CN113041359B - 一种谷胱甘肽响应性抗骨肉瘤前药纳米粒子及其制备方法和用途 - Google Patents

一种谷胱甘肽响应性抗骨肉瘤前药纳米粒子及其制备方法和用途 Download PDF

Info

Publication number
CN113041359B
CN113041359B CN202110337784.7A CN202110337784A CN113041359B CN 113041359 B CN113041359 B CN 113041359B CN 202110337784 A CN202110337784 A CN 202110337784A CN 113041359 B CN113041359 B CN 113041359B
Authority
CN
China
Prior art keywords
glutathione
osteosarcoma
mtx
mixture
pga
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.)
Active
Application number
CN202110337784.7A
Other languages
English (en)
Other versions
CN113041359A (zh
Inventor
陶晓军
易杨非
李玉飞
何纯莲
徐康为
郑扬帆
黄智�
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.)
Hunan Normal University
Original Assignee
Hunan Normal 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 Hunan Normal University filed Critical Hunan Normal University
Publication of CN113041359A publication Critical patent/CN113041359A/zh
Application granted granted Critical
Publication of CN113041359B publication Critical patent/CN113041359B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

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
    • A61K47/6921—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
    • A61K47/6939—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 the polymer being a polysaccharide, e.g. starch, chitosan, chitin, cellulose or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—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 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • 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
    • A61K47/58—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 by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • 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
    • A61K47/61—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 the organic macromolecular compound being a polysaccharide or a derivative thereof
    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • 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
    • A61K47/6933—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 the polymer being obtained by reactions only involving carbon to carbon, e.g. poly(meth)acrylate, polystyrene, polyvinylpyrrolidone or polyvinylalcohol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nanotechnology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

本申请提供了一种谷胱甘肽响应性抗骨肉瘤前药纳米粒子，由疏水抗癌药物及其混合物和亲水性聚γ‑谷氨酸(PGA)制备而成，具有氧化还原敏感性、较高的溶解度和稳定性。纳米粒子能有效进入癌细胞，靶向释放疏水性抗癌药物，具有更优的抗癌活性，对正常细胞毒副作用小，在提高抗癌药物治疗作用的同时有效降低了药物的副作用。

