CN110300602A - 基于外来体的纳米颗粒复合体及其制备方法 - Google Patents

基于外来体的纳米颗粒复合体及其制备方法 Download PDF

Info

Publication number
CN110300602A
CN110300602A CN201880011966.1A CN201880011966A CN110300602A CN 110300602 A CN110300602 A CN 110300602A CN 201880011966 A CN201880011966 A CN 201880011966A CN 110300602 A CN110300602 A CN 110300602A
Authority
CN
China
Prior art keywords
drug
allochthon
reinforcement body
core shell
particles reinforcement
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201880011966.1A
Other languages
English (en)
Inventor
陆淳鸿
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Korea University
Original Assignee
Korea University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Korea University filed Critical Korea University
Publication of CN110300602A publication Critical patent/CN110300602A/zh
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K47/6905—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
    • 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
    • A61K47/6915—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 the form being a liposome with polymerisable or polymerized bilayer-forming substances, e.g. polymersomes
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/13—Tumour cells, irrespective of tissue of origin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/15—Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • A61K47/6921—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 particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—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 particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—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 particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • 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
    • A61K47/6921—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 particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—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 particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—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 particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A61K47/6931—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 particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • 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
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Cell Biology (AREA)
  • Virology (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Zoology (AREA)
  • Nanotechnology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Biotechnology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Biophysics (AREA)
  • Botany (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及基于外来体的纳米颗粒复合体及其制造方法，更详细而言，涉及通过利用从细胞中分离的外来体和基于生物相容性的高分子而提高了体内稳定性和再分散性的基于外来体的纳米颗粒复合体及其制造方法。根据本发明可以提供如下的纳米颗粒复合体，该纳米颗粒复合体通过提高体内稳定性和水溶液中的再分散性，无论药物所具有的溶解度如何，都显示出稳定且持续的药物溶出模式，并且能够实现优异的癌细胞蓄积性。

