WO2022012479A1 - 一种超分子细胞载体、载药体系及其制备方法 - Google Patents

一种超分子细胞载体、载药体系及其制备方法 Download PDF

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WO2022012479A1
WO2022012479A1 PCT/CN2021/105845 CN2021105845W WO2022012479A1 WO 2022012479 A1 WO2022012479 A1 WO 2022012479A1 CN 2021105845 W CN2021105845 W CN 2021105845W WO 2022012479 A1 WO2022012479 A1 WO 2022012479A1
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cell
supramolecular
molecule
peg
membrane
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French (fr)
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王瑞兵
高成
成谦
李铭源
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澳门大学
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    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5063—Compounds of unknown constitution, e.g. material from plants or animals
    • A61K9/5068—Cell membranes or bacterial membranes enclosing drugs
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6901—Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • 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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    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
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    • A61K47/6911—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome
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    • A61K47/6949—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
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    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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Definitions

  • the present application relates to the technical fields of supramolecular chemistry, supramolecular materials and cell preparations, and in particular, to a supramolecular cell carrier, a drug-carrying system and a preparation method thereof.
  • Inflammation is closely related to various diseases of the human body, including major diseases such as cancer and nervous system diseases.
  • major diseases such as cancer and nervous system diseases.
  • the current traditional pharmaceutical preparations and synthetic targeted preparations have no obvious therapeutic effects on these major diseases, which may be related to the clearance of the reticuloendothelial system in the blood circulation process, the physiological barrier effect before reaching the diseased tissue, and the effect on the diseased tissue.
  • Weak targeting selectivity and other factors are related, and these influencing factors will affect the final concentration and therapeutic effect of the drug. Therefore, for these major diseases related to inflammation, it is necessary to find new delivery vehicles and new targeting pathways, and develop a new generation of drug preparations with high biocompatibility, high physiological barrier permeability, and high targeting. Research and clinical problems to be solved.
  • the purpose of this application is to provide a supramolecular cell carrier, a drug-carrying system and a preparation method thereof to solve the above-mentioned technical problems.
  • a supramolecular cell carrier comprising a first part and a second part interconnected by host-guest interaction, the first part is a first cell modified by a macrocyclic host molecule, and the second part is a nanoparticle modified by a guest molecule or a guest molecule modified In the second cell, the macrocyclic host molecule in the first part is embedded in the cell membrane of the first cell by coupling the intercalation material.
  • Cells are the basic units that constitute the structure of organisms and perform biological functions. If cells are used as drug delivery carriers, they have many natural advantages. However, there are few related studies on the use of cells as drug carriers, and there are also construction methods for cell carriers. Some inevitable flaws. One of them is to realize the loading of drug carriers by cells through endocytosis of drug carriers. However, the phagocytosed drug carriers may be degraded in the intracellular environment and cause cytotoxicity, thereby affecting the drug delivery based on cellular physiological functions. . Another is to achieve cell loading of drug carriers through covalent binding of cell surfaces to drug carriers or specific ligand-receptor binding, where covalent binding involves complex multi-step chemical reactions on the cell membrane. May affect cell activity; while binding via specific ligand-receptor interactions is limited to specific cells expressing the relevant receptor, its application is limited.
  • the inventor creatively provides an idea of embedding a membrane material into the cell membrane of the first cell, which avoids the decrease of cell activity caused by the covalent binding of the cell surface and the drug carrier, and is not limited to specific cells expressing relevant receptors.
  • the provided first cells can be adaptively adjusted according to drug loading requirements, and have a wide range of applications.
  • a macrocyclic host molecule is coupled to one end of the membrane-embedded material, and the macrocyclic host molecule can be connected with the guest molecule through the host-guest interaction to form a supramolecular cellular carrier.
  • the membrane-embedded material is similar to the structural components of the cell membrane, and self-assembles with the phospholipid layer on the surface of the cell membrane through hydrophobic interaction.
  • Host-guest chemistry is a new research direction that has arisen in recent years. It is a non-covalent bond between host molecules and guest molecules. Most of the research is on the host of ⁇ -cyclodextrin and adamantane. In the case of guest interaction, in water, the guest molecule adamantane will automatically combine with the hydrophobic cavity of the host molecule cyclodextrin due to its hydrophobicity to form a relatively stable host-guest interaction product.
  • the targeted delivery effect based on cell function can be achieved through the host-guest interaction and the incorporation of the macrocyclic host molecule's coupled membrane material into the supramolecular cell carrier constructed by the first cell.
  • the supramolecular cell carrier overcomes the defect of the prior art that the drug carrier can be loaded by cells through endocytosis of the cell.
