CN116549657B - Method for promoting endocytosis of animal albumin and application thereof - Google Patents

Method for promoting endocytosis of animal albumin and application thereof Download PDF

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CN116549657B
CN116549657B CN202310847601.5A CN202310847601A CN116549657B CN 116549657 B CN116549657 B CN 116549657B CN 202310847601 A CN202310847601 A CN 202310847601A CN 116549657 B CN116549657 B CN 116549657B
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hsa
albumin
cancer cell
animal
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CN116549657A (en
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任发政
张伟博
陈冲
李依璇
王鹏杰
张炎
孙亚楠
刘思源
申月敏
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China Agricultural University
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    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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Abstract

The application relates to a method for promoting endocytosis of animal albumin cells and application thereof, adopting Fe 2+ Formation of Fe with animal Albumin 2+ The animal albumin complex promotes the endocytosis of the animal albumin cells, so that the albumin absorption efficiency is effectively improved, and the cellular absorption of albumin can be promoted; in addition, when the compound is used for delivering medicines, the bioavailability of the medicines can be greatly increased, the dosage of the medicines can be reduced, the side effect can be reduced, the effective rate of the medicines can be improved, and the curative effect of the medicines can be enhanced.

Description

Method for promoting endocytosis of animal albumin and application thereof
Technical Field
The application belongs to the field of biological medicine, and particularly relates to a method for promoting animal albumin endocytosis and application thereof.
Background
Human Serum Albumin (HSA) is a 66.5 kDa non-glycosylated, globular water-soluble protein encoded by the ALB gene. HSA is the most abundant protein in human serum, 30-50 mg/ml in content, synthesized mainly in the liver, with a half-life of up to 19 days. In addition, human serum albumin has multiple bondable sites that can facilitate the transport, distribution and metabolism of endogenous and exogenous molecules (e.g., fatty acids, thyroid hormones, metals, peptides, and drugs), thereby facilitating their transport between physiological organs.
Albumin has very wide application as a drug carrier. Strategies for drug delivery using albumin can be broadly divided into exogenous and in situ binding formulations, and drugs can be covalently attached, non-covalently bound or encapsulated in albumin-based nanoparticles, and these approaches delivered with albumin particles have met with significant clinical success. For example, paclitaxel is limited in its application due to problems of solubility and solution stability, and albumin-bound paclitaxel solves the problems of solubility and solution stability of paclitaxel, and at the same time, tumor targeting is stronger and cytotoxicity is weakened, and albumin-bound paclitaxel is the first albumin drug approved for oncology. In addition, low molecular weight proteins typically have limited biological activity because they are rapidly removed from the circulation. Some albumin binding proteins have been shown to increase half-life, with recombinant immunotoxins having albumin binding domains having longer half-lives and higher antitumor activity.
However, the endocytosis process of albumin is often hindered in vivo, and the endocytosis process of albumin is blocked, so that intracellular substance transport can be blocked, and a plurality of serious diseases occur, such as Megalin/cubilin/Amn is a receptor for re-absorbing serum albumin by glomerular cells, and proteinuria is easy to be caused when the receptor is abnormally expressed (A molecular mechanism explaining albuminuria in kidney disease [ J ]. Nature Metabolism, 2020.2 (5): p.461-474); the prior art has found that serum albumin levels are inversely related to brain beta-amyloid deposition (Alzheimer's disease) by clinical evaluation of 396 elderly. Studies have shown that albumin can carry beta-amyloid into cells and when albumin is reduced, it can cause deposition of beta-amyloid in the brain, leading to Alzheimer's disease (Serum albumin and beta-amyloid deposition in the human brain [ J. ] Neurology, 2020.95 (7): p.815-826.).
Therefore, finding a method to improve the endocytosis efficiency of albumin has important physiological significance and clinical value, and can provide a more efficient scheme for drug treatment taking albumin as a carrier.
Disclosure of Invention
The present application aims to provide a method capable of promoting albumin endocytosis and promoting drug delivery.
The application aims at realizing the following technical scheme:
in a first aspect, the application provides a method for promoting endocytosis of animal albumin cells, which adopts Fe 2+ Formation of Fe with animal Albumin 2+ -an animal albumin complex.
Further, the animal albumin is human serum albumin, alpha serum albumin or bovine serum albumin.
Preferably, the animal albumin is human serum albumin.
Further, the cell is a mammalian cell, preferably, the cell comprises: murine cells, porcine cells, bovine cells, buffalo cells, ovine cells, caprine cells, deer cells, bison cells, camel cells, red deer cells, rabbit cells and/or human cells, more preferably human cells;
and/or the cell is an epithelial cell, an endothelial cell, a macrophage, a renal tubular cell, a hepatic parenchymal cell, a hepatic cell, a myocardial cell, a breast cancer cell, a gastric cancer cell, a lung cancer cell, a liver cancer cell, a cervical cancer cell, a lymphoma cell, a thyroid cancer cell, an esophageal cancer cell, a renal cancer cell, a pancreatic cancer cell, a glioma cell, a melanoma cell, a bladder cancer cell, or a prostate cancer cell.
The method of promoting endocytosis of an animal albumin is of non-therapeutic interest.
In a second aspect the application provides a method of facilitating drug delivery;
the method adopts Fe 2+ Formation of Fe with the animal albumin 2+ -animal albumin complex, combining a drug with said Fe 2+ Animal albumin complex formation of Fe 2+ -animal albumin-drug complex.
The method of promoting drug delivery is for non-therapeutic purposes, the Fe 2+ The animal albumin-drug complex is capable of facilitating drug delivery.
Further, the animal albumin is human serum albumin, alpha serum albumin or bovine serum albumin;
preferably, the animal albumin is human serum albumin.