Description

基于外来体的纳米颗粒复合体及其制备方法
技术领域
本发明涉及基于外来体的纳米颗粒复合体及其制造方法，更详细而言，涉及通过利用从细胞中分离的外来体和基于生物相容性的高分子而提高了体内稳定性和再分散性的基于外来体的纳米颗粒复合体及其制造方法。
背景技术
大部分药物分为疏水性药物和亲水性药物。在疏水性药物的情况下，由于在水溶液相中显示出有限的溶解度，因此无法形成有效的体内递送。当亲水性药物的情况下，由于高溶解度而初期药效发挥优异，但在持续的药效体现上存在困难而需要频繁的药物给药。为了克服这种困难，正在进行利用纳米颗粒的各种药物递送体的开发，正在积极进行利用高分子药物递送体、脂质药物递送体、纳米管的研究。作为高分子药物递送体，有高分子-药物结合体、高分子胶束、树枝状聚合物等。
但是，如上所述的递送药物的递送体由于在水溶液中的不稳定性而显示出快速药物释放形态，特别是在填充有水溶性药物或蛋白性药物和抗体的情况下，由于在水溶液中的优异的溶解度而引起快速药物释放，从而难以实现所需的药效。作为克服该问题的方案，需要药物的重复给药，在昂贵的蛋白性药物或抗体的情况下，预计治疗费用会提高。
另一方面，脂质体可以由各种脂质分子构成，由于构成脂质体的大部分磷脂(phospolipid)对人体无毒、无害，因此，作为有效的药物递送体而受到关注。然而，利用脂质体的颗粒尚不能确保物理稳定性，因而尝试了用于确保稳定性的各种研究。例如，向脂质体添加特定的表面活性剂而诱导稳定性的增加，在脂质体构成要素中添加正电荷脂质，或导入甾醇、阴离子性脂质或鞘脂。如此，虽然持续进行了用于提高脂质体的稳定性的研究，但上述技术的物理稳定性不充分而在应用于药学领域时存在限制。
为了克服这种物理稳定性，本发明人在韩国授权专利第10-0792557号中公开了由构成脂质体的卵磷脂核和泊洛沙姆壳构成的核/壳结构的药物递送体。但是，在上述药物递送体的情况下，由于以脂质体为基础而非来自人体细胞，从而在生物相容性(biocompatibility)和生物利用度(bioavailability)方面不可避免地具有局限性。
另一方面，在开发注射剂型抗癌药物递送体的情况下，为了使抗癌药物副作用最小化，向递送体赋予癌细胞蓄积性(肿瘤靶向(tumor targeting))功能。然而，最近，负责实现癌细胞蓄积性的一个轴的作为被动(passive)癌细胞蓄积性的主要递送机构的EPR(高渗透长滞留效应，enhanced permeation and retention)效果的局限性已经浮出水面。
因此，迫切需要开发一种生物相容性颗粒，其能够克服生物相容性和生物利用度的限制，不仅体内稳定性和在水溶液中的再分散性优异，并且无需复杂的表面改性即可实现主动(active)癌细胞蓄积性。
(专利文献1)韩国授权专利第10-0792557号
发明内容
技术课题
本发明是为了解决上述的问题而提供的，本发明提供一种纳米颗粒复合体，其通过提高体内稳定性和在水溶液中的再分散性而显示出稳定且持续的药物溶出模式，并且可以实现优异的癌细胞蓄积性。
另外，本发明提供一种上述纳米颗粒复合体的制造方法。
课题解决方法
本发明为了解决上述课题而提供一种核/壳纳米颗粒复合体，包含：
内部封入药物的来自细胞株的外来体核；以及
与上述来自细胞株的外来体核的表面缔合的PEO-PPO-PEO共聚物壳。
另外，本发明为了解决上述课题而提供一种核/壳纳米颗粒复合体的制造方法，包括：
(a)将细胞株离心分离而从上述细胞株中分离外来体的步骤；
(b)将上述被分离的外来体和药物进行混合来制造内部封入有药物的外来体的步骤；以及
(c)将上述封入有药物的外来体和PEO-PPO-PEO共聚物水溶液混合后进行冷冻干燥的步骤。
发明效果
根据本发明，可以提供如下的纳米颗粒复合体，该纳米颗粒复合体通过利用来自人体细胞的外来体和生物相容性高分子来提高体内稳定性和在水溶液中的再分散性，无论药物所具有的溶解度如何，都显示出稳定且持续的药物溶出模式并且能够实现优异的癌细胞蓄积性。
附图说明
图1是根据本发明的核/壳纳米颗粒复合体的模式图。
图2是表示根据本发明的核/壳纳米颗粒复合体的制造过程的模式图。
图3是表示已有的核/壳纳米颗粒复合体的根据EPR效果的生物体内行为的模式图。
图4是根据本发明的实施例1-1的核/壳纳米颗粒复合体的TEM图像。
图5是根据本发明的实施例1-2的核/壳纳米颗粒复合体的TEM图像。
图6是表示根据本发明的实施例1-1的核/壳纳米颗粒复合体的粒度分布的图表。
图7是表示根据本发明的实施例1-1和比较例1的核/壳纳米颗粒复合体的根据时间的药物释放形态的图表。
图8是表示根据本发明的实施例2和比较例2的核/壳纳米颗粒复合体在产生癌组织的动物模型中的生物分布的图。
具体实施方式
下面，对本发明更详细地进行说明。
以往，基于脂质体的药物递送体利用了由从大豆或蛋黄等中提取的卵磷脂形成的脂质体。然而，在上述药物递送体的情况下，由于以脂质体为基础而非以来自人体的细胞为基础，因此在生物相容性(biocompatibility)和生物利用度(bioavailability)方面必然具有局限性。
因此，迫切需要开一种新型生物相容性颗粒，其不仅能够克服生物相容性和生物利用度的限制，从而体内稳定性和在水溶液中的再分散性优异，而且无需复杂的表面改性即可实现EPR效果和主动(active)癌细胞蓄积性。
在这种技术背景下，本发明人在对新型生物相容性颗粒进行研究的过程中确认了在将来自细胞株的外来体作为基础的情况下，不仅体内稳定性和在水溶液中的再分散性优异，而且与基于脂质体的药物递送体相比，药物溶出模式的持续性、癌细胞蓄积性显著提高，从而完成了本发明。