Description

一种谷胱甘肽响应性抗骨肉瘤前药纳米粒子及其制备方法和 用途
本发明要求中国专利申请CN202110328288.5的优先权，该优先权文件的说明书、说明书附图和权利要求书所记载的内容全文引入本发明的说明书并被作为本发明说明书原始记载的一部分。申请人进一步声明，申请人拥有基于该优先权文件修改本发明的说明书和权利要求书的权利。
技术领域
本发明属于药物制剂领域，具体涉及一种谷胱甘肽响应性抗骨肉瘤前药纳米粒子及其制备方法和用途。
背景技术
骨肉瘤(OS)是最常见的起源于骨组织的恶性肿瘤。甲氨蝶呤(MTX)已广泛应用于骨肉瘤的临床实践。主要通过抑制二氢叶酸还原酶来抑制肿瘤细胞的合成，抑制肿瘤细胞的生长繁殖。然而，频繁使用化疗药物后，会出现疗效低、靶向性差、毒副作用大等问题。如何有效地将药物运送到肿瘤组织是提高机体疗效的关键。
近年来，脂质体、囊泡和胶束等各种纳米载体都利用肿瘤组织提供丰富的血流，并具有特殊的高渗透性和滞留效应(增强渗透性和保留效应，EPR)。纳米粒子可以通过EPR效应穿过肿瘤组织的血管内皮，实现肿瘤组织的被动靶向。纳米载体在肿瘤治疗和生物医学领域具有重要的应用前景。然而，如何保持胶束系统的稳定性，减少药物在给药过程中的渗漏，有效应对肿瘤微环境刺激来控制药物的释放，是胶束给药系统面临的重要挑战。
针对传统胶束在体内循环过程中稳定性较差，药物容易泄漏等缺陷，当纳米粒子作为药物载体时，通过修饰纳米粒子的结构，疏水药物可以通过化学键接枝到亲水性材料上从而提高药物的溶解度、生物利用度，增强纳米粒子在体内的稳定性。
基于肿瘤细胞中谷胱甘肽(GSH)浓度远高于正常细胞(可达1000倍)，细胞外微环境(约2-10μM)和肿瘤细胞内微环境(约2-10mM)介于GSH梯度降低之间，可以快速释放肿瘤细胞中以二硫键为特征的药物传递系统，显著增强药物的疗效。
木樨草素为一种天然四羟基黄酮化合物，具有抗炎、抗氧化、神经保护、抑制肿瘤细胞增殖、诱导肿瘤细胞凋亡以及增敏抗癌药物等活性。
本发明将疏水抗癌药物和亲水性聚γ-谷氨酸(PGA)通过胱胺二盐酸盐(二硫键)偶联形成共轭物，具有良好的生物相容性，可作为药物载体，为药物传递系统和化疗的研究开辟了新的途径。本发明还进一步筛选研究了谷胱甘肽响应性抗骨肉瘤前药纳米粒子中抗癌药物的组合对骨肉瘤治疗效果的影响，并获得了一种具有协同增效作用的谷胱甘肽响应性抗骨肉瘤前药纳米粒子。
发明内容
本发明的目的是提供一种谷胱甘肽响应性抗骨肉瘤前药纳米粒子及其制备方法和用途。
一方面，本发明提供一种谷胱甘肽响应性抗骨肉瘤前药纳米粒子，其特征在于由疏水抗癌药物和亲水性聚合物制备而成。
优选的，所述疏水性抗癌药物选自甲氨蝶呤、紫杉醇、阿霉素、5-氟尿嘧啶、喜树碱、木樨草素中的一种或多种混合物等；更优选的，所述疏水性抗癌药物选自甲氨蝶呤、阿霉素、喜树碱、木樨草素中的一种或多种混合物；最优选的，所述疏水性抗癌药物选自甲氨蝶呤与木樨草素的混合物。
优选的，所述甲氨蝶呤与木樨草素的重量比为1-8：2-10；更优选的，所述甲氨蝶呤与木樨草素的重量比为2-4：6-8；最优选的，所述甲氨蝶呤与木樨草素的重量比为3：7。
优选的，所述亲水性聚合物选自聚γ-谷氨酸(PGA)、纤维素衍生物、聚丙烯酸、聚丙烯酞胺、聚乙烯醇、聚酞胺等。
优选的所述疏水抗癌药物和亲水性聚合物的重量比选自：1-10：10-0.1；更优选的，所述疏水抗癌药物和亲水性聚合物的重量比选自：3-5：0.5-2；最优选的，所述疏水抗癌药物和亲水性聚合物的重量比选自4：1。
本发明的再一个目的是提供一种谷胱甘肽响应性抗骨肉瘤前药纳米粒子的制备方法，其特征在于包括以下步骤：
(1)将疏水性抗癌药物溶解后，加入NHS、EDC·HCl，在20-50℃避光磁力搅拌4小时。然后向其中加入胱胺二盐酸盐，使反应混合物在20-50℃氮气保护下搅拌24h，并透析24小时以除去多余的疏水性抗癌药物，EDC·HCl和NHS，得混合物1；
(2)将混合物1滴加于亲水性聚合物水溶液中，20℃-50℃下搅拌24h-72h，透析12-36h，得到所述谷胱甘肽响应性抗骨肉瘤前药纳米粒子。
本发明的另一个目的是提供了谷胱甘肽响应性抗骨肉瘤前药纳米粒子在制备靶向抗肉瘤药物外中的用途，其特征在于，所述谷胱甘肽响应性抗骨肉瘤前药纳米粒子由疏水抗癌药物和亲水性聚合物制备而成。