Further, the medicament comprises: anticholinergic, M-cholinergic blocking agents, adrenoceptor agonists, adrenoceptor blocking agents, antiepileptic and convulsive agents, antiparkinsonian, antipsychotic, local anesthetic, sedative hypnotic, analgesic, antipyretic analgesic, calcium antagonist, antiarrhythmic, antianginal, therapeutic congestive heart failure, antiatherosclerotic, antihypertensive, diuretic, histamine receptor blocking agents, digestive system agents, respiratory agents, adrenocortical hormone, thyroid hormone, antithyroid, insulin and hypoglycemic agents, blood and hematopoietic agents, beta-lactams, macrolides, lincomycin, aminoglycoside antibiotics, tetracyclines and antibiotics, artificially synthesized antibacterial, antifungal and antiviral agents, antituberculosis agents, antimalarial and/or antimanic agents, preferably, said antimalogenic agents comprising: curcumin, paclitaxel, immunotoxin, gefitinib (Gefitinib), erlotinib (Erlotinib), osiertinib (octreotide AZD 9291), necitumumab (naixituzumab), afatinib (afatinib), ceritinib (celetinib), aletinib (aletinib), lorlatinib (lalatinib), brinatinib (buntinib), crizotinii (critinib), dabraffinab (dasatinib), trametainibb (trimatinib), nivoltimab (nivalnemab), pembrontizumab (pemanitizumab), tistimab (cerinib, ceriniband monoclonal antibody), atezolizumab (alelizumab), sintiltimituab (melituab), cerinib mesylate, atelizumab (alemtuzumab), durvalnemab (duvalatinib), brinib (brinib), britinib (britinib), daivalnib (critinib), critinib (critimab), critimatib (critimatinib) and bevanab (pratinib, critimab), BLU-667), palbociclib (pie Bai Xili), ribociclib (Rabociclib), abemaciclib (Abbe cilomide), ado-Trastuzumab (Enmetrastuzumab, T-DM 1), pertuzumab (Pertuzumab), trastuzumab (Trastuzumab), neratinib (Nalatinib), fam-Trastuzumab deruxtecan-nxki (DS-8201), tucatinib (Tucatinib), lapatinib (Lapatinib), everolimus (Everolimus), olaparib (Olaparib), talazopanib (Talazopanib), alpelizumab (Abelist), atezolizumab (Abelizumab), sacituzumab govitecan-hziy (cetuzumab), cetuximab (cetuzumab), panitumumab (Paenimab), regorafenib (Regorafenib), ziv-aflibept (Abelipt), ramucicrumab (ramucilomab), bevacizumab (Bevacizumab), nivolumab (Na Wu Liyou mab), pembrolizumab (Pabolizumab), ipilimumab (Ipimab), pembrolizumab (Pabolizumab), regorafenib (Regorafinib), imatinib (imatinib), tinib (sultinib), avirinib (Avirinib), rivalenib (Rivalenib), ratimonib (Ratimonib) Trastuzumab (Trastuzumab), vidiximab, pembrolizumab (pamtirizumab), nivolumab (nano Wu Liyou mab), sorafenib (Sorafenib), regorafenib (Regorafenib), nivolumab (nano Wu Liyou mab), cabozantinib (Cabozantinib), lenvantinib (lenvaryinib), ramucirumab (ramucimab), pembrolizumab (palivizumab), tisielizumab (lanrelizumab), sintillimab (signal di Li Shan mab), atezolizumab (actlizumab), bevacizumab (Bevacizumab), ipilimab (ipilimab), erlotinib (Erlotinib), erbzatinib (Everolimus), everolimus (Everolimus), sulatib (oltinib), epranib (palivizumab), pemigatinib, olaparib, nilaparib, pamatinib, ruaparib, pembrolizumab, bevacizumab, pembryizumab, pembrolizumab, pelolizumab, avelaumumab, lenvaizumab, ipilimab, pembrolizumab Pazopanib (pelpanib), sorafenib (Sorafenib), sunitinib (Sunitinib), bevacizumab (Bevacizumab), axitinib (acitinib), cabozantinib (carbotinib), atezilizumab (atinib) Durvauumab (Durvauumab You Shan antibody), avelumab (Avermeb), pembrolizumab (palivizumab), nivolumab (Na Wu Liyou antibody), terlipressin Li Shan antibody, erdafiib (erdastinib), enfortumab vedotin-ejfy, sipueucel-T, abiraterone (Abituril), olaparib (Rucapanib), imatinib (Imatinib), nilotinib (Nilotinib), dasatinib (Dasatinib), bosutinib (sultinib), potinib (Ponatinib) Nana, midostaurin, gilteerinib, ibrutinib, obtuzumab, rituximab, alemetuzumab, idelalisib, blinaumomab, venetoclax, gemtuzumab ozogamicin, enasadinib, lvosidenib, glasdegib, duvelisib, moxetumomab, inotuzumab ozogamicin, acalabrutinib, ibrutinib, zanubrutinib, acalabrutinib, rituximab, ibritumomab tiuxetan, onutuzumab Tositumomab (Tositumomab), brentuximab vedotstatin (vitamin b), romidepsin (Romidepsin), vorinostat (Vorinostat), belinostat (Belinostat), copanliib (kunessi), idelalisib (alilarisst), nivolumab (nano Wu Liyou mab), pembrolizumab (palbolizumab), bortezomib (Bortezomib), ventoclax (vitamin c la), polatuzumab vedotin-Piiq (POLIVY), 823-kpkc (Poteligeo), tazemetostat (tazistat), selinexor (Li Nisuo), brexucabtagene autoleucel (tecarbs), tafasimab-cxix, panobinostat (panitustat), carfilzomib (Carfilzomib), bortezomib (Bortezomib), ixazomib (ixapyraab (Umamab), das-62. Tumab (Umamab), isatuximab-irfc, belantamab mafodotin-bimf, selinexor (Se Li Nisuo), elotuzumab (erlotinib), vandetanib (Vandetanib), cabozantinib (cabotinib), lenvantinib (lenvartinib), sorafenib (Sorafenib), anlotinib (An Luoti ni), dabrafenaib (Darafenib), trametinib (Trametinib), selpercatinib, cetuximab (cetuximab), nivolumab (Na Wu Liyou mab), pembrolizumab (palivizumab), terrappride Li Shan antibody, caririzumab, pembrolizumab (palbocavib), nivolumab (Na Wu Liyou mab), bimimanib (Bimipheneb), dabrahenib (Darafenib), vemurafenib (Mo Feini) Encodefenib (Kang Naifei), trametinib (trametetinib), cobimetainib (carbitinib), iplimizumab (Ipilimumab), atezolizumab (Abelizumab), cemiplimab-rwlc Pembrolizumab (Pabrizumab), pazopanib (Papanib), imatinib (imatinib), tazemetostat, denosumab (Desulumab), vismodygib (Vermod), sonidegib (Sonidege), dinutuximab, bevacizumab (bevacizumab), niraparib (Nilapatinib), avenumab (Avenumab), pembizumab (Pabrizumab), pexidartinib, tagraxofusp-Erzs (ELZONRIS), ipilimab (Ilimab), nivolimab (Na Wu Liyou mab), encritimab (Entretinib), larotrectinib (larotinib) or Pembrolizumab (palbociclizumab).