因此，本发明提供一种核/壳纳米颗粒复合体，包含：内部封入有药物的来自细胞株的外来体核；以及与上述来自细胞株的外来体核的表面缔合的PEO-PPO-PEO共聚物壳。
图1是表示在根据本发明的核/壳纳米颗粒复合体中，在外来体核的表面缔合PEO-PPO-PEO共聚物的模样的模式图。
在本发明中，缔合(association)包含：在外来体核的表面上，PEO-PPO-PEO共聚物通过静电引力等与外来体核结合，或者外来体核的磷脂双层的至少一部分与PEO-PPO-PEO共聚物彼此缠住的状态(纠缠(entangle)或干扰(intervene)的状态)。
参照图1，PEO-PPO-PEO共聚物交叉结合在封入有药物的外来体核的表面以及外来体的磷脂双层的至少一部分上而使外来体的表面稳定。上述PEO-PPO-PEO共聚物通过外来体的双层并与外来体双层结实地交叉而使其结合。此外，在外来体外壁上形成由PEO-PPO-PEO共聚物构成的表面层，从而起到维持外来体结构不受外部存在的各种使外来体不稳定的因素的影响的作用。
另外，本发明的核/壳纳米颗粒复合体显示出优异的分散性，不发生凝聚现象，为了体内给药而在水溶液等溶液中分散时，在溶解的过程中可以容易地再分散。
本发明的核/壳纳米颗粒复合体为具有约100至约1000nm、优选为具有约300至约700nm的粒径的细粉末形态。此外，由于药物被外来体核和PEO-PPO-PEO共聚物壳所保护而保存稳定性优异。
本发明的核/壳纳米颗粒复合体可以以干燥状态长期保存，因此可以向保存、移动和给药提供便利性。
被封入上述外来体核中的药物并不限定于特别的药物，但包含难溶性药物、水溶性药物、离子性药物、蛋白质药物、抗体和造影剂等。上述难溶性药物是指在水中的溶解度低而难以溶解的药物，例如有抗癌药物或动脉硬化、高脂血症等心血管系统疾病治疗剂等，但并不限定于此，可以包含难以溶解的所有难溶性药物。具体而言，上述难溶性药物例如包含紫杉醇、多西紫杉醇、帕莫辛(pamoxin)、阿那曲唑、卡铂、托泊替康、贝洛替康、伊马替尼、伊立替康、氟尿苷、长春瑞滨、吉西他滨、亮丙瑞林(leuprolide)、氟他胺、唑来膦酸盐、甲氨蝶呤、喜树碱、顺铂、长春新碱、硫酸羟脲、链脲霉素、戊柔比星、洛伐他汀、辛伐他汀、氟伐他汀、阿托伐他汀、匹伐他汀、普伐他汀、或瑞舒伐他汀等，但并不限定于此。
另外，上述离子性药物例如可以包含阿霉素-HCl(doxorubicin-HCl)、多沙唑嗪-HCl(doxazosin HCl)、哌甲酯(methylphenidate)、奥昔布宁氯化物(oxybutyninchloride)、伪麻黄碱(pseudoephedrine HCl)、硫酸沙丁胺醇(albuterol sulfate)、丁吡卡因-HCl等，但并不限定于此。
另外，上述蛋白质和抗体例如可以包含胰岛素(Insulin)、艾塞那肽(Exenatide)、Hgh(人生长激素，Human growth hormone)、VEGF(血管内皮生长因子，vascularendotherial growth factor)、EGF(表皮生长因子，epidermal growth factor)、TNF-α(肿瘤坏死因子-α，Tumor Necrosis Factor-α)等，但并不限定于此。
另外，上述造影剂可以包含例如选自锰、钆、铒、铬、铁、钴、镍、镧系元素、锕系元素及其组合中的一种以上的顺磁性物质。例如，造影剂可以为Gd-DOTA复合体((1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸)钆(III)，(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)gadolinium(III))。Gd-DOTA复合体是用于MRI(磁共振成像，Magnetic Resonance Imaging)的造影剂，在填充到本发明的核/壳纳米颗粒复合体的外来体核内部时具有提高分子成像效应，特别是对发生癌的部分有效地进行造影的效果。
上述PEO-PPO-PEO共聚物可以为由下述化学式1表示的三嵌段(triblock)共聚物。
[化学式1]
HO-(C2H4O)a(C3H6O)b(C2H4O)c-H
上述化学式1中，b为10以上的整数，a+c为使末端部分((C2H4O)a和(C2H4O)c)占共聚物的5至95重量％、优选占20至90重量％的数。
上述PEO-PPO-PEO共聚物的性质取决于聚氧丙烯嵌段和聚氧乙烯嵌段的比率，即上述化学式1中b和a+c的比率。上述PEO-PPO-PEO共聚物可以通过公知的文献中记载的方法进行制造或者使用预先制造而市场上市售的产品。本发明的制造方法中使用的PEO-PPO-PEO共聚物没有特别限定，但例如可以具有约1000至约16000的分子量。
另一方面，已知上述PEO-PPO-PEO共聚物还称为泊洛沙姆(poloxamer)或普兰尼克(pluronic)。泊洛沙姆在室温条件下为固体，并且具有溶解于水和乙醇的性质。根据本发明的一实施例，作为上述PEO-PPO-PEO共聚物可以使用泊洛沙姆68、泊洛沙姆127、泊洛沙姆188、泊洛沙姆237、泊洛沙姆338或泊洛沙姆407等，但并不限定于此。例如，泊洛沙姆188是指在上述化学式2中b为30、a+c为75的化合物，是分子量为约8350的泊洛沙姆。
本发明的核/壳纳米颗粒复合体使用来自细胞株的外来体，可以显著提高生物相容性。这时，上述外来体只要是来自细胞株就均可以使用，但可以优选为来自巨噬细胞株或癌细胞株的外来体。
这时，上述巨噬细胞株可以为RAW264.7细胞株，从下述实施例的结果可知，在使用来自巨噬细胞株RAW264.7的外来体的情况下，可以显示出与基于脂质体的复合体相比显著提高的释放行为。