  • the supramolecular cell carrier does not induce cytotoxicity and has bioorthogonality.
  • the macrocyclic host molecule is cyclodextrin (CD), cucurbituril (CB), calixarene, pillar arene or crown ether; preferably, the macrocyclic host molecule is ⁇ -ring dextrin.
  • the crown ether may be any one of bicyclic crown ethers, tricyclic crown ethers, polycyclic crown ethers and heterocrown ethers.
  • the above-mentioned macrocyclic host molecules have high binding constants with many guest molecules, which help to improve the stability of the host-guest complex in vivo.
  • the macrocyclic host molecule is located on the outer surface layer of the cell membrane, and the phospholipid end linked by the macrocyclic molecule is fused with the cell membrane phospholipid bilayer to be embedded in the cell membrane.
  • the first cell is selected from any one of macrophages, neutrophils, erythrocytes, stem cells, lymphocytes, dendritic cells, platelets and adipocytes.
  • the supramolecular cell carrier provided in this application can select the corresponding first cell according to the needs.
  • Macrophages can be M1 type or M2 type macrophages.
  • the lymphocytes can be at least one of T cells, B cells and NK cells.
  • Adipocytes can be white adipocytes or brown adipocytes.
  • the molar ratio of the macrocyclic host molecule to the guest molecule is 1-10:1-10; preferably 1:1;
  • the guest molecule is adamantane or ferrocene.
  • the macrocyclic host molecule and the guest molecule can simply and quickly realize the preparation of supramolecular cell carrier under the above molar ratio.
  • the guest molecule needs to match the host molecule, and can also be substituted as required in other embodiments.
  • the above-mentioned nanoparticles are at least one of liposomes, micelles, nanogels, inorganic nanoparticles and nanocapsules.
  • the second cells are hepatocytes, stem cells, lymphocytes, dendritic cells, platelets and adipocytes or red blood cells.
  • any cell whose surface can be embedded with a "DSPE-PEG-guest molecule" can serve as a second cell.
  • Liposomes facilitate transmembrane transport of supramolecular cellular carriers, enabling targeted drug delivery through similar polarities.
  • the second cell is hepatocyte or red blood cell, which is beneficial to improve the targeted therapy ability of supramolecular cell carrier for major diseases.
  • the above-mentioned membrane embedding material is PEG-DMPE, PEG-DPPE, PEG-DSPE or PEG-CHOL.
  • PEG-DMPE means PEG- dimyristoyl phosphatidyl ethanolamine
  • PEG-DPPE means PEG-dipalmitoyl phosphatidyl ethanolamine
  • PEG-DSPE means PEG-distearoyl phosphatidyl ethanolamine
  • PEG-CHOL means PEG-cholesterol.
  • DSPE-PEG-ADA cholesterol, and lecithin can be used to prepare ADA (adamantane)-enriched liposomes on the surface.
  • ADA adamantane
  • hepatocytes with surface-modified guest molecule adamantane can be constructed by the intercalation effect of DSPE-PEG-ADA.
  • a preparation method of a supramolecular cell carrier comprising: co-incubating a macrocyclic host molecule coupled with a membrane-embedding material and a first cell to obtain a first part, and then adding a nanoparticle modified with a guest molecule or a nanoparticle modified with the guest molecule. The second cell was incubated with the first part mixed.
  • the preparation method of the supramolecular cell carrier provided by the present application has the advantages of simple and rapid preparation process, mild conditions, and universality, and the method has bioorthogonality.
  • the above preparation method further comprises first coupling the macrocyclic host molecule with the membrane-embedding material, and then embedding the macrocyclic host molecule coupled with the membrane-embedding material into the cell membrane of the first cell;
  • the macrocyclic host molecule is covalently linked to the PEG in the embedded membrane material; preferably, the co-incubation time of the macrocyclic host molecule coupled with the embedded membrane material and the first cell is greater than 30 minutes; The concentration of the macrocyclic host molecule of the membrane material is 1 ⁇ M-1 mM.
  • macrocyclic host molecules coupled with intercalation materials or nanoparticles modified with guest molecules can also be purchased directly.
  • the above-mentioned nanoparticle modified with a guest molecule or the second cell modified with a guest molecule and the first part are mixed and incubated for ⁇ 10 seconds.
  • a drug loading system the carrier system includes a supramolecular cell carrier and a drug, and the drug is loaded in a nanoparticle or a second cell; preferably, the nanoparticle is a liposome.
  • the supramolecular cellular carrier provided in this application can be used to deliver liposomes or cells.
  • Drugs can be loaded in liposomes, that is, as nano-drugs pulled by cells for targeted delivery, and the release mechanism is also mainly related to the properties of liposomes themselves.