Preferably, the animal albumin is human serum albumin.
In a third aspect, the present application provides an albumin pharmaceutical composition comprising Fe 2+ Formation of Fe with animal Albumin 2+ -animal albumin complex, combining a drug with said Fe 2+ Animal albumin complex formation of Fe 2+ -animal albumin-drug complex.
Further, the animal albumin is human serum albumin, alpha serum albumin or bovine serum albumin;
and/or, the medicament comprises: anticholinergic agents, M-cholinergic blockers, adrenoceptor agonists, adrenoceptor blockers, antiepileptics and convulsives, antiparkinsonian agents, antipsychotics, local anesthetics, sedative hypnotics, analgesics, antipyretics, calcium antagonists, antiarrhythmics, antianginals, agents for treating congestive heart failure, antiatherosclerotic agents, antihypertensives, diuretics, histamine receptor blockers, digestive system agents, respiratory agents, adrenocortical hormone, thyroid hormones, antithyroid, insulin and hypoglycemic agents, blood and hematopoietic organ agents, beta-lactams, macrolides, lincomycin, aminoglycoside antibiotics, tetracyclines and antibiotics, artificially synthesized antibacterials, antifungals, antivirals, antituberculosis agents, antimalarials and/or antimalogenic agents;
preferably, the anti-malignant tumor agent comprises: curcumin, paclitaxel, immunotoxin, gefitinib (Gefitinib), erlotinib (Erlotinib), osiertinib (octreotide AZD 9291), necitumumab (naixituzumab), afatinib (afatinib), ceritinib (celetinib), aletinib (aletinib), lorlatinib (lalatinib), brinatinib (buntinib), crizotinii (critinib), dabraffinab (dasatinib), trametainibb (trimatinib), nivoltimab (nivalnemab), pembrontizumab (pemanitizumab), tistimab (cerinib, ceriniband monoclonal antibody), atezolizumab (alelizumab), sintiltimituab (melituab), cerinib mesylate, atelizumab (alemtuzumab), durvalnemab (duvalatinib), brinib (brinib), britinib (britinib), daivalnib (critinib), critinib (critimab), critimatib (critimatinib) and bevanab (pratinib, critimab), BLU-667), palbociclib (pie Bai Xili), ribociclib (Rabociclib), abemaciclib (Abbe cilomide), ado-Trastuzumab (Enmetrastuzumab, T-DM 1), pertuzumab (Pertuzumab), trastuzumab (Trastuzumab), neratinib (Nalatinib), fam-Trastuzumab deruxtecan-nxki (DS-8201), tucatinib (Tucatinib), lapatinib (Lapatinib), everolimus (Everolimus), olaparib (Olaparib), talazopanib (Talazopanib), alpelizumab (Abelist), atezolizumab (Abelizumab), sacituzumab govitecan-hziy (cetuzumab), cetuximab (cetuzumab), panitumumab (Paenimab), regorafenib (Regorafenib), ziv-aflibept (Abelipt), ramucicrumab (ramucilomab), bevacizumab (Bevacizumab), nivolumab (Na Wu Liyou mab), pembrolizumab (Pabolizumab), ipilimumab (Ipimab), pembrolizumab (Pabolizumab), regorafenib (Regorafinib), imatinib (imatinib), tinib (sultinib), avirinib (Avirinib), rivalenib (Rivalenib), ratimonib (Ratimonib) Trastuzumab (Trastuzumab), vidiximab, pembrolizumab (pamtirizumab), nivolumab (nano Wu Liyou mab), sorafenib (Sorafenib), regorafenib (Regorafenib), nivolumab (nano Wu Liyou mab), cabozantinib (Cabozantinib), lenvantinib (lenvaryinib), ramucirumab (ramucimab), pembrolizumab (palivizumab), tisielizumab (lanrelizumab), sintillimab (signal di Li Shan mab), atezolizumab (actlizumab), bevacizumab (Bevacizumab), ipilimab (ipilimab), erlotinib (Erlotinib), erbzatinib (Everolimus), everolimus (Everolimus), sulatib (oltinib), epranib (palivizumab), pemigatinib, olaparib, nilaparib, pamatinib, ruaparib, pembrolizumab, bevacizumab, pembryizumab, pembrolizumab, pelolizumab, avelaumumab, lenvaizumab, ipilimab, pembrolizumab Pazopanib (pelpanib), sorafenib (Sorafenib), sunitinib (Sunitinib), bevacizumab (Bevacizumab), axitinib (acitinib), cabozantinib (carbotinib), atezilizumab (atinib) Durvauumab (Durvauumab You Shan antibody), avelumab (Avermeb), pembrolizumab (palivizumab), nivolumab (Na Wu Liyou antibody), terlipressin Li Shan antibody, erdafiib (erdastinib), enfortumab