另外，上述癌细胞株可以为全部癌细胞，可以优选为乳腺癌细胞株或鳞状上皮细胞癌细胞株。这时，上述乳腺癌细胞株例如可以为MDA-MB231，上述鳞状上皮细胞癌细胞株可以为SCC-7。此外，当利用根据本发明的核/壳纳米颗粒复合体作为抗癌药物递送体或抗癌治疗用药物组合物的情况下，为了实现显著提高的癌细胞蓄积性，优选利用从与成为治疗对象的癌相同种类的癌细胞株分离的外来体。在下述实施例中确认了，在使用基于来自乳腺癌细胞株MDA-MB231的外来体的核/壳纳米颗粒复合体时，对于乳腺癌的癌细胞蓄积性远远优于使用基于来自SCC-7细胞株的外来体的核/壳纳米颗粒复合体的情况。
本发明的核/壳纳米颗粒复合体还可以分散于其它溶剂而向体内进行给药。由于被封入外来体核内的上述药物以稳定的状态存在，因此无论药物所具有的固有溶解度如何都可以显著提高生物利用率。此外，基于来自细胞株的外来体还可以显著提高生物相容性。此外，从下述实施例的结果可知，由于显示出与基于脂质体的药物递送体相比提高的持续释放型溶出模式，因此可以有用地适用于要求在生物体内长期持续释放的缓释制剂。例如，本发明的核/壳纳米颗粒复合体在向生物体内给药后，可以在几日至几个月的时间内在生物体内以稳定的速度持续释放药物。
另外，根据本发明的核/壳纳米颗粒复合体在无需复杂的表面改性的前提下可以实现EPR效果和主动(active)癌细胞蓄积性，其通过与基于脂质体的药物递送体相比癌细胞蓄积性得到提高的下述实施例的结果被证明，根据本发明的核/壳纳米颗粒复合体可以作为有效的药物递送体来利用。
本发明的核/壳纳米颗粒复合体可以通过公知的常规方法制造成颗粒剂、胶囊剂、片剂等口服给药用制剂或静脉注射、皮下注射、肌肉注射等非口服给药用制剂等，通过制剂学公知的各种赋形剂和剂型设计，可以作为有效的药物递送体而利用。
另外，由于本发明的核/壳纳米颗粒复合体是流动性优异的粉末状态，因此有利于长期保存。因此，包含本发明的核/壳纳米颗粒复合体的药物学制剂具有提高的保存稳定性，在长期的流通和保管过程中也几乎没有变质的情况。
另外，本发明提供包括下述步骤的核/壳纳米颗粒复合体的制造方法(图2)。
(a)将细胞株离心分离而从上述细胞株中分离外来体的步骤；
(b)将上述被分离的外来体和药物进行混合来制造内部封入有药物的外来体的步骤；以及
(c)将上述封入有药物的外来体和PEO-PPO-PEO共聚物水溶液混合后进行冷冻干燥的步骤。
首先，在(a)步骤中，通过离心分离而从细胞株中分离外来体。这时，上述离心分离可以通过该领域中通常公知的方法实施，例如可以利用差速超速离心分离法(C.Thery,S.Amigorena,G.Raposo,A.Clayton,Isolation and characterization of exosomesfrom cell culture supernatants and biological fluids,Current protocols incell biology,Chapter 3(2006)Unit 3 22.)。
其次，在(b)步骤中，将上述被分离的外来体与药物进行混合来制造内部封入有药物的外来体。这时，上述被封入的药物并不限定于特别的药物，但包含难溶性药物、水溶性药物、离子性药物、蛋白质药物、抗体和造影剂等。
接着，上述(c)步骤是将封入有上述药物的外来体和PEO-PPO-PEO共聚物水溶液进行混合并搅拌后冷冻干燥的步骤。通过上述(c)步骤，封入有药物的外来体形成核，在上述外来体核表面缔合有PEO-PPO-PEO共聚物而形成壳，上述核/壳纳米颗粒复合体通过冷冻干燥过程被粉末化。
这时，上述PEO-PPO-PEO共聚物水溶液可以使用以1至30重量％包含PEO-PPO-PEO共聚物的水溶液。
根据本发明，在上述(b)步骤中，可以以封入有药物的外来体和PEO-PPO-PEO共聚物的重量比成为1:0.1至1:99、优选为1:1至1:20、更优选为1:1至1:5的方式进行混合。当相对于封入有上述药物的外来体包含过少的PEO-PPO-PEO共聚物时，基于PEO-PPO-PEO共聚物的外来体表面的稳定化效果微乎其微。相反，当相对于封入有上述药物的外来体包含过多的PEO-PPO-PEO共聚物时，抑制填充的药物的释放而可能发生无法实现期望的治疗效果的问题。
PEO-PPO-PEO共聚物起到在封入有药物的外来体表面和外来体的磷脂双层的至少一部分缔合PEO-PPO-PEO共聚物而维持外来体的结构的作用。
通过如上所述的制造方法得到的本发明的核/壳纳米颗粒复合体是微细粉末形态，显示出优异的分散性且不发生凝聚现象，因此，为了体内给药而分散于水溶液等溶液中时，在溶解过程中可以容易地再分散。此外，不使用可能对人体带来有害影响的有机溶剂或其它赋形剂，使用来自细胞株的外来体与作为生物相容性高分子的PEO-PPO-PEO共聚物，通过简单的方法进行制造，因此可以同时实现体内稳定性和工序容易性。而且，储存稳定性提高而可以作为各种药剂学制剂进行利用。
发明的实施方式
下面，举出优选实施例等对本发明更详细地进行说明。但是，这些实施例是用于更具体地对本发明进行说明，对于本领域技术人员来说，本发明的范围并不限定于此是显而易见的。
<实施例>
实施例1.基于来自RAW264.7细胞株的外来体的核/壳纳米颗粒复合体的制造
(1)实施例1-1
首先，通过离心分离，从RAW264.7细胞株分离了10mg的外来体。将上述被分离的外来体与10mg的阿霉素-HCl混合2小时而制造了均匀的混合体。在上述混合体中添加10重量％的普兰尼克F-68水溶液50mg并进行搅拌。进行搅拌直至上述混合物成为完全均匀的溶液后，冷冻干燥48小时而得到了粉末化的核/壳纳米颗粒复合体。