优选的，所述疏水性抗癌药物选自甲氨蝶呤、紫杉醇、阿霉素、5-氟尿嘧啶、喜树碱、木樨草素中的一种或多种混合物等；更优选的，所述疏水性抗癌药物选自甲氨蝶呤、阿霉素、喜树碱、木樨草素中的一种或多种混合物；最优选的，所述疏水性抗癌药物选自甲氨蝶呤与木樨草素的混合物。
优选的，所述甲氨蝶呤与木樨草素的重量比为1-8：2-10；更优选的，所述甲氨蝶呤与木樨草素的重量比为2-4：6-8；最优选的，所述甲氨蝶呤与木樨草素的重量比为3：7。
优选的，所述亲水性聚合物选自聚γ-谷氨酸(PGA)、纤维素衍生物、聚丙烯酸、聚丙烯酞胺、聚乙烯醇、聚酞胺等。
优选的所述疏水抗癌药物和亲水性聚合物的重量比选自：1-10：10-0.1；更优选的，所述疏水抗癌药物和亲水性聚合物的重量比选自：3-5：0.5-2；最优选的，所述疏水抗癌药物和亲水性聚合物的重量比选自4：1。
本发明有益效果
本发明将疏水抗癌药物和亲水性聚合物在制备成具有氧化还原敏感性骨肉瘤的靶向胶束系统。具有良好的生物相容性、骨肉瘤靶向性，在提高骨肉瘤治疗效果的同时，有利于降低抗癌药物的使用剂量，降低抗癌药物的副作用，提高患者依从性。
本发明进一步筛选研究了谷胱甘肽响应性抗骨肉瘤前药纳米粒子中抗癌药物的组合对骨肉瘤治疗效果的影响，并获得了可与甲氨蝶呤协同增效的甲氨蝶呤与木樨草素的组合，在保证骨肉瘤治疗效果的同时可进一步降低甲氨蝶呤的使用剂量，从而可在保证治疗效果的同时进一步降低甲氨蝶呤的副作用，提高患者依从性。
附图说明：
图1：A:PGA,MTX,MTX-SS-PGA共轭物的红外光谱；B:MTX和MTX-SS-PGA NPs的紫外光谱
图2：A:MTX-SS-PGA NPs的粒径分布；B:MTX-SS-PGA NPs的电位图；C,D:MTX-SS-PGA NPs的TEM图像；E,F:MTX-SS-PGA NPs+5mM GSH的TEM图像
图3：不同投料比的MTX-SS-PGA NPs的平均粒径和zeta电位
图4：0,0.5,2,10mM GSH存在下体外MTX的释放
图5：用DAPI和MTX-SS-PGA-iCG NPs染色143b细胞的荧光图像
图6：(A)Huvec细胞和(B)143b细胞经MTX,MTX-ss-PGA纳米粒子处理48小时后的细胞存活率
图7：MTX-ss-PGA NPs对143b细胞的AO/EB染色结果(A:对照B:6.25μM C:12.5μMD:25μM)
具体实施方式
在下文中更详细地描述了本发明以有助于对本发明的理解。
实施例1：一种谷胱甘肽响应性抗骨肉瘤前药纳米粒子
将MTX(100mg，0.22mmol)溶于10mL DMSO中，然后在溶液中加入NHS(56mg，0.484mmol)，EDC·HCl(92mg，0.484mmol)，在37℃避光磁力搅拌4小时。然后向其中加入胱胺二盐酸盐(109mg，0.484mmol)，使反应混合物在25℃氮气保护下搅拌24h，形成具有二硫键的配合物(MTX-SS-NH2)，并透析24小时以除去多余的MTX，EDC·HCl和NHS。
将MTX-SS-NH2混合物滴加于γ-PGA水溶液(2.08mg/mL)中，30℃下搅拌48h，透析24h，除去多余的MTX-SS-NH2，EDC·HCl和NHS，得到氧化还原反应纳米粒子(MTX-SS-PGANPs)。
实施例2：MTX-SS-PGA纳米粒子表征
在MTX-SS-PGA的红外光谱中，峰值在1636cm-1的峰可归因于羰基C＝O的伸缩振动峰，即酰胺I带峰。这种伸缩振动峰的出现表明MTX-SS-NH2的氨基与PGA的羧基成功结合，形成酰胺键。峰值在3296cm-1处的伸缩振动表明存在伯氨基(MTX)。MTX-SS-PGA中该伯胺基团的伸缩振动峰消失，表明MTX-SS-NH2与PGA成功连接(参见图1)。
将MTX和MTX-SS-PGA纳米粒子在220-550nm波长范围内进行紫外扫描。甲氨蝶呤标准溶液的最大紫外吸收波长为304nm，MTX-SS-PGA纳米粒子的最大紫外吸收波长为309nm。由于体系的共轭基团增加，使得波长红移，纳米粒子的整体光谱与甲氨蝶呤标准溶液的光谱一致，证明了MTX-SS-PGA偶联物的成功合成。
