for 24h to give CAF cells. Free C6, C6/L, C/L-A (C6 final concentration 200 ng/mL) was added to each well and incubated at 37℃for 0.5h Cells of the AEAA+C6/L-A group were pretreated with AEAA for 1h before adding C6/L-A to block AEAA mediated targeting. For flow cytometry analysis, the incubated cells were trypsinized and resuspended in PBS for flow cytometry analysis (BD Accuri C6, BD, USA). FIG. 4 shows the results of cellular uptake of lipid nanoparticles of different targeting ability. The results show that the targeted modification group C6/L-A shows higher C6 fluorescence intensity (about 1.46 times) than that of the non-targeted group C6/L, and both groups are stronger than the free group C6, and the AEAA has obvious CAF targeting property, can help the medicine to better reach a CAF barrier, increases the accumulation of the tumor part of the medicine and improves the curative effect.
Experimental example 2
Preparation of AEAA-modified lipid nanoparticle (CP 4126/L-A) carrying CP4126 alone, lipid nanoparticle (CC/L) carrying CP4126 and C16 ceramide without AEAA modification, and lipid nanoparticle (CC/L-A) carrying CP4126 and C16 ceramide with AEAA modification were carried out in the same manner as in example 3. Mice carrying pancreatic tumors subcutaneously (10 6 Individual cells Panc02 and 5 x 10 5 The individual cells NIH/3T 3) were randomly divided into 4 groups (5 mice/group), NS (saline group), CP4126/L-A, CC/L and CC/L-A. When tumors grow to about 80 cubic millimeters, mice are given a total of 4 intravenous injections every 3 days. Tumor size was recorded every two days. After 16 days, the tumor inhibition rates of each group relative to the NS group are calculated to be CP4126/L-A:69.57% + -2.12%, CC/L81.62% + -5.81%, CC/L-A:90.65% ± 3.04%. Compared with the CP4126/L-A group, the tumor inhibition rate of the CC/L-A group is obviously improved, which proves that the application of the C16 ceramide can increase the crossing of the CP4126 to the deep tumor part by the CAF barrier, and improve the anti-tumor effect Compared with the CC/L group, the tumor inhibition rate of the CC/L-A group is also obviously improved, which proves that the modification of AEAA can increase the accumulation of the medicine in the CAF barrier, and is beneficial to improving the anti-tumor effect. The CC/L-A group has the mostThe high tumor inhibition rate shows that only the combined application of the three components can maximize the anti-tumor effect.
Claims (10)
1. The CAF targeted drug-loaded lipid nanoparticle is characterized by comprising phospholipid, distearoyl phosphatidylethanolamine-polyethylene glycol-targeting molecules, ceramide and a hydrophobic antitumor drug.
2. The CAF-targeted drug-loaded lipid nanoparticle of claim 1, wherein the phospholipid is one or more of soybean lecithin, egg yolk lecithin, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, and sphingomyelin.
3. The CAF-targeted drug-loaded lipid nanoparticle of claim 1, wherein the targeting molecule is one or more of an amine acetamides, telmisartan, FH peptide, AE105 peptide, fibroblast activation protein antibody.
4. The CAF-targeted drug-loaded lipid nanoparticle of claim 1, wherein the ceramide is one or more of C18 ceramide, C16 ceramide, C6 ceramide.
5. The CAF targeted drug-loaded lipid nanoparticle of claim 1, wherein the hydrophobic anti-tumor drug is one or more of CP4126, paclitaxel, doxorubicin, sorafenib.
6. The CAF-targeted drug-loaded lipid nanoparticle according to claim 1, wherein the mass ratio of the phospholipid to the distearoyl phosphatidylethanolamine-polyethylene glycol-targeting molecule is 1:1-1:0.05.
7. The CAF-targeted drug-loaded lipid nanoparticle according to claim 1, wherein the mass ratio of phospholipid, distearoyl phosphatidylethanolamine-polyethylene glycol-targeted molecule, antitumor drug and ceramide is 10-20:1-10:1-5:0.1-5.
8. The method for preparing CAF-targeted drug-loaded lipid nanoparticles according to claim 1, comprising the steps of:
(1) Adding a certain proportion of phospholipid, distearoyl phosphatidylethanolamine-polyethylene glycol-targeting molecule, an anti-tumor drug and ceramide into an organic solvent, and stirring to form a clear solution;
(2) Injecting the clarified solution into the isotonic solution at a constant rate at room temperature, and continuously stirring during injection;
(3) And (3) continuously stirring for 2 hours after the clear solution is completely injected to volatilize the organic solvent completely, so as to obtain the lipid nanoparticle aqueous solution with the CAF targeting function, which contains the active drug and the ceramide.
9. Use of CAF-targeted drug-loaded lipid nanoparticles according to claim 1 in the preparation of a pancreatic cancer drug.
10. Use of CAF-targeted drug-loaded lipid nanoparticles according to claim 1 in the preparation of a medicament for overcoming the CAF barrier of pancreatic cancer.
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