(2)实施例1-2
使用10重量％的普兰尼克F-127水溶液代替10重量％的普兰尼克F-68水溶液，除此以外，通过与上述实施例1-1相同的方法制造了粉末化的核/壳纳米颗粒复合体。
实施例2.基于来自MDA-MB231细胞株的外来体的核/壳纳米颗粒复合体的制造
首先，通过离心分离，从MDA-MB231细胞株分离了10mg的外来体。将上述被分离的外来体与1mg的Cy5.5(用于测定生物分布的荧光物质)混合2小时而制造了均匀的混合体。在上述混合体中添加10重量％的普兰尼克F-68水溶液50mg而进行搅拌。进行搅拌直至上述混合物完全成为均匀的溶液后，冷冻干燥48小时而得到了粉末化的核/壳纳米颗粒复合体。
比较例1.基于脂质体的核/壳纳米颗粒复合体的制造
将由10mg的阿霉素-HCl和从蛋黄(egg yolk)中提取的磷脂酰胆碱(phosphatidylcholine)构成的脂质体混合2小时而制造了均匀的混合体。在上述混合体中添加10重量％的普兰尼克F-68水溶液50mg而进行搅拌。进行搅拌直至上述混合物成为完全均匀的溶液后，冷冻干燥48小时而得到了粉末化的核/壳纳米颗粒复合体。
比较例2.基于来自SCC-7癌细胞株的外来体的核/壳纳米颗粒复合体的制造
首先，通过离心分离，从SCC-7癌细胞株分离了10mg的外来体。将上述被分离的外来体与1mg的Cy 5.5(用于测定生物分布的荧光物质)混合2小时而制造了均匀的混合体。在上述混合体中添加10重量％的普兰尼克F-68水溶液50mg而进行搅拌。进行搅拌直至上述混合物完全成为均匀的溶液后，冷冻干燥48小时而得到了粉末化的核/壳纳米颗粒复合体。
<实验例>
实验例1.粒度分布分析
将通过实施例1-1得到的根据本发明的核/壳纳米颗粒复合体的粒度分布示于图6。此外，将通过本发明的实施例1-1和1-2得到的核/壳纳米颗粒复合体的TEM图像分别示于图4和图5。
通过图4-6可知，根据本发明的核/壳纳米颗粒复合体示出约500nm左右的粒径，显示出比较均匀的粒度分布。
实验例2.药物释放模式分析
为了确认封入根据本发明的核/壳纳米颗粒复合体内的药物的释放模式而实施了如下的实验。
称量相当于含有10mg的阿霉素-HCl的核/壳纳米颗粒复合体的量的根据实施例1-1制造的核/壳纳米颗粒复合体并加入到透析袋(dialysis bag,分子量过滤限制-100000)，将其含浸到30ml的磷酸盐缓冲溶液(PBS,pH7.4)中。温度维持37.5℃的同时用100rpm搅拌磷酸盐缓冲溶液。经过一定时间后，取5ml的磷酸盐缓冲溶液，用HPLC测定了释放的药物量。在采取样品后去除全部剩余磷酸盐缓冲溶液，用新磷酸盐缓冲溶液替代。释放的阿霉素-HCl量用紫外可见分光光度计(UV-Vis spectrometer)(G1103A,Agilent,USA)进行测定。
为了比较，将10mg的阿霉素-HCl、根据比较例1制造的基于脂质体的核/壳纳米颗粒复合体(含有10mg的阿霉素-HCl)分别添加到10mL的蒸馏水中而制造成水溶液后，通过与上述的方法相同的方法测定药物释放行为。
图7是表示根据本发明的实施例1-1和比较例1的核/壳纳米颗粒复合体的根据时间的药物释放形态的图表。
由此确认，在体温(37℃)下阿霉素-HCl迅速释放，在24小时内释放出相当于95％以上的药物而释放到磷酸盐缓冲溶液中。此外，可知，在封入根据比较例1的基于脂质体的核/壳纳米颗粒复合体中的阿霉素-HCl的情况下，显示出释放速度降低且持续的溶出行为，在释放行为实验实施72小时以后也显示出溶出度以65％以下缓慢释放的倾向。
但是，确认了根据本发明的实施例1的基于来自RAW264.7细胞株的外来体的核/壳纳米颗粒复合体在释放行为实验实施72小时以后溶出度为40％以下，与根据比较例1的基于脂质体的核/壳纳米颗粒复合体相比更显著地延迟释放，在释放行为实验实施72小时以后，药物依然以一定的速度徐徐释放。由此确认，根据本发明的基于外来体的核/壳纳米颗粒复合体显示出与基于脂质体的核/壳纳米颗粒复合体相比更稳定且持续的药物释放形态。
实验例3.生物分布(biodistribution)测定
为了通过根据本发明的核/壳纳米颗粒复合体的生物分布来确认生物体内行为而实施了如下实验。
具体而言，对5.5周龄的C3H/HeN小鼠移植MDA-MB231癌细胞株，生长到癌组织大小成为250-300mm3左右时，将基于从MDA-MB231癌细胞株分离的外来体的核/壳纳米颗粒复合体(实施例2)与基于从SCC-7癌细胞株分离的外来体的核/壳纳米颗粒复合体(比较例2)分别从小鼠的尾静脉注射后，确认了生物行为。这时生物行为利用IVIS SPECTRUM(Xenogen,Alameda,CA)进行观察(参照Journal of Controlled Release 228(2016)141-149)。
图8是表示根据本发明的实施例2和比较例2的核/壳纳米颗粒复合体在产生癌组织的动物模型中的生物分布的图。
由此确认了，基于从相同癌细胞(MDA-MB 231、乳腺癌)株中分离的外来体的核/壳纳米粒子递送体(实施例2)与基于来自作为其它癌细胞的SCC-7癌细胞株的外来体的核/壳纳米颗粒复合体(比较例2)相比，显示出高的癌细胞蓄积性。因此，利用这种特性，利用基于来自相同癌细胞株的外来体而制造的复合体时可以显著提高癌细胞蓄积性。
产业上的利用可能性
根据本发明的纳米颗粒复合体的体内稳定性和水溶液中的再分散性优异，无论药物所具有的溶解度如何，都显示出稳定且持续的药物溶出模式，可以实现优异的癌细胞蓄积性，可以广泛应用于药物递送体领域。