MTX-SS-PGA纳米粒子的平均粒径为100.5nm，多分散性指数(PDI)为0.131。MTX-SS-PGA纳米粒子的zeta电位均带负电荷，证明聚谷氨酸带负电荷的羧基主要分布在纳米粒子的球形表面，甲氨蝶呤的疏水段内聚形成内核。这种纳米粒子可以保证药物在血液中的稳定性，防止药物在传递过程中与血浆蛋白相互作用。
透射电镜图像(图2-C，D)表明，MTX-SS-PGA纳米粒子均匀分散，直径约为100nm。当加入5mM谷胱甘肽时，纳米粒子的骨架解体，释放不溶性甲氨蝶呤，进一步验证了二硫键对谷胱甘肽的反应释放机制(图2-E，F)。
低分子量(1w MCO)聚谷氨酸和甲氨蝶呤不同投料比时组成的MTX-SS-PGA纳米粒子的平均粒径和zeta电位。由表1可以看出，不同投料比的纳米粒子粒径和zeta电位变化不大，粒径仍在300nm以内，多分散性指数(PDI)小于0.36。多分散性指数可以用来表示纳米粒子分散的宽度和尺寸分布的均匀性。不同投料比的纳米粒子表面仍带负电，说明表面为亲水性聚谷氨酸(参见图3)。
表1不同投料比的MTX-NH2:PGA组成的纳米粒子的粒径、zeta电位和载药量
Figure BDA0002998247570000061
实施例3：MTX-SS-PGA纳米粒子体外释药研究
将40mg的MTX偶联物溶于20mL DMSO中，在37℃下轻轻摇动，得到2mg/mL偶联液。在100mL蒸馏水中透析12小时，用透析袋(MWCO＝8000-14000KDa)进行5次换水，得到自组装的MTX-SS-PGA纳米粒子。样品存放在4℃。
采用透析法评价MTX-SS-PGA纳米粒子的体外释药效果。体外MTX-SS-PGA纳米粒子的MTX释放实验模拟还原条件，将5mL的MTX-SS-PGA纳米粒子放置在pH6.5磷酸盐缓冲液(0，0.5，2，10mM谷胱甘肽)环境下的透析袋(MWCO＝8-14KDa)中，浸泡在37℃下的20mL缓冲液中，搅拌速度为100r/min。在预定的时间间隔内，收集5mL透析液，并补充相同体积的新鲜培养基。用紫外分光光度计在304nm处确认MTX的释放。在每个条件下设置三个平行对照，取平均值作为最终结果。
释放率＝(It–I0)/Imax x 100％,其中Io和It分别表示t＝0和加入谷胱甘肽后任意给定时间t的发射强度。
实验结果参见图4，在正常生理环境pH7.4条件下，MTX-SS-PGA纳米粒子在72h的MTX释放仅为8.14％。由此可以推断，当MTX-SS-PGA纳米粒子在血液中循环时，可以抑制药物泄漏。相反，在10mM GSH的存在下，MTX在8h内迅速释放35.25％，72h内累积释放为90.1％。证实了二硫键容易被谷胱甘肽裂解，从而导致纳米粒子结构的解体和MTX的完全释放。上述体外释放研究表明，在正常生理环境下，MTX-SS-PGA纳米粒子可以有效地减少药物的损失。当MTX-SS-PGA纳米粒子到达肿瘤细胞时，纳米粒子可以智能地响应还原刺激并被破坏，显著提高药物的传递效率。
用倒置荧光显微镜(OLYMPUS TH4-200)研究了ICG标记的MTX-SS-PGA纳米粒子的细胞摄取和细胞内定位)。在培养基中与癌细胞孵育6h后，ICG标记的MTX-SS-PGA纳米粒子的红色荧光与DAPI的蓝色荧光重叠，证明纳米粒子主要位于143b癌细胞的细胞核中。荧光纳米粒子的分布表明，细胞中内源性谷胱甘肽破坏了二硫键，MTX进入细胞核发挥作用。可携带荧光的MTX-SS-PGA纳米粒子可用于监测癌细胞的药物释放过程(参见图5)。
实施例4：MTX-SS-PGA纳米粒子体外细胞毒性研究
将40mg的MTX偶联物溶于20mL DMSO中，在37℃下轻轻摇动，得到2mg/mL偶联液。在100mL蒸馏水中透析12小时，用透析袋(MWCO＝8000-14000KDa)进行5次换水，得到自组装的MTX-SS-PGA纳米粒子。样品存放在4℃。
用MTT法检测游离MTX和MTX-ss-PGA纳米粒子对143b癌细胞和HUVEC正常细胞的毒性。结果如图6所示：HUVEC正常细胞中的MTX-ss-PGA纳米粒子的浓度为20μM，细胞存活率仍为81.99％，表明MTX-ss-PGA纳米粒子对Huvec细胞无明显细胞毒性。然而，游离MTX对HUVEC有很大的毒性作用。纳米粒子的低毒性也意味着MTX-ss-PGA纳米粒子在谷胱甘肽浓度较低的血液循环过程中可能具有缓慢的药物释放和低毒性。