vedotin-ejfy, sipueucel-T, abiraterone (Abituril), olaparib (Rucapanib), imatinib (Imatinib), nilotinib (Nilotinib), dasatinib (Dasatinib), bosutinib (sultinib), potinib (Ponatinib) Nana, midostaurin, gilteerinib, ibutinib, obtutinib, obtuzumab, rituximab, rituximab, alemetuzumab, idelalisib, blinaumomab, venetoclax, gemtuzumab ozogamicin, enasadinib, lvosidenib, glasdegib, granatinib, duvelisib, moxetumomab, inotuzumab ozogamicin, acalabrutinib, ibutinib, zanubrutinib, acalabrutinib, rituximab, ibritumomab tiuxetan, obinuzumab Tositumomab (Tositumomab), brentuximab vedotstatin (vitamin b), romidepsin (Romidepsin), vorinostat (Vorinostat), belinostat (Belinostat), copanliib (kunessi), idelalisib (alilarisst), nivolumab (nano Wu Liyou mab), pembrolizumab (palbolizumab), bortezomib (Bortezomib), ventoclax (vitamin c la), polatuzumab vedotin-Piiq (POLIVY), 823-kpkc (Poteligeo), tazemetostat (tazistat), selinexor (Li Nisuo), brexucabtagene autoleucel (tecarbs), tafasimab-cxix, panobinostat (panitustat), carfilzomib (Carfilzomib), bortezomib (Bortezomib), ixazomib (ixapyraab (Umamab), das-62. Tumab (Umamab), isatuximab-irfc, belantamab mafodotin-bimf, selinexor (Se Li Nisuo), elotuzumab (erlotinib), vandetanib (Vandetanib), cabozantinib (cabotinib), lenvantinib (lenvartinib), sorafenib (Sorafenib), anlotinib (An Luoti ni), dabrafenaib (Darafenib), trametinib (Trametinib), selpercatinib, cetuximab (cetuximab), nivolumab (Na Wu Liyou mab), pembrolizumab (palivizumab), terrappride Li Shan antibody, caririzumab, pembrolizumab (palbocavib), nivolumab (Na Wu Liyou mab), bimimanib (Bimipheneb), dabrahenib (Darafenib), vemurafenib (Mo Feini) Encodefenib (Kang Naifei), trametinib (trametetinib), cobimetainib (carbitinib), iplimizumab (Ipilimumab), atezolizumab (Abelizumab), cemiplimab-rwlc Pembrolizumab (Pabrizumab), pazopanib (Papanib), imatinib (imatinib), tazemetostat, denosumab (Desulumab), vismodygib (Vermod), sonidegib (Sonidege), dinutuximab, bevacizumab (bevacizumab), niraparib (Nilapatinib), avenumab (Avenumab), pembizumab (Pabrizumab), pexidartinib, tagraxofusp-Erzs (ELZONRIS), ipilimab (Ilimab), nivolimab (Na Wu Liyou mab), encritimab (Entretinib), larotrectinib (larotinib) or Pembrolizumab (palbociclizumab).
The fourth aspect of the present application provides a pharmaceutical composition comprising the protein pharmaceutical complex according to the third aspect of the present application and pharmaceutically acceptable excipients selected from the group consisting of: a carrier, diluent, binder, lubricant or wetting agent;
preferably, the dosage form of the pharmaceutical composition comprises: tablets, capsules, pills, injections, emulsions, nanoparticles, inhalants, gels, powders, suppositories, creams, jellies or sprays;
more preferably, the pharmaceutical composition may be administered in a manner comprising: oral, subcutaneous, intramuscular, intravenous, rectal, vaginal, nasal, transdermal, subconjunctival, intra-ocular, orbital, retrobulbar, retinal, choroidal or intrathecal injection.
In a fifth aspect, the present application provides a use of a complex according to the third aspect or a composition according to the fourth aspect for the manufacture of a medicament for the treatment and/or prophylaxis of a disease;
the disease is a tumor, an autoimmune disease, a viral disease or a bacterial disease.
The application has the beneficial effects that:
1. the application adopts Fe 2+ Formation of Fe with animal Albumin 2+ The animal albumin complex promotes the endocytosis process, can effectively improve the albumin absorption efficiency and can promote the cell absorption;
2. when Fe of the present application 2+ When the animal albumin compound is loaded with the medicine, the compound can greatly increase the bioavailability of the medicine, reduce the dosage of the medicine, reduce side effects, improve the effective rate of the medicine and further enhance the curative effect of the medicine.