Claims (11)

1.一种核/壳纳米颗粒复合体，包含：
内部封入有药物的来自细胞株的外来体核；以及
与所述来自细胞株的外来体核的表面缔合的PEO-PPO-PEO共聚物壳。
2.根据权利要求1所述的核/壳纳米颗粒复合体，其特征在于，所述药物为选自难溶性药物、水溶性药物、离子性药物、蛋白质药物、抗体和造影剂中的1种以上。
3.根据权利要求1所述的核/壳纳米颗粒复合体，其特征在于，所述复合体为粉末形态。
4.根据权利要求1所述的核/壳纳米颗粒复合体，其特征在于，所述PEO-PPO-PEO共聚物为选自泊洛沙姆68、泊洛沙姆127、泊洛沙姆188、泊洛沙姆237、泊洛沙姆338和泊洛沙姆407中的1种以上。
5.根据权利要求1所述的核/壳纳米颗粒复合体，其特征在于，所述外来体来自巨噬细胞株或癌细胞株。
6.根据权利要求5所述的核/壳纳米颗粒复合体，其特征在于，所述癌细胞株为乳腺癌细胞株或鳞状上皮细胞癌细胞株。
7.一种核/壳纳米颗粒复合体的制造方法，包括：
(a)将细胞株离心分离而从所述细胞株中分离外来体的步骤；
(b)将所述被分离的外来体和药物进行混合来制造内部封入有药物的外来体的步骤；以及
(c)将所述封入有药物的外来体和PEO-PPO-PEO共聚物水溶液混合后进行冷冻干燥的步骤。
8.根据权利要求7所述的核/壳纳米颗粒复合体的制造方法，其特征在于，所述药物为选自难溶性药物、水溶性药物、离子性药物、蛋白质药物、抗体和造影剂中的1种以上。
9.根据权利要求7所述的核/壳纳米颗粒复合体的制造方法，其特征在于，所述PEO-PPO-PEO共聚物为选自泊洛沙姆68、泊洛沙姆127、泊洛沙姆188、泊洛沙姆237、泊洛沙姆338和泊洛沙姆407中的1种以上。
10.根据权利要求7所述的核/壳纳米颗粒复合体的制造方法，其特征在于，所述PEO-PPO-PEO共聚物水溶液包含1至30重量％的PEO-PPO-PEO共聚物。
11.根据权利要求7所述的核/壳纳米颗粒复合体的制造方法，其特征在于，在所述(b)步骤中，以封入有药物的外来体与PEO-PPO-PEO共聚物的重量比成为1:0.1至1:99的方式进行混合。
CN201880011966.1A 2017-02-15 2018-02-02 基于外来体的纳米颗粒复合体及其制备方法 Pending CN110300602A (zh)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
KR10-2017-0020293 2017-02-15
KR1020170020293A KR102036051B1 (ko) 2017-02-15 2017-02-15 엑소좀 기반의 나노입자 복합체 및 이의 제조방법
PCT/KR2018/001432 WO2018151445A1 (ko) 2017-02-15 2018-02-02 엑소좀 기반의 나노입자 복합체 및 이의 제조방법