MTX-ss-PGA纳米粒子在143b癌细胞中，在48h时的IC50值为10μM，低于游离MTX的细胞毒性(48h时的IC50值为2.5μM)。浓度为10μM时，MTX-ss-PGA纳米粒子的细胞毒性接近游离MTX。MTX-ss-PGA纳米粒子进入143b细胞后，随着时间的额增加，MTX的累计释放量增加，这与游离MTX对143b细胞的毒性相似。体外细胞毒性结果显示，10μM MTX-ss-PGA纳米粒子对正常细胞的毒副作用较小，而对癌细胞的毒副作用较大。这表明，这种新型的纳米粒子是一种具有响应性释放的靶向前药纳米粒子(参见图6)。
实施例5：MTX-SS-PGA纳米粒子体外细胞凋亡的研究
将40mg的MTX偶联物溶于20mL DMSO中，在37℃下轻轻摇动，得到2mg/mL偶联液。在100mL蒸馏水中透析12小时，用透析袋(MWCO＝8000-14000KDa)进行5次换水，得到自组装的MTX-SS-PGA纳米粒子。样品存放在4℃。
采用AO/EB双染色试剂盒检测不同浓度的MTX-ss-PGA纳米粒子(6.25,12.5,25μM)对143b细胞形态的影响。细胞经AO/EB染色后，荧光显微镜下观察到：活细胞核呈绿色荧光，凋亡细胞核呈橙红色荧光，且凋亡程度越高，荧光强度越强。当MTX-ss-PGA纳米粒子浓度为25μM时，143b细胞呈现典型的凋亡特征，例如细胞核高度集中、破碎，且细胞损伤明显(参见图7).
实施例6：谷胱甘肽响应性抗骨肉瘤前药纳米粒子中抗癌药物的组合对骨肉瘤治疗效果的影响
实验药物：甲氨蝶呤、木樨草素、混合物1(甲氨蝶呤：木樨草素＝1：10)、混合物2(甲氨蝶呤：木樨草素＝1：4)、混合物3(甲氨蝶呤：木樨草素＝3：7)、混合物4(甲氨蝶呤：木樨草素＝7：3)、混合物5(甲氨蝶呤：木樨草素＝4：1)、混合物6(甲氨蝶呤：木樨草素＝10：1)，以上药物均按照实施例1所述方法以实验药物和亲水性聚合物的重量比为4：1制备得到氧化还原反应纳米粒子，并使用不含血清的DMEM培养基配置所述氧化还原反应纳米粒子的浓度为100μM。
实验方法：通过MTT方法检测各实验药物氧化还原反应纳米粒子对143b癌细胞的抑制率。取对数生长期的143b癌细胞，以每孔1×105个细胞的密度接种于96孔板中，每孔添加含10％胎牛血清的DMEM培养基至180μL，将接种于96孔板的细胞分为空白组、甲氨蝶呤组、木樨草素组、混合物1-6组，每组平行五孔，将96孔板置于5％CO2、37℃培养箱培养12h后，各组分别加入相应药物20μL，其中空白组添加不含血清的DMEM培养基20μL。继续培养36h，加入浓度为5mg/mL的MTT溶液20μL继续培养4h，弃去上清，使用PBS溶液冲洗1遍后每孔加入DMSO 100μL，振荡20min，于酶标仪测试570nm的吸光度值，计算各实验药物组的细胞抑制率，具体实验结果见表2，其中：
抑制率(％)＝(空白组吸光度-实验组吸光度)/空白组吸光度×100％。
实验结果：
表2抗癌药物的组合对骨肉瘤治疗效果的影响
组别 抑制率(％)
空白组 -
甲氨蝶呤 47.63
木樨草素 27.24
混合物1 25.49
混合物2 33.52
混合物3 51.80
混合物4 43.86
混合物5 45.58
混合物6 46.35
表2实验结果显示了单独的甲氨蝶呤、木樨草素及甲氨蝶呤与木樨草素的混合物都显示了一定的对143b癌细胞的抑制活性，其中尤其以氨蝶呤：木樨草素＝3：7的混合物3组对143b癌细胞的抑制活性最为显著，在甲氨蝶呤的使用剂量仅相当于了单独甲氨蝶呤组中甲氨蝶呤剂量的30％情况下，取得了更加优于单独甲氨蝶呤的143b癌细胞的抑制效果，从而进一步降低了毒副作用较大的甲氨蝶呤的使用剂量，进一步降低了甲氨蝶呤的副作用，有利于在保证治疗效果的同时提高患者的生活质量，从而提高患者的依从性。
以上描述了本发明优选实施方式，然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。