Drawings
FIG. 1 shows Ca at various doses 2+ Effects on IEC-6 and Caco-2 endocytic efficiency of HSA;
FIG. 2 shows different doses of Mg 2+ Effects on IEC-6 and Caco-2 endocytic efficiency of HSA;
FIG. 3 shows different dosages of Zn 2+ Influence on Caco-2 endocytosis efficiency of HSA, and its advantages are high effect on the cell surface of HSAIndicating significant differences between groups, P<0.05)；
FIG. 4A shows the different dosages of Fe 2+ Influence on Caco-2 endocytosis efficiency of HSAIndicating significant differences between groups, P<0.05)；
FIG. 4B shows different dosages of Fe 2+ Influence on IEC-6 endocytosis efficiency of HSAIndicating significant differences between groups, P<0.05)；
FIG. 5A shows Fe 2+ Profile of fluorescent signal affecting Caco-2 cell number of endocytic HSA;
FIG. 5B shows Fe 2+ Profile of fluorescence signal affected by IEC-6 cell number endocytic HSA;
FIG. 6 shows HSA/Fe 2+ Immunofluorescence plot of distribution and localization within cells (scale 20 μm);
FIG. 7A shows Fe 2+ Profile of fluorescence signal on the effect of HSA-binding Caco-2 cell number;
FIG. 7B shows Fe 2+ Profile of fluorescence signal on the effect of IEC-6 cell number binding to HSA;
FIG. 8A shows HSA/Fe 2+ Photograph for remarkably enhancing the remission effect of curcumin on mice with colon inflammation;
FIG. 8B shows HSA/Fe 2+ A rectum length chart for remarkably enhancing the relief effect of curcumin on mice with colon inflammation;
FIG. 8C shows HSA/Fe 2+ Significantly enhancing the remission effect of curcumin on mice with colon inflammation.
FIG. 9 shows Fe 2+ Influence on HSA particle sizeRepresenting that Fe is not added 2+ Significant difference in HSA group, P<0.05)；
FIG. 10 shows Fe 2+ Influence on HSA potentialShows significant difference from HSA group without Fe2+, P<0.05）。
Detailed Description
Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application relates.
In the present application, the term "endocytosis" means endocytosis or endocytosis (endocytosis) which is an important way for cells to take macromolecules and particulate materials from outside, and is a physiological phenomenon commonly found in eukaryotic cells. Extracellular material is encapsulated by the plasma membrane, which invaginates and forms membrane-coated vesicles that break away from the plasma membrane into the cell and produce a range of physiological activities and functions within the cell. Endocytosis is intimately involved in a variety of vital activities, such as immune response, neurotransmitter trafficking, cellular signal transduction, cellular and tissue metabolic balance, etc.;
in the present application, the term "HSA" refers to human serum albumin;
in the present application, the term "Caco-2 cell" refers to a human cloned colon adenocarcinoma cell which has a structure and function similar to those of differentiated small intestine epithelial cells, has a structure of microvilli and the like, contains an enzyme system related to brush border epithelium of small intestine, and can be used for performing experiments simulating intestinal transport in vivo. Under cell culture conditions, cells grown on porous permeable polycarbonate membranes can fuse and differentiate into intestinal epithelial cells, forming a continuous monolayer, unlike the case where normal mature small intestinal epithelial cells undergo retrodifferentiation during in vitro incubation. Cell sub-microscopic structure research shows that Caco-2 cells are similar to human small intestine epithelial cells in morphology, and have the same cell polarity and tight connection. Detection of pinocytosis also indicates that Caco-2 cells are similar to human small intestine epithelial cells;
in the present application, the term "IEC-6 cells" refers to a cell line isolated from rat small intestine epithelium, which is often used as a model for studying intestinal physiology and disease mechanism. These cells have morphological features and functions of epithelial cells, including coating the surface area of intestinal epithelium and cell brush borders expressing various digestive enzymes. IEC-6 cells can be used for researching the absorption, transportation, secretion, adhesion functions and the like of intestinal tracts, and can also be used for simulating diseases such as inflammation, tumors, intestinal tract infection and the like.
In the present application, the term "Western blot" refers to Western blotting (immunoblotting test) which is based on the staining of gel-electrophoretically treated cell or biological tissue samples by specific antibodies. Information on the expression of a specific protein in the analyzed cell or tissue is obtained by analyzing the position of staining and the depth of staining.
In the present application, the term "dextran sulfate (DSS) induction" is commonly used in experimental animal models-induced colitis, glucose sodium sulfate salt (dextran sodium sulfate), english Dextran Sulfate Sodium Salt, abbreviated DSS, is a polyanionic derivative of dextran formed by esterification of dextran and chlorohuang acid. Wherein the sulfur content is about 17%, and the average content of sulfuric acid groups in each glucose residue corresponding to the glucan molecule is 1.9, so that the glucan is an inducer of enteritis modeling agents.
In the present application, the term "HSA/Fe 2+ "means Fe 2+ -a complex of HSA.
In the present application, the term "flow cytometry" and "FC" (flow cytometer), also known as flow cytometry, are modern cell analysis techniques for measuring suspended cells (or particles) by a flow cytometer. The method comprehensively utilizes a plurality of modern high and new technologies to analyze a plurality of characteristics and functions of a large number of cells (or particles) simultaneously in a very short time, has important significance for researching physiological functions of the cells, occurrence and development rules of diseases and the like, and has very wide application in the fields of cell biology, hematology, immunology, oncology and the like.
Embodiments of the present application will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present application and should not be construed as limiting the scope of the present application. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1 Effect of different kinds of divalent cations on endocytosis of Human Serum Albumin (HSA)
1.1 preparation of solutions containing ions of different concentrations and human serum albumin
Adding HSA with a certain concentration and Ca with different concentrations respectively 2+ 、Mg 2+ 、Zn 2+ 、Fe 2+ Mixing in centrifuge tube, incubating at 37deg.C for 15min, diluting the complex with DMEM medium, and Ca 2+ 、Mg 2+ 、Fe 2+ Final concentration of divalent ions is 0 [ mu ] M,30 [ mu ] M,60 [ mu ] M,120 [ mu ] M and Zn respectively 2+ The final concentration of HSA in all culture media is respectively 0 mu M,15 mu M,30 mu M and 60 mu M, and the final concentration of HSA in all culture media is 15 mu M, so that culture media of divalent cations and human serum albumin complexes of different types are formed.
