CN116459232A - 一种温敏载药复合纳米颗粒的制备及应用 - Google Patents
一种温敏载药复合纳米颗粒的制备及应用 Download PDFInfo
- Publication number
- CN116459232A CN116459232A CN202310583091.5A CN202310583091A CN116459232A CN 116459232 A CN116459232 A CN 116459232A CN 202310583091 A CN202310583091 A CN 202310583091A CN 116459232 A CN116459232 A CN 116459232A
- Authority
- CN
- China
- Prior art keywords
- particles
- hbcos
- drug
- composite
- temperature
- 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.)
- Granted
Links
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 124
- 239000002131 composite material Substances 0.000 title claims abstract description 114
- 239000003814 drug Substances 0.000 title claims abstract description 49
- 229940079593 drug Drugs 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- AZKVWQKMDGGDSV-BCMRRPTOSA-N Genipin Chemical compound COC(=O)C1=CO[C@@H](O)[C@@H]2C(CO)=CC[C@H]12 AZKVWQKMDGGDSV-BCMRRPTOSA-N 0.000 claims abstract description 21
- AZKVWQKMDGGDSV-UHFFFAOYSA-N genipin Natural products COC(=O)C1=COC(O)C2C(CO)=CCC12 AZKVWQKMDGGDSV-UHFFFAOYSA-N 0.000 claims abstract description 21
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 11
- 230000001105 regulatory effect Effects 0.000 claims description 17
- 238000000502 dialysis Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 13
- 238000004108 freeze drying Methods 0.000 claims description 11
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 8
- 239000012498 ultrapure water Substances 0.000 claims description 8
- -1 hydroxybutyl Chemical group 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 229920001661 Chitosan Polymers 0.000 claims description 4
- 229940080237 sodium caseinate Drugs 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 102000011632 Caseins Human genes 0.000 claims description 3
- 108010076119 Caseins Proteins 0.000 claims description 3
- 230000035945 sensitivity Effects 0.000 abstract description 14
- 239000002246 antineoplastic agent Substances 0.000 abstract description 9
- 210000004369 blood Anatomy 0.000 abstract description 7
- 239000008280 blood Substances 0.000 abstract description 7
- 238000010790 dilution Methods 0.000 abstract description 7
- 239000012895 dilution Substances 0.000 abstract description 7
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 4
- 229940044683 chemotherapy drug Drugs 0.000 abstract description 4
- 238000013270 controlled release Methods 0.000 abstract description 4
- 239000000969 carrier Substances 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- 239000003431 cross linking reagent Substances 0.000 abstract description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 74
- 229940071162 caseinate Drugs 0.000 description 38
- 229960004679 doxorubicin Drugs 0.000 description 37
- 210000004027 cell Anatomy 0.000 description 20
- 239000000463 material Substances 0.000 description 9
- 230000004044 response Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000002539 nanocarrier Substances 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 230000009881 electrostatic interaction Effects 0.000 description 6
- 231100000135 cytotoxicity Toxicity 0.000 description 5
- 230000003013 cytotoxicity Effects 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 206010018910 Haemolysis Diseases 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000012377 drug delivery Methods 0.000 description 4