  • the drug-loaded liposomes can be separated from the supramolecular cell carrier in the following ways: one is due to the fluidity of the cell membrane, and the other is that the drug-loaded liposome is directly phagocytosed and digested by the carrier cells or target tissue cells, resulting in intracellular drugs. freed.
  • the drug loading system provided in the present application can be used for loading anti-inflammatory drugs, antibiotics, targeted cancer, and therapeutic agents for nervous system diseases.
  • the anti-inflammatory drug can be dendrobetin.
  • the anti-inflammatory drug dendrobetin is loaded in liposomes, and after conjugation with macrophage supramolecules, it is targeted and delivered to the site of pneumonia to treat acute pneumonia.
  • the drug loading system can be used to load doxorubicin.
  • the application provides a supramolecular cell carrier, a drug-carrying system and a preparation method thereof.
  • the supramolecular cell carrier constructed based on supramolecular host-guest interaction can achieve targeted delivery effect based on cell function, with high biocompatibility, high physiological barrier permeability and high targeting. Covalent modification of the cell surface is not required, and there is no effect on the physiological function of the modified cells.
  • the preparation method of the supramolecular cell carrier provided by the present application has the advantages of simple preparation process, rapidity, mild conditions and universality, and the method is bioorthogonal.
  • a drug loading system is also provided, which can realize drug loading for targeted drug therapy.
  • FIG. 1 is a fluorescence imaging diagram of the supramolecular cell and liposome conjugate of Example 1 of the application;
  • Fig. 2 is the scanning electron microscope image of the supramolecular cell and liposome conjugate of the embodiment 1 of the application;
  • FIG. 3 is a fluorescence imaging diagram of supramolecular cells and cell complexes according to Example 5 of the application;
  • FIG. 4 is a scanning electron microscope image of the supramolecular cell-cell combination in Example 5 of the present application.
  • This embodiment provides a supramolecular cell carrier and a preparation method thereof.
  • the first cell is a macrophage
  • both DSPE-PEG- ⁇ -CD and DSPE-PEG-ADA are purchased from Xi'an Ruixi Biotechnology Co., Ltd.
  • DMEM medium was purchased from Thermo Fisher Scientific (China) Co., Ltd.
  • doxorubicin was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.
  • Macrophages were incubated in blank DMEM medium containing 10 ⁇ M of DSPE-PEG- ⁇ -CD at 37°C for 2 hours.
  • the prepared supramolecular cell-liposome conjugates were subjected to fluorescence imaging and scanning electron microscope imaging.
  • the fluorescence imaging diagram of the supramolecular cell and the liposome conjugate is shown in FIG. 1
  • the scanning electron microscope image of the supramolecular cell and the liposome conjugate is shown in FIG. 2 .
  • This example provides a supramolecular cell carrier and a preparation method thereof.
  • DSPE-PEG- ⁇ -CD and DMEM medium are purchased from the same sources as those in Example 1.
  • the first cells were macrophages, and the macrophages were incubated in blank DMEM medium containing 50 ⁇ M of DSPE-PEG- ⁇ -CD at 37° C. for 1 hour.
  • DSPE-PEG- ⁇ -CD 50 ⁇ M DSPE-PEG-ADA modified liposomes were added and incubated for 2 minutes. After a final wash of unbound liposomes, supramolecular cell-liposome conjugates were obtained.
  • This example provides a supramolecular cell carrier and a preparation method thereof.
  • DMPE-PEG-CB[7] and DMPE-PEG-ADA are self-made in the laboratory.
  • neutrophils were incubated in blank DMEM medium containing 100 ⁇ M of DMPE-PEG-CB[7] (CB[7] is cucurbit[7]uril) for 2 hours at 37°C.
  • This example provides a supramolecular cell carrier and a preparation method thereof.
  • DPPE-PEG-CB[7] and DPPE-PEG-ADA are self-made in the laboratory.
  • hematopoietic stem cells were incubated in blank DMEM medium containing 40 ⁇ M of DPPE-PEG-CB[7] at 37°C for 1.5 hours.
  • This embodiment provides a supramolecular cell carrier and a preparation method thereof.
  • DiD and DiO are purchased from Shanghai Biyuntian Biotechnology Co., Ltd.
  • macrophages were incubated in blank DMEM medium containing 10 ⁇ M DSPE-PEG- ⁇ -CD at 37°C for 2 hours, and 10 ⁇ M DSPE was added after washing off excess DSPE-PEG- ⁇ -CD.
  • -PEG-ADA modified human hepatocytes were incubated for 2 minutes, and after washing away unbound hepatocytes, supramolecular cell-cell conjugates were prepared.