Claims (6)

1.一种谷胱甘肽响应性抗骨肉瘤前药纳米粒子，其特征在于，由疏水抗癌药物和亲水性聚合物制备而成，所述疏水性抗癌药物选自甲氨蝶呤与木樨草素的混合物，所述甲氨蝶呤与木樨草素的重量比为3：7，所述亲水性聚合物为聚γ-谷氨酸，所述谷胱甘肽响应性抗骨肉瘤前药纳米粒子按照以下步骤制备：
（1）将疏水性抗癌药物溶解后，加入NHS、EDC·HCl，在20-50°C避光磁力搅拌4小时;然后向其中加入胱胺二盐酸盐，使反应混合物在20-50℃氮气保护下搅拌24h，并透析24小时以除去多余的疏水性抗癌药物，EDC·HCl和NHS，得混合物1；
（2）将混合物1滴加于亲水性聚合物水溶液中，20℃-50℃下搅拌24h-72h，透析12-36h，得到所述谷胱甘肽响应性抗骨肉瘤前药纳米粒子。
2.根据权利要求1所述的谷胱甘肽响应性抗骨肉瘤前药纳米粒子，其特征在于，所述疏水抗癌药物和亲水性聚合物的重量比选自：1-10：10-0.1。
3.根据权利要求2所述的谷胱甘肽响应性抗骨肉瘤前药纳米粒子，其特征在于，所述疏水抗癌药物和亲水性聚合物的重量比选自：3-5：0.5-2。
4.根据权利要求3所述的谷胱甘肽响应性抗骨肉瘤前药纳米粒子，其特征在于，所述疏水抗癌药物和亲水性聚合物的重量比选自4：1。
5.根据权利要求1-4任一项所述的谷胱甘肽响应性抗骨肉瘤前药纳米粒子的制备方法，其特征在于，包括以下步骤：
（1）将疏水性抗癌药物溶解后，加入NHS、EDC·HCl，在20-50°C避光磁力搅拌4小时;然后向其中加入胱胺二盐酸盐，使反应混合物在20-50℃氮气保护下搅拌24h，并透析24小时以除去多余的疏水性抗癌药物，EDC·HCl和NHS，得混合物1；
（2）将混合物1滴加于亲水性聚合物水溶液中，20℃-50℃下搅拌24h-72h，透析12-36h，得到所述谷胱甘肽响应性抗骨肉瘤前药纳米粒子。
6.权利要求1-4任一项所述的谷胱甘肽响应性抗骨肉瘤前药纳米粒子在制备靶向抗肉瘤药物中的用途。
CN202110337784.7A 2021-03-26 2021-03-30 一种谷胱甘肽响应性抗骨肉瘤前药纳米粒子及其制备方法和用途 Active CN113041359B (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2021103282885 2021-03-26
CN202110328288 2021-03-26