Publications (1)

Publication Number Publication Date
CN110300602A true CN110300602A (zh) 2019-10-01

Family

ID=63170015

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201880011966.1A Pending CN110300602A (zh) 2017-02-15 2018-02-02 基于外来体的纳米颗粒复合体及其制备方法

Country Status (5)

Country Link
US (1) US20200046647A1 (zh)
EP (1) EP3583955A4 (zh)
KR (1) KR102036051B1 (zh)
CN (1) CN110300602A (zh)
WO (1) WO2018151445A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114306316A (zh) * 2021-12-29 2022-04-12 中国医学科学院输血研究所 一种肿瘤靶向性的复合纳米药物及其制备方法和用途

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021062057A1 (en) * 2019-09-25 2021-04-01 Codiak Biosciences, Inc. Exogenous loading of exosomes via lyophilization
CN111494413A (zh) * 2020-05-06 2020-08-07 南方医科大学深圳医院 一种含未成熟树突状细胞外泌体的缓释微球及其制备方法
CN111588911B (zh) * 2020-05-26 2022-05-27 南开大学 一种缓释外泌体的复合材料及其制备方法与应用
KR20240032637A (ko) 2022-08-30 2024-03-12 한양대학교 산학협력단 세포막 유래 핵산 전달용 나노소낭 및 이의 제조 방법