  • the obtained supramolecular cell-cell conjugates were subjected to fluorescence imaging and scanning electron microscopy imaging.
  • the fluorescence imaging diagram is shown in FIG. 3
  • the scanning electron microscope imaging diagram is shown in FIG. 4 .
  • the macrophages were stained with DiD (red), and the human hepatocytes were stained with DiO (green).
  • This example provides a supramolecular cell carrier and a preparation method thereof.
  • Fc was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., and DSPE-PEG-Fc was self-made in a laboratory.
  • macrophages were incubated in blank DMEM medium containing 10 ⁇ M of DSPE-PEG- ⁇ -CD at 37° C. for 2 hours. After incubation, the excess DSPE-PEG- ⁇ -CD was washed away, and 10 ⁇ M of DSPE-PEG-Fc (Fc is ferrocene) modified human hepatocytes was added to continue to incubate for 2 minutes. Supramolecular cell-cell complexes.
  • This embodiment provides a supramolecular cell carrier and a preparation method thereof, and DMPE-PEG-P5 is self-made in a laboratory.
  • centrioles were incubated in blank DMEM medium containing 60 ⁇ M of DMPE-PEG-P5 (P5 is column[5]arene) at 37°C for 2 hours. After incubation, the excess DMPE-PEG-P5 was washed away, then 30 ⁇ M DSPE-PEG-Fc (Fc is ferrocene) modified erythrocytes was added and incubated for 2 min. After washing away the unbound cells, the cell-cell binding was obtained. body.
  • Hematopoietic stem cells are derived from American Type Culture Collection (ATCC), and DPPE-PEG- ⁇ -CD and DPPE-PEG-ADA are self-made in the laboratory.
  • ATCC American Type Culture Collection
  • hematopoietic stem cells were incubated in blank DMEM medium containing 100 ⁇ M DPPE-PEG- ⁇ -CD at 37°C for 2 hours, and after washing off excess DPPE-PEG- ⁇ -CD, 150 ⁇ M DPPE- The PEG-ADA modified erythrocytes were incubated for 2 minutes, and after washing away unbound cells, cell-cell conjugates were obtained.
  • Embryonic stem cells were incubated in blank DMEM medium containing 10 ⁇ M DPPE-PEG-CB[7] at 37°C for 5 minutes, and 10 ⁇ M DPPE-PEG-ADA was added after washing off excess DPPE-PEG-CB[7] for modification