Publications (2)

Publication Number Publication Date
CN113041359A CN113041359A (zh) 2021-06-29
CN113041359B true CN113041359B (zh) 2022-05-20

Family

ID=76516152

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110337784.7A Active CN113041359B (zh) 2021-03-26 2021-03-30 一种谷胱甘肽响应性抗骨肉瘤前药纳米粒子及其制备方法和用途

Country Status (1)

Country Link
CN (1) CN113041359B (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013127885A1 (en) * 2012-02-27 2013-09-06 Instytut Immunologii i Terapii Doświadczalnej PAN A conjugate of methotrexate and hydroxyethyl starch for use in the treatment cancer
CN104491871A (zh) * 2014-12-02 2015-04-08 江南大学 一种基于聚谷氨酸和胱胺的pH与还原敏感性的纳米微凝胶
CN111265478A (zh) * 2020-01-20 2020-06-12 华南师范大学 一种具有还原性响应的阿霉素聚前药纳米胶束及其制备方法和应用
CN111936145A (zh) * 2018-02-14 2020-11-13 L.E.A.F.控股集团公司 γ聚谷氨酸化氨甲蝶呤及其用途

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7348026B2 (en) * 2004-10-05 2008-03-25 Hsing-Wen Sung Nanoparticles for targeting hepatoma cells
WO2009048780A1 (en) * 2007-10-08 2009-04-16 The University Of Kentucky Research Foundation Polymer-metal chelator conjugates and uses thereof
CA3073181A1 (en) * 2017-08-18 2019-02-21 Thomas Jefferson University Protection of normal tissue in cancer treatment
CN109010846B (zh) * 2017-12-27 2021-11-02 湖南师范大学 聚乙二醇-壳聚糖-姜黄素聚合物、及其载药纳米粒子和制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013127885A1 (en) * 2012-02-27 2013-09-06 Instytut Immunologii i Terapii Doświadczalnej PAN A conjugate of methotrexate and hydroxyethyl starch for use in the treatment cancer
CN104491871A (zh) * 2014-12-02 2015-04-08 江南大学 一种基于聚谷氨酸和胱胺的pH与还原敏感性的纳米微凝胶
CN111936145A (zh) * 2018-02-14 2020-11-13 L.E.A.F.控股集团公司 γ聚谷氨酸化氨甲蝶呤及其用途
CN111265478A (zh) * 2020-01-20 2020-06-12 华南师范大学 一种具有还原性响应的阿霉素聚前药纳米胶束及其制备方法和应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
基于聚( L-谷氨酸) 树状分子的智能药物释放系统研究;江超;《高分子学报》;20110831(第8期);第845页左栏最后一段,第847页图1 *
负载阿霉素的肿瘤靶向肽修饰的纳米凝胶对骨肉瘤的治疗作用;王立哲;《中国优秀博硕士学位论文全文数据库(博士) 医药卫生科技辑》;20191215(第12期);第41页第4.1 *