Each prepared culture medium is added into each hole of a 12-hole plate respectively, 3 parallel treatments are arranged on each group, after the treatment is carried out for 4 hours at 37 ℃, the supernatant is discarded, the culture medium is washed 3 times by ice PBS, the hole plate is placed on ice, and protein is extracted for Western blot analysis or cells are collected for flow cytometry analysis.
1.2 experimental results
1.2.1. Ca 2+ Effect on HSA endocytosis efficiency
The prior art can not clearly add Ca exogenously 2+ Whether or not to affect the endocytic efficiency of HSA, therefore, to clarify Ca 2+ Influence on HSA cell endocytosis efficiency, firstly, determining exogenous addition of Ca with different dosages by using a Western blot method 2+ Effect on HSA endocytosis of Caco-2 and IEC-6 cells (using medium configured in 1.1). The results are shown in FIG. 1, with Ca 2+ The content of the endocytosis HSA is not obviously changed due to the increase of the adding proportionP＞0.05) Indicating Ca 2+ Has no significant effect on the endocytic efficiency of HSA.
1.2.2 Mg 2+ Effect on HSA endocytosis efficiency
Mg 2+ Is the most abundant divalent cation in cells and plays an important role in a variety of physiological processes, including protein synthesis and cell proliferation, which also plays a key role in calcium metabolism. Determination of different doses of Mg added 2+ Effects on HSA endocytosis by Caco-2 cells and IEC-6 cells (using the medium configured in 1.1), as shown in FIG. 2, western blot results show following Mg 2+ The increase of the adding proportion has no obvious influence on the content of the endocytosis HSAP ＞ 0.05)。
1.2.3 Zn 2+ Effect on HSA endocytosis efficiency
Zn 2+ Can influence the intake of nutrient substances and has important effect on the growth and development of organisms. This example measures the addition of Zn at different doses 2+ Effect on endocytosis efficiency of HSA in Caco-2 cells (using formulation medium in 1.1). As shown in FIG. 3, the Western blot results show that with Zn 2+ Increasing the addition content, remarkably increasing the HSA content in cellsP< 0.05) Indicating Zn 2+ Promoting endocytosis of HSA.
1.2.4 Fe 2+ Effect on HSA endocytosis efficiency
As shown in FIG. 4A and FIG. 4B, western blot results show that with Fe, the culture medium prepared in 1.1 was used 2+ An increase in the addition ratio significantly increased the amount of HSA in the cells, indicating Fe 2+ Is added to promote endocytosis of HSA.
Determination of Fe Using flow cytometer 2+ Effect on HSA endocytosis efficiency figures 5A and 5B are distributions of fluorescence signals of human serum albumin in cells measured by flow cytometry. For Caco-2 cells and IEC-6 cells, the cell fraction of endocytic HSA was 1.21% and 1.77%, respectively; adding 30 mu M Fe 2+ When endocytic HSA was present, the cell fractions were 26.83% and 10.90%, respectively; 60 mu M Fe was added 2+ When endocytic HSA cell fractions were 34.81% and 25.11%, respectively; 120 mu M Fe was added 2+ When endocytic HSA cell fractions were 42.35% and 48.46%, respectively; this is consistent with the Western blot results, along with Fe 2+ The increase of the addition proportion shows that the fluorescence signal of HSA in the cells is gradually enhanced, namely that Fe 2+ Is added to promote endocytosis of HSA.
From the above, zn 2+ Promoting endocytosis of HSA, fe 2+ Significantly promotes the endocytosis of HSA, thus, the application selects and researches Fe 2+ Effects on endocytosis.
Example 2 Fe 2+ And intracellular distribution and localization of HSA complexes
2.1 Experimental procedure
Preparation of Fe with different concentrations 2+ And HSA complexAnd (2) a compound: wherein Fe is 2+ The concentration of (1) is 0 mu M,300 mu M,600 mu M,1200 mu M and the HSA concentration is 150 mu M respectively. Adding a certain amount of HSA and Fe with different concentrations respectively 2+ In a centrifuge tube, incubating at 37deg.C for 15min, diluting the complex with DMEM medium, and mixing Fe in the diluted medium 2+ The final concentration of divalent ions is 0 mu M,30 mu M,60 mu M,120 mu M, and the final concentration of HSA is 15 mu M respectively.
Determination of Fe by immunofluorescence 2+ And localization and distribution in cells after treatment of Caco-2 and IEC-6 cells with HSA complexes.
2.2 Experimental results
Research results of Western blot and flow cytometry show that Fe 2+ Promoting the endocytosis of HSA, further, the application also measures Fe 2+ And intracellular distribution and localization of HSA complexes, as shown in FIG. 6, showing fluorescence patterns detected in CaCO-2 and IEC-6 cells when treated with different media mixtures in 2.1 experimental steps for 8 h. The nuclei are fluorescently labeled with DAPI dye, the oval shaped shading represents the nuclei, the bright color of the HSA row indicates the HSA distribution within the cell, the superimposed column is the result of the three fluorescent signals being superimposed together, and the superimposed column row contains the oval bright ring with the highest brightness as the cell membrane. As can be seen from fig. 6, HSA starts to enter the cytoplasm and follows Fe 2+ The increase in the amount of additive, the bright color of the HSA row is more and more, and the bright color is mainly located between the cell membrane and the cell nucleus, which indicates that HSA does endocytose, and in addition, again proves that Fe 2+ Promoting endocytosis of HSA.