  • the doxorubicin-loaded liposomes were incubated for 5 minutes, and after washing away the unbound liposomes, fluorescence imaging was performed, and no red fluorescence was found on the embryonic cell membrane.
  • the supramolecular cell carriers in the examples of the present application are formed by interconnecting host-guest interactions, and are a new generation of cell preparations based on supramolecular host-guest interactions, which can achieve targeted delivery effects based on cell functions;
  • the preparation method of the supramolecular cell carrier is as follows: the macrocyclic host molecule is coupled to the membrane-embedding material and embedded in the cell membrane of the first cell; the guest molecule is modified on the surface of the nanoparticle or the cell membrane of the second cell; and the supramolecular is obtained after thorough mixing. cell carrier.
  • the preparation process is simple, rapid, mild in conditions, universal and bioorthogonal, does not require covalent bond modification on the cell surface, and has no influence on the physiological function of the modified cells.

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Abstract

提供了一种超分子细胞载体、载药体系及其制备方法，涉及超分子化学，超分子材料和细胞制剂技术领域。基于超分子主客体作用构建的超分子细胞载体可实现基于细胞功能的靶向递送效果，具有高生物相容性、高生理屏障透过性和高靶向性。不需要对细胞表面进行共价键修饰，对修饰的细胞生理功能没有影响。提供的超分子细胞载体的制备方法具有制备工艺简单、快速、条件温和和普适性的优势，该方法具有生物正交性。此外，还提供了一种载药体系，可以实现靶向药物治疗的载药。

Description

一种超分子细胞载体、载药体系及其制备方法
相关申请的交叉引用
本申请要求于2020年7月14日提交中国国家知识产权局的申请号为202010677793.6、名称为“一种超分子细胞载体、载药体系及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本申请涉及超分子化学，超分子材料和细胞制剂技术领域，具体而言，涉及一种超分子细胞载体、载药体系及其制备方法。
背景技术
炎症与人体各种疾病息息相关，其中也包括癌症、神经系统疾病等重大疾病。然而目前传统药物制剂以及人工合成的靶向制剂对这些重大疾病的治疗效果均不明显，可能与血液循环过程中网状内皮系统的清除作用、到达病变组织前的生理屏障作用以及对病变组织较弱的靶向选择性等因素有关，这些影响因素都会影响药物的最终作用浓度和治疗效果。因此，针对这些与炎症相关的重大疾病，寻找新的递送载体和新的靶向作用途径，开发出新一代具有高生物相容性、高生理屏障透过性、高靶向性的药物制剂是研究和临床上亟待解决的问题。
鉴于此，特提出本申请。
发明内容
本申请的目的在于提供一种超分子细胞载体、载药体系及其制备方法以解决上述技术问题。
本申请是这样实现的：
一种超分子细胞载体，其包括通过主客体作用相互连接的第一部分和第二部分，第一部分为大环主体分子修饰的第一细胞，第二部分为客体分子修饰的纳米粒子或客体分子修饰的第二细胞，第一部分中的大环主体分子通过偶联嵌膜材料嵌入第一细胞的细胞膜中。