Also Published As

Publication number Publication date
CN113041359A (zh) 2021-06-29

Similar Documents

Publication Publication Date Title
EP3372226B1 (en) Targeted hydrophobic anti-tumour drug nanoformulation and preparation method thereof
KR101736149B1 (ko) 여드름 피부개선을 위한 광민감성 물질을 함유한 건식다중캡슐형 조성물 및 그의 제조방법
CN111617246B (zh) 一种纯光敏剂自组装纳米粒及其制备和应用
CN109718207A (zh) 化疗药-光敏剂共组装纳米粒及其构建
CN110591075B (zh) 一种PEG-Peptide线性-树状给药系统及其制备方法和用途
WO2014155142A1 (en) Stable nanocomposition comprising doxorubicin, process for the preparation thereof, its use and pharmaceutical compositions containing it
CN113663079B (zh) 一种无载体自组装纳米粒子及其制备方法和应用
CN112999153B (zh) 载化疗药物/光敏剂的纳米胶束及其制备方法和应用
CN108339124B (zh) 一种双级脑靶向聚合物胶束递药系统的制备方法和应用
US10117837B2 (en) Methods of preparing stimuli-responsive multifunctional nanoparticles
Dong et al. Investigation of the intracellular oxidative stress amplification, safety and anti-tumor effect of a kind of novel redox-responsive micelle
Wang et al. Development and evaluation of hyaluronic acid-based polymeric micelles for targeted delivery of photosensitizer for photodynamic therapy in vitro
CN107982217A (zh) 一种包载疏水性药物的具靶向和放疗增敏双重功能脂质-聚合物、其制备方法及其应用
CN113648401B (zh) 一种蛋白酶体抑制增敏光动力治疗的杂化纳米组装体及其制备与应用
CN110585132A (zh) 一种槲皮素纳米胶束及其制备方法和用途
CN107007550B (zh) 一种氧化还原响应性两亲性共聚物及其制备方法和应用
CN113041359B (zh) 一种谷胱甘肽响应性抗骨肉瘤前药纳米粒子及其制备方法和用途
CN113908276A (zh) 一种光控释药纳米粒子及其制备方法和应用
CN106619569A (zh) 共载化疗药物和核酸的肿瘤靶向纳米粒子及制备方法
CN109718242B (zh) 抑制Rac1表达的干扰RNA及在增加乳腺癌化疗敏感性中的应用
Chung et al. Nano-self assembled photosensitizer composed of methoxy poly (ethylene glycol)-conjugated chlorin e6 for enhanced photosensing of HCT116 cells
CN111888333A (zh) 一种转铁蛋白受体靶向的纳米胶束及其制备方法与应用
Yin et al. A new type of nanogel carrier based on mixed Pluronic loaded with low-dose antitumor drugs
CN110279856A (zh) 一种PEG-Peptide光动力-化疗联用给药系统及其制备方法和用途
CN110922587A (zh) 一种纳米药物的制备方法及其在治疗骨肉瘤中的应用

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
GR01 Patent grant
GR01 Patent grant
CP02 Change in the address of a patent holder

Address after: 410013 Hunan Key Laboratory for research and creation of small molecule targeted drugs, Changsha City, Hunan Province, Department of pharmacy, medical college, Hunan Normal University

Patentee after: HUNAN NORMAL University

Address before: 410006 36 Yuelu District Lu Shan Road, Changsha, Hunan

Patentee before: HUNAN NORMAL University

CP02 Change in the address of a patent holder