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20070003247A (ko) * 2005-07-01 2007-01-05 한남대학교 산학협력단 나노 캡슐화를 이용한 핵 및 쉘 구조를 갖는 나노 미립구제조방법
US20150010616A1 (en) * 2012-01-18 2015-01-08 Korea University Research And Business Foundation Biocompatible Particles and Method for Preparing Same

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100792557B1 (ko) 2006-04-05 2008-01-09 한남대학교 산학협력단 나노 캡슐화를 이용하여 제조된 지질 핵 및 고분자 쉘구조를 갖는 단백질 약물 전달용 나노 미립구

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20070003247A (ko) * 2005-07-01 2007-01-05 한남대학교 산학협력단 나노 캡슐화를 이용한 핵 및 쉘 구조를 갖는 나노 미립구제조방법
US20150010616A1 (en) * 2012-01-18 2015-01-08 Korea University Research And Business Foundation Biocompatible Particles and Method for Preparing Same

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HUIPING SUN ET AL.: "Cancer-Cell-Biomimetic Nanoparticles for Targeted Therapy of Homotypic Tumors", 《ADVANCED MATERIALS》 *
RUENN CHAILAI ET AL.: "Exosomes for drug delivery — a novel application for the mesenchymal stem cell", 《BIOTECHNOLOGY ADVANCES》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114306316A (zh) * 2021-12-29 2022-04-12 中国医学科学院输血研究所 一种肿瘤靶向性的复合纳米药物及其制备方法和用途
CN114306316B (zh) * 2021-12-29 2023-08-18 中国医学科学院输血研究所 一种肿瘤靶向性的复合纳米药物及其制备方法和用途

Also Published As

Publication number Publication date
EP3583955A4 (en) 2020-11-25
KR102036051B1 (ko) 2019-10-24
US20200046647A1 (en) 2020-02-13
WO2018151445A1 (ko) 2018-08-23
KR20180094232A (ko) 2018-08-23
EP3583955A1 (en) 2019-12-25

Similar Documents

Publication Publication Date Title
CN110300602A (zh) 基于外来体的纳米颗粒复合体及其制备方法
Torchilin Targeted polymeric micelles for delivery of poorly soluble drugs
US20150110713A1 (en) Method and composition for treating cancer
Bassyouni et al. Advances and new technologies applied in controlled drug delivery system
CN101940792B (zh) PCL-b-PEG-b-PCL载疏水性药物聚合物囊泡及制备方法及用途
US20200009050A1 (en) Pharmaceutical composition, preparation and uses thereof
US9415019B2 (en) Nanocapsules with a polymer shell
Tao et al. Reduction-responsive gold-nanoparticle-conjugated Pluronic micelles: an effective anti-cancer drug delivery system
KR20150132131A (ko) 약물 전달 담체로서 생체분해가능하고 임상적으로 상용가능한 나노입자
JP2018527413A (ja) アニオン性薬物含有医薬組成物及びその製造方法
Imran et al. Amphiphilic block copolymers–based micelles for drug delivery
US9265728B2 (en) Biocompatible particles and method for preparing same
Zhang et al. The anticancer efficacy of paclitaxel liposomes modified with low-toxicity hydrophobic cell-penetrating peptides in breast cancer: an in vitro and in vivo evaluation
CN101953778B (zh) 一种叶酸靶向载疏水性药物聚合物囊泡及制备方法及用途
EP3434258A2 (en) Temperature-sensitive composite and method for preparing same
Chauhan et al. Development and characterization of micelles for nucleolin-targeted co-delivery of docetaxel and upconversion nanoparticles for theranostic applications in brain cancer therapy
CN107126425A (zh) 一种丹参酮iiapeg‑plga‑peg纳米粒及其制备方法
EP3834822B1 (en) Polymer nanoparticle composition for delivering virus, and preparation method therefor
US20160128971A1 (en) Nanoparticle Compositions
KR101304597B1 (ko) 멀티-코어 구조를 갖는 생체적합성 입자의 제조방법 및 이에 의해 제조된 멀티-코어 구조를 갖는 생체적합성 입자
Jing-Jing et al. Fabrication of a folic acid-modified arsenic trioxide prodrug liposome and assessment of its anti-hepatocellular carcinoma activity
US20190328903A1 (en) Polymer nanoparticle composition for plasmid dna delivery, and preparation method therefor
Moniruzzaman et al. Nanotechnology: a possible healer in drug delivery system
Vaage et al. TISSUE UPTAKE AND THERAPEUTIC EFFECTS
CN109718204A (zh) 表面修饰有丛生蛋白的长循环纳米粒及其制备方法

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20191001