细胞是构成生物体结构和进行生物功能的基本单位，若将细胞作为药物递送载体则具有许多天然的优势，但是目前关于利用细胞作为药物载体的相关研究较少，且细胞载体的构建方法也存在一些不可避免的缺陷。其中一种是通过细胞对药物载体的内吞作用来实现细胞对药物载体的负载，然而被吞噬的药物载体可能在胞内环境中发生降解并引起细胞毒性，从而影响基于细胞生理功能的药物递送。还有一种是通过细胞表面与药物载体的共价结合或者特定的配体-受体结合来实现细胞对药物载体的负载，其中共价结合方式涉及到在细胞膜上进行复杂的多步化学反应，可能会影响细胞活性；而通过特定配体-受体相互作用的结合方式仅限于表达相关受体的特定细胞，其应用范围局限性较大。
发明人创造性的提供了一种嵌膜材料嵌入第一细胞的细胞膜的思路，避免了细胞表面与药物载体的共价结合导致细胞活性下降，同时也不仅限于表达相关受体的特定细胞，本申请提供的第一细胞可以根据载药需求进行自适应调整，其应用范围广。在嵌膜材料的一端偶联大环主体分子，大环主体分子可以通过主客体作用与客体分子连接，从而组成超分子细胞载体。
嵌膜材料与细胞膜的结构成分及其类似，通过疏水作用力与细胞膜表面的 磷脂层自组装结合。
主客体化学是近些年来兴起的新的研究方向，它是通过主体分子与客体分子之间以非共价键的方式产生键合，研究较多的是β-环糊精与金刚烷的主客体作用，在水中客体分子金刚烷由于疏水性会自动与主体分子环糊精的疏水性空腔结合，形成较为稳定的主客体作用产物。
通过主客体作用以及大环主体分子的偶联嵌膜材料嵌入第一细胞构建的超分子细胞载体可以实现基于细胞功能的靶向递送效果。该超分子细胞载体克服了现有技术需要通过细胞对药物载体的内吞作用才能实现细胞对药物载体的负载的缺陷，该超分子细胞载体不会引发细胞毒性，具有生物正交性。
在本申请应用较佳的实施方式中，上述大环主体分子为环糊精(CD)、葫芦脲(CB)、杯芳烃、柱芳烃或冠醚；优选的，大环主体分子为β-环糊精。
冠醚可以是双环冠醚、三环冠醚、多环冠醚和杂冠醚中的任意一种。
上述大环主体分子与许多客体分子有着较高的结合常数，有助于提升主客体复合物在体内的稳定性。
大环主体分子位于细胞膜的外表面层，大环分子链接的磷脂端与细胞膜磷脂双分子层融合从而嵌入细胞膜中。
在本申请应用较佳的实施方式中，上述第一细胞选自巨噬细胞、中性粒细胞、红细胞、干细胞、淋巴细胞、树突细胞、血小板和脂肪细胞中的任意一种。
不同的细胞类型具有不同的生理功能，如免疫细胞的炎症趋向性和干细胞的归巢作用等，这些细胞不同的生理功能也赋予了相应细胞较强的内在靶向驱动力，因此可根据疾病的病理特点选择合适类型的细胞作为靶向递送载体。本申请提供的超分子细胞载体可以根据需要选择相应的第一细胞。
巨噬细胞可以是M1型或M2型巨噬细胞。淋巴细胞可以是T细胞、B细 胞和NK细胞中的至少一种。
脂肪细胞可以是白色脂肪细胞或褐色脂肪细胞。
在本申请应用较佳的实施方式中，上述大环主体分子与客体分子的摩尔比为1-10：1-10；优选为1:1；
优选的，客体分子为金刚烷或二茂铁。
大环主体分子与客体分子在上述摩尔比下可以简单快速的实现超分子细胞载体的制备。
客体分子需与主体分子相匹配，在其他实施方式中也可以根据需要进行置换。
在本申请应用较佳的实施方式中，上述纳米粒子为脂质体、胶束、纳米凝胶、无机纳米粒和纳米囊中的至少一种。
优选的，第二细胞为肝细胞、干细胞、淋巴细胞、树突细胞、血小板和脂肪细胞或红细胞。
在其他实施方式中，所有表面能够被“DSPE-PEG-客体分子”嵌膜的细胞都可作为第二细胞。
脂质体有利于超分子细胞载体跨膜运输，通过相似的极性实现靶向药物的递送。第二细胞为肝细胞或红细胞有利于提升超分子细胞载体对于重大疾病的靶向治疗能力。
在本申请应用较佳的实施方式中，上述嵌膜材料为PEG-DMPE、PEG-DPPE、PEG-DSPE或PEG-CHOL。
PEG-DMPE即PEG-二肉豆蔻酰基磷脂酰乙醇胺，PEG-DPPE即PEG-二棕榈酰基磷脂酰乙醇胺，PEG-DSPE即PEG-二硬脂酰基磷脂酰乙醇胺，PEG-CHOL即PEG-胆固醇。
在一种实施方式中，可以利用DSPE-PEG-ADA、胆固醇和卵磷脂为制备出表面富含ADA(金刚烷)的脂质体。
在另一种实施方式中，可以利用DSPE-PEG-ADA的嵌膜作用构建表面修饰客体分子金刚烷的肝细胞。
一种超分子细胞载体的制备方法，其包括：将偶联有嵌膜材料的大环主体分子与第一细胞共孵育得到第一部分，再将修饰有客体分子的纳米粒子或修饰有客体分子的第二细胞与第一部分混合孵育。
本申请提供的超分子细胞载体的制备方法，制备工艺简单、快速、条件温和、具有普适性，且该方法具有生物正交性。
在本申请应用较佳的实施方式中，上述制备方法还包括先将大环主体分子偶联嵌膜材料，再将偶联有嵌膜材料的大环主体分子嵌入第一细胞的细胞膜中；
优选的，大环主体分子与嵌膜材料中的PEG以共价键连接；优选的，偶联有嵌膜材料的大环主体分子与第一细胞共孵育的时间大于30分钟；偶联有嵌膜材料的大环主体分子的浓度为1μM-1mM。
在其他实施方式中，也可以直接购买偶联嵌膜材料的大环主体分子或修饰有客体分子的纳米粒子。
在本申请应用较佳的实施方式中，上述修饰有客体分子的纳米粒子或修饰有客体分子的第二细胞与第一部分混合孵育的时间≥10秒。
一种载药体系，载体体系包括超分子细胞载体和药物，药物装载在纳米粒子中或第二细胞中；优选的，纳米粒子为脂质体。