Example 3 Fe 2+ Effect on the efficiency of binding of human serum albumin to cell membranes
3.1 Experimental procedure
Endocytosis is an energy dependent process, and low temperatures can inhibit endocytosis. To determine Fe 2+ The influence of the addition of HSA on the binding of HSA to cell membranes was determined at 4℃in the present application 2+ Effects on HSA binding to cell membranes.
Formulated to contain different concentrationsFe 2+ And HSA complex: wherein Fe is 2+ The concentration of (1) is 0 mu M,300 mu M,600 mu M and 1200 mu M respectively, and the concentration of HSA is 150 mu M. Adding HSA with a certain concentration and Fe with different concentrations respectively 2+ In a centrifuge tube, incubating at 37deg.C for 15min, and diluting the complex with culture medium to obtain Fe in diluted culture medium mixture 2+ The final concentration of divalent ions is 0 mu M,30 mu M,60 mu M and 120 mu M respectively, and the final concentration of each group of HSA is 15 mu M. Culturing the cells at 4deg.C for 30 min, and mixing the above prepared materials containing Fe 2+ And the culture medium mixture of the HSA complex was added to each well of a 12-well plate, 3 parallel treatments were set for each group, after 1 hour of treatment at 4 ℃, the supernatant was discarded, washed 3 times with PBS, and the well plate was placed on ice to collect cells for FC analysis.
3.2 Experimental results
The results are shown in FIGS. 7A and 7B, with HSA binding to cell membrane at 1.08% and 0.32% for Caco-2 and IEC-6 cells, respectively; adding 30 mu M Fe 2+ When HSA was associated with cell membranes, the cell ratios were 3.31% and 8.56%, respectively; 60 mu M Fe was added 2+ When HSA was associated with cell membranes, the cell fractions were 7.62% and 10.84%, respectively; 120 mu M Fe was added 2+ When HSA was associated with cell membranes, the cell fractions were 12.49% and 18.56%, respectively; indicated Fe 2+ The addition of (2) promotes the binding of HSA to the cell membrane.
Example 4 Fe 2+ And HSA complexes enhance the inflammatory effects of curcumin
Human serum albumin has an important transport function, and has a plurality of binding sites, and can bind and transport endogenous and exogenous molecules, thereby promoting the transportation of the endogenous and exogenous molecules among physiological organs. The results of examples 1 to 3 demonstrate Fe 2+ Can promote the endocytosis efficiency of HSA, and endocytosis is a precondition of the running transport function. In this example, curcumin was used as a drug model to measure Fe 2+ Whether the bound HSA can more efficiently promote the relief of the inflammatory bowel disease by curcumin. And the literature reports that Curcumin (CUR) has low bioavailability due to its poor solubility, resulting in a minimum effective dose of 50 mg/kg for oral or rectal administration,the application selects curcumin with the dosage of only 10 mg/kg to explore Fe 2+ And whether the promoting effect of the HSA complex can achieve the purpose of reducing inflammation.
4.1 Experimental procedure
In the embodiment, the colitis model mouse is constructed by adopting a dextran sulfate (DSS) induction method, and the pathological characteristics of the colitis model mouse are mainly that the colon length is shortened and the weight is reduced. The specific grouping situation is as follows: normal mice were not model and were given PBS (Control group), model-based rectal PBS (DSS), model-based rectal curcumin (dds+cur), model-based rectal HSA and curcumin complex (dss+h+cur), model-based rectal HSA, low dose Fe 2+ And curcumin complex (DSS+HL+CUR), and rectal administration of HSA and high dose Fe based on molding 2+ And curcumin complexes (dss+hh+cur).
Colitis mouse model construction conditions: preparing 3.0% DSS solution, and changing the DSS solution into normal deionized water after drinking water for 6 days. The body weight of the mice was measured daily.
The treatment conditions of the mice of different experimental groups are as follows:
1. preparing curcumin: curcumin solution of 2mg/ml was prepared as stock solution and the mice were dosed at 10 mg/kg.
2. Preparation of HSA and curcumin complexes: a100 mg/mL HSA solution was prepared and contained 2mg/mL of a stock solution of curcumin at a dose of 0.5 g/kg for rectal administration at a dose of 10 mg/kg for curcumin.
3. HSA, low dose Fe 2+ And formulation of curcumin complexes: first, fe is prepared 2+ HSA stock solution HSA 100mg/mL (1.50 mM), fe 2+ After 15min of reaction at 37℃at a concentration of 3 mM, bound Fe was produced 2+ Is a HSA of (2). Curcumin was then added at a final concentration of 2mg/mL and mixed well. HSA dose in rectal administration was 0.5 g/kg, feCl 2’ 4H 2 The dosage of O was 2.9715mg/kg and the dosage of curcumin was 10 mg/kg.
4. HSA, high dose Fe 2+ And formulation of curcumin complexes: first, fe is prepared 2+ HSA stock solution, wherein the concentration of HSA was 100mg/mL (1.50. 1.50 mM), fe 2+ After 15min of reaction at 37℃at a concentration of 12 mM, bound Fe was formed 2+ Is a HSA of (2). Curcumin was then added at a final concentration of 2mg/mL and mixed well. HSA dose in rectal administration was 0.5 g/kg, feCl 2’ 4H 2 The dosage of O was 11.886 mg/kg and the dosage of curcumin was 10 mg/kg.
4.2 Experimental results
The results of the study found that the colon length of the model building block (DDS) was significantly reduced compared to the control group (control), indicating successful establishment of the mouse colitis model. The results are shown in fig. 8A, 8B and 8C, and when the CUR alone (dds+cur group) or the HSA and curcumin complex (dss+h+cur) were administered rectally, the colon length of the mice was not significantly different from the body weight and model group at the late stage of molding, indicating that the CUR alone or h+cur had no significant remission effect on the enteritis mice. Whereas when hl+cur or hh+cur was administered, the colon length was significantly increased compared to the model (DSS), the body weight of mice was significantly increased compared to the model, indicating that both hl+cur and hh+cur had significant relief from colonitis mice, the application demonstrated Fe in vivo 2+ And HSA complexes may more efficiently facilitate transport of curcumin between tissues than HSA. Therefore, fe is utilized 2+ Promoting endocytosis of albumin can more widely increase the drug delivery efficiency taking albumin as a carrier, thereby improving the therapeutic effect.