本申请提供的超分子细胞载体，可以用来递送脂质体或者细胞。药物可以装载在脂质体中，也就是作为纳米药物被细胞拉着靶向递送，其释放机制也主 要涉及到脂质体本身的性质。载药脂质体脱离超分子细胞载体可以是如下几种方式：一是由于细胞膜的流动性所致脱落，二是载药脂质体被载体细胞或者靶组织细胞直接吞噬消化，造成胞内药物释放。
本申请提供的载药体系可以用于负载抗炎药物、抗生素、靶向癌症、神经系统疾病治疗剂。
抗炎药物可以是斛皮素，将抗炎药物斛皮素负载在脂质体中，与巨噬细胞超分子共轭后靶向递送到肺炎部位治疗急性肺炎。
载药体系可以用于负载阿霉素。
本申请具有以下有益效果：
本申请提供了一种超分子细胞载体、载药体系及其制备方法。基于超分子主客体作用构建的超分子细胞载体可实现基于细胞功能的靶向递送效果，具有高生物相容性、高生理屏障透过性和高靶向性。不需要对细胞表面进行共价键修饰，对修饰的细胞生理功能没有影响。本申请提供的超分子细胞载体的制备方法具有制备工艺简单、快速、条件温和和普适性的优势，该方法具有生物正交性。此外，还提供了一种载药体系，可以实现靶向药物治疗的载药。
附图说明
为了更清楚地说明本申请实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本申请的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的附图。
图1为本申请实施例1的超分子细胞与脂质体结合体的荧光成像图；
图2为本申请实施例1的超分子细胞与脂质体结合体的扫描电镜图；
图3为本申请实施例5的超分子细胞与细胞结合体的荧光成像图；
图4为本申请实施例5的超分子细胞与细胞结合体的扫描电镜图。
具体实施方式
为使本申请实施例的目的、技术方案和优点更加清楚，下面将对本申请实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
以下结合实施例对本申请的特征和性能作进一步的详细描述。
实施例1
本实施例提供了一种超分子细胞载体及其制备方法，本实施例中，第一细胞为巨噬细胞，DSPE-PEG-β-CD和DSPE-PEG-ADA均购自西安瑞禧生物科技有限公司，DMEM培养基购自赛默飞世尔科技(中国)有限公司，阿霉素购自上海阿拉丁生化科技股份有限公司。
将巨噬细胞在含有10μM的DSPE-PEG-β-CD的空白DMEM培养基中于37℃孵育2小时。
孵育后，洗去多余的DSPE-PEG-β-CD，再加入10μM的DSPE-PEG-ADA修饰的负载阿霉素的脂质体继续孵育2分钟。
洗去未结合的脂质体后，制得超分子细胞-脂质体结合体。
由于阿霉素有红色荧光，将制得的超分子细胞-脂质体结合体进行荧光成像和扫描电镜成像。超分子细胞与脂质体结合体的荧光成像图参照图1所示， 超分子细胞与脂质体结合体的扫描电镜图参照图2所示。
实施例2
本实施例提供了一种超分子细胞载体及其制备方法，本实施例中，DSPE-PEG-β-CD和DMEM培养基与实施例1购买来源相同。本实施例中，第一细胞为巨噬细胞，将巨噬细胞在含有50μM的DSPE-PEG-β-CD的空白DMEM培养基中于37℃孵育1小时。
洗去多余的DSPE-PEG-β-CD后，加入50μM的DSPE-PEG-ADA修饰的脂质体继续孵育2分钟。最后洗去未结合的脂质体后，获得超分子细胞-脂质体结合体。
实施例3
本实施例提供了一种超分子细胞载体及其制备方法，DMPE-PEG-CB[7]和DMPE-PEG-ADA为实验室自制。本实施例中，将中性粒细胞在含有100μM的DMPE-PEG-CB[7](CB[7]为葫芦[7]脲)的空白DMEM培养基中于37℃孵育2小时。
然后洗去多余的DMPE-PEG-CB[7]，加入100μM的DMPE-PEG-ADA修饰的脂质体继续孵育1分钟，洗去未结合的脂质体后。获得超分子细胞-脂质体结合体。
实施例4
本实施例提供了一种超分子细胞载体及其制备方法，DPPE-PEG-CB[7]和DPPE-PEG-ADA为实验室自制。本实施例中，将造血干细胞在含有40μM的DPPE-PEG-CB[7]的空白DMEM培养基中于37℃孵育1.5小时。
然后洗去多余的DPPE-PEG-CB[7]，加入80μM的DPPE-PEG-ADA修饰的脂质体继续孵育5分钟，洗去未结合的脂质体后。获得超分子细胞-脂质体 结合体。
实施例5
本实施例提供了一种超分子细胞载体及其制备方法，DiD和DiO均购自上海碧云天生物技术有限公司。本实施例中，将巨噬细胞在含有10μM的DSPE-PEG-β-CD的空白DMEM培养基中于37℃孵育2小时，在洗去多余的DSPE-PEG-β-CD后加入10μM的DSPE-PEG-ADA修饰的人体肝细胞继续孵育2分钟，洗去未结合的肝细胞后，制得超分子细胞-细胞结合体。
将获得的超分子细胞-细胞结合体进行荧光成像和扫描电镜成像。荧光成像图参照图3所示，扫描电镜成像图参照图4所示。其中巨噬细胞采用DiD(红色)染色，人体肝细胞采用DiO(绿色)染色。
实施例6
本实施例提供了一种超分子细胞载体及其制备方法，Fc购自上海阿拉丁生化科技股份有限公司，DSPE-PEG-Fc为实验室自制。本实施例中，将巨噬细胞在含有10μM的DSPE-PEG-β-CD的空白DMEM培养基中于37℃孵育2小时。孵育后洗去多余的DSPE-PEG-β-CD，并加入10μM的DSPE-PEG-Fc(Fc为二茂铁)修饰的人体肝细胞继续孵育2分钟，洗去未结合的细胞后，即获得超分子细胞-细胞结合体。
实施例7
本实施例提供了一种超分子细胞载体及其制备方法，DMPE-PEG-P5为实验室自制。本实施例中，将中心粒细胞在含有60μM的DMPE-PEG-P5(P5为柱[5]芳烃)的空白DMEM培养基中于37℃孵育2小时。孵育后，洗去多余的DMPE-PEG-P5，然后加入30μM的DSPE-PEG-Fc(Fc为二茂铁)修饰的红细胞继续孵育2分钟，洗去未结合的细胞后，获得细胞-细胞结合体。
实施例8
本实施例提供了一种超分子细胞载体及其制备方法，造血干细胞来源美国模式培养物集存库(ATCC)，DPPE-PEG-β-CD和DPPE-PEG-ADA为实验室自制。本实施例中，将造血干细胞在含有100μM的DPPE-PEG-β-CD的空白DMEM培养基中于37℃孵育2小时，在洗去多余的DPPE-PEG-β-CD后加入150μM的DPPE-PEG-ADA修饰的红细胞继续孵育2分钟，洗去未结合的细胞后，获得细胞-细胞结合体。
对比例
将胚胎干细胞在含有10μM的DPPE-PEG-CB[7]的空白DMEM培养基中于37℃孵育5分钟，在洗去多余的DPPE-PEG-CB[7]后加入10μM DPPE-PEG-ADA修饰的载阿霉素脂质体继续孵育5分钟，洗去未结合的脂质体后，进行荧光成像，未发现胚胎细胞膜上有红色荧光。
综上所述，本申请实施例的超分子细胞载体是通过主客体作用相互连接形成的，是基于超分子主客体作用构建的新一代细胞制剂，可实现基于细胞功能的靶向递送效果；该超分子细胞载体的制备方法是将大环主体分子偶联嵌膜材料并嵌入第一细胞的细胞膜中；将客体分子修饰在纳米粒子表面或者第二细胞的细胞膜上；充分混合后即得超分子细胞载体。制备工艺简单、快速、条件温和、具有普适性和生物正交性，不需要对细胞表面进行共价键修饰，对修饰的细胞生理功能没有影响。
以上所述仅为本申请的优选实施例而已，并不用于限制本申请，对于本领域的技术人员来说，本申请可以有各种更改和变化。凡在本申请的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本申请的保护范围之内。

Claims (10)

  1. 一种超分子细胞载体，其特征在于，其包括通过主客体作用相互连接的第一部分和第二部分，所述第一部分为大环主体分子修饰的第一细胞，所述第二部分为客体分子修饰的纳米粒子或客体分子修饰的第二细胞，所述第一部分中的大环主体分子通过偶联嵌膜材料嵌入所述第一细胞的细胞膜中，所述大环主体分子与所述客体分子相对应。
  2. 根据权利要求1所述的超分子细胞载体，其特征在于，所述大环主体分子为环糊精、葫芦脲、杯芳烃、柱芳烃或冠醚；优选的，所述大环主体分子为β-环糊精。
  3. 根据权利要求2所述的超分子细胞载体，其特征在于，所述第一细胞选自巨噬细胞、中性粒细胞、红细胞、干细胞、淋巴细胞、树突细胞、血小板和脂肪细胞中的任意一种。
  4. 根据权利要求1所述的超分子细胞载体，其特征在于，所述大环主体分子与客体分子的摩尔比为1-10：1-10；优选为1:1；
    优选的，所述客体分子为金刚烷或二茂铁。
  5. 根据权利要求1所述的超分子细胞载体，其特征在于，所述纳米粒子为脂质体、胶束、纳米凝胶、无机纳米粒和纳米囊中的至少一种；
    优选的，所述第二细胞为肝细胞、干细胞、淋巴细胞、树突细胞、血小板和脂肪细胞或红细胞。
  6. 根据权利要求5所述的超分子细胞载体，其特征在于，所述嵌膜材料为PEG-DMPE、PEG-DPPE、PEG-DSPE或PEG-CHOL。
  7. 一种如权利要求1-6任一项所述的超分子细胞载体的制备方法，其特征 在于，其包括：将偶联有嵌膜材料的大环主体分子与第一细胞共孵育得到第一部分，再将修饰有客体分子的纳米粒子或修饰有客体分子的第二细胞与第一部分混合。
  8. 根据权利要求7所述的超分子细胞载体的制备方法，其特征在于，所述制备方法还包括先将大环主体分子偶联嵌膜材料，再将偶联有嵌膜材料的大环主体分子嵌入第一细胞的细胞膜中；
    优选的，所述大环主体分子与所述嵌膜材料中的PEG以共价键连接；优选的，偶联有嵌膜材料的大环主体分子与第一细胞共孵育的时间大于30分钟；所述偶联有嵌膜材料的大环主体分子的浓度为1μM-1mM。
  9. 根据权利要求7所述的超分子细胞载体的制备方法，其特征在于，修饰有客体分子的纳米粒子或修饰有客体分子的第二细胞与第一部分混合孵育的时间≥10秒。
  10. 一种载药体系，其特征在于，所述载药体系包括权利要求1-6任一项所述的超分子细胞载体和药物，所述药物装载在所述纳米粒子中或所述第二细胞中；优选的，所述纳米粒子为脂质体。
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