Example 5 Fe 2+ Binding to HSA
The method comprises the following steps:
1. particle size analysis
An amount of HSA was weighed and dissolved in 10 mM Na 2 HPO 4 /KH 2 PO 4 In the buffer solution, the final concentration is 15 mu M, and a certain amount of Fe is taken 2+ Diluting in HSA to final concentration of 7.5, 15, 30, 60, 120, 240, 360 and 480 μm, reacting at 37deg.C for 15min, and preparing as-is as a sample to be tested;
dispersing 100 mu L of sample to be measured in 10 mL ultrapure water, and performing dynamic light scattering test to obtain Fe 2+ Spontaneous phase of Brownian motion of HSA particlesThe number diameter of the function can be automatically calculated by fitting the instrument. The detection conditions are as follows: the temperature was measured at 25℃and the refractive index of the solvent was 1.333 and the viscosity was 1.002 mPa.s.
2. Potentiometric analysis
100. Mu.L of the sample to be measured was dispersed in 10 mL of ultrapure water at a detection temperature of 25℃and a refractive index of the solvent of 1.333 and a viscosity of 1.002 mPa.s. The sample was equilibrated for 2 min before testing to allow the temperature of the sample and the test temperature to equilibrate. Fitting by adopting a shock equation of the instrument, and directly obtaining Fe through calculation 2+ -the electrical potential value of HSA particles.
Experimental results
5.1 Fe 2+ Effect on HSA particle size
The application adopts Dynamic Light Scattering (DLS) technology to measure and combine Fe with different dosages 2+ The raw data of the experiment was then fitted to the Brownian motion of the HSA particles using the theoretical formula established in the instrument to obtain the particle size distribution of the particles, and the number average was taken in the experiment to represent the particle size distribution of HSA. As shown in fig. 9. When Fe is 2+ When the addition amount is 0 to 120. Mu.M, the HSA has a diameter of 5 to 6 nm. When Fe is 2+ When the amount of addition of (2) is larger than 120. Mu.M, the particle size of HSA increases significantly to 33-35 nm, possibly due to the formation of multimers. These results indicate that when Fe 2+ When the addition amount is 0-120 mu M, fe 2+ Has no obvious influence on the grain diameter of HSA, when Fe is continuously added 2+ When added in an amount of HSA, the particle size of HSA increases significantly.
5.2、Fe 2+ Effect on HSA potential
The surface potential is the electrostatic potential present on the shear plane of the particle and is related to the surface charge of the particle and the local environment. In colloid science, the potential is often used as an important parameter for understanding the electrostatic interactions of colloids. To study Fe 2+ Interaction with HSA, the application adopts a Markov particle size potentiometer to measure and add Fe with different concentrations 2+ Effect on HSA potential. As shown in fig. 10, the HSA has a negative potential, indicating that it is negatively charged, mainly due to the isoelectric point of HSA being about 4.7, which is electronegative under neutral conditions. When Fe is 2+ When the addition amount of (C) is 0-120 mu M, fe 2+ No significant difference between the surface potential of HSA and HSA itselfP>0.05). When Fe is 2+ When the addition amount of (C) is more than 120. Mu.M, fe 2+ The absolute value of the surface potential of HSA is significantly reduced compared to HSA itselfP ＜ 0.05). This is probably because when Fe 2+ At lower amounts, it binds inside the HSA molecule, so the HSA potential is unchanged. When Fe is 2+ At higher addition levels, it may bind to the HSA molecule surface, thus the potential of HSA decreases and Fe 2+ Positively charged, resulting in a decrease in the absolute value of its surface potential. These experimental results indicate that HSA and Fe 2+ Intermolecular binding occurs.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present application, and not for limiting the same; although the application has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the application.

Claims (6)

1. A method for promoting endocytosis of animal albumin is characterized by adopting Fe 2+ Formation of Fe with animal Albumin 2+ -an animal albumin complex, said method being of non-therapeutic or diagnostic interest.
2. The method of claim 1, wherein the animal albumin is human serum albumin or bovine serum albumin.
3. The method of claim 1, wherein the cell is an epithelial cell, an endothelial cell, a macrophage, a tubular cell, a hepatic parenchymal cell, a hepatic cell, a myocardial cell, a breast cancer cell, a gastric cancer cell, a lung cancer cell, a liver cancer cell, a cervical cancer cell, a lymphoma cell, a thyroid cancer cell, an esophageal cancer cell, a renal cancer cell, a pancreatic cancer cell, a glioma cell, a melanoma cell, a bladder cancer cell, or a prostate cancer cell.
4. An animal albumin medicine compound is characterized in that Fe is adopted 2+ Formation of Fe with animal Albumin 2+ -animal albumin complex, combining a drug with said Fe 2+ Animal albumin complex formation of Fe 2+ -an animal albumin-drug complex, the animal albumin being human serum albumin; the medicine is curcumin.
5. A pharmaceutical composition comprising the pharmaceutical composition of claim 4 and a pharmaceutically acceptable adjuvant comprising a carrier, diluent, binder, lubricant and/or wetting agent.
6. Use of a pharmaceutical complex according to claim 4 or a pharmaceutical composition according to claim 5 for the preparation of a medicament for the treatment and/or prophylaxis of a disease.
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