- 230000008588 hemolysis Effects 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000010609 cell counting kit-8 assay Methods 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 238000005538 encapsulation Methods 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 102000004225 Cathepsin B Human genes 0.000 description 2
- 108090000712 Cathepsin B Proteins 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 2
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 2
- 102000057297 Pepsin A Human genes 0.000 description 2
- 108090000284 Pepsin A Proteins 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229940111202 pepsin Drugs 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229920000867 polyelectrolyte Polymers 0.000 description 2
- 230000004043 responsiveness Effects 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- BZQFBWGGLXLEPQ-UHFFFAOYSA-N O-phosphoryl-L-serine Natural products OC(=O)C(N)COP(O)(O)=O BZQFBWGGLXLEPQ-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229950006137 dexfosfoserine Drugs 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 210000001163 endosome Anatomy 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 210000003617 erythrocyte membrane Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229920001977 poly(N,N-diethylacrylamides) Polymers 0.000 description 1
- 229920003213 poly(N-isopropyl acrylamide) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000011896 sensitive detection Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000003911 water pollution Methods 0.000 description 1
Classifications
-
- 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
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
-
- 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
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
-
- 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
- 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
- A61K9/5169—Proteins, e.g. albumin, gelatin
-
- 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)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Nanotechnology (AREA)
- Optics & Photonics (AREA)
- Physics & Mathematics (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明提供一种温敏载药复合纳米颗粒的制备及应用。首次利用CN和HBCOS溶解后加入交联剂京尼平,获得具有温度敏感的纳米颗粒,其本申请对于细胞具有低毒性和良好的稀释稳定性和血液相容性;当获得的复合纳米颗粒作为载体与化疗药物混合制备获得载药复合纳米颗粒时,其具有良好温度敏感性;可用于包埋DOX等抗肿瘤药物,实现载药纳米颗粒的温敏控制释放,治疗癌症。
Description
技术领域
本发明属于生物化学领域,具体涉及温度敏感的药物递送载体的制备。
背景技术
癌症在世界各国均是导致死亡的主要原因,也是缩短预期寿命的一个重要因素。化疗是治疗癌症的重要手段,然而,化疗药物的选择性差、药物利用率低、毒副作用强。因此,针对肿瘤微环境和正常组织的差异性(如温度、pH、酶),设计具有刺激响应性特性的纳米载体提高肿瘤的选择性、增强药物在肿瘤部位的靶向积累和控制释放成为肿瘤治疗的重要手段。刺激响应性纳米载体是在特定物理化学刺激(包括温度、pH、光和离子强度)下具有可控收缩或膨胀行为的材料,因其刺激响应特性使其可以在适当的时间和位置释放被包埋的药物。在各种刺激中,温度是刺激响应给药研究最广泛的刺激之一,因为温度刺激可以由内源或远程控制的热变化诱导。
许多合成的温度响应材料包括聚(N-异丙基丙烯酰胺)、聚(N,N-二乙基丙烯酰胺)和聚(环氧乙烷)等被开发出来应用于生物医学领域。但是这些合成类聚合物的生物相容性或可生物降解性差,制约了其应用。天然产物衍生出来聚合物如羟丁基壳聚糖、羟丁基壳寡糖和羟丙基纤维素也具有温度响应特性,同时具有良好的生物相容性和生物可降解性。然而,这些材料的温敏性都具有浓度依赖性,在低浓度下其温度响应临界点上升或者温度响应特性消失,因此主要应用于智能窗户、重金属清除、伤口敷料、水污染治理等方面。而聚合物在生物医药领域的应用过程中,势必会经由各种途径而导致浓度被稀释,导致其温敏作用减弱甚至消失。因此,被用于药物递送的载体必须具有稀释稳定性,浓度依赖型的温敏响应聚合物在药物递送应用中受限。
发明内容:
解决浓度依赖型的温敏响应聚合物在药物递送应用中的不足。
我们利用带正电的温敏性羟丁基壳寡糖(HBCOS)与带负电的酪蛋白酸钠(CN)通过静电相互作用形成稳定的聚电解质复合物。CN具有磷酸丝氨酸和羧基,可以通过静电相互作用与带正电的羟丁基壳寡糖结合或者装载带正电的药物如阿霉素(DOX)。由于CN容易被胰蛋白酶、胃蛋白酶、基质金属蛋白酶和组织蛋白酶B等水解,CN与其他材料复合后可以产生易于生物降解的材料。将HBCOS与CN通过静电相互作用结合得到复合纳米颗粒进行交联,可以得到稳定的温敏性复合纳米颗粒,可用于包埋DOX等抗肿瘤药物,实现载药纳米颗粒的温敏控制释放,治疗癌症。
本发明的第一个方面是提供一种温敏复合纳米颗粒,所述的纳米颗粒由羟丁基壳聚糖(HBCOS)和酪蛋白酸钠(CN)组成,具体由如下方法制备:
(1)将CN和HBCOS分别溶于水中,将CN与HBCOS混合使CN与HBCOS的质量比为1:0.4-0.8,调节pH,形成复合纳米颗粒;
(2)加入京尼平,35℃~39反应24~72h,调pH后透析1~3天后冻干,得到交联后的复合纳米颗粒。
在一个优选的实施例中,所述的CN为浓度为0.5~1.5mg/mL,HBCOS的浓度为30-50mg/mL;在另外一个优选的实施例中,所述的CN与HBCOS的质量比为:1:0.4-0.8;在另外一个具体的实施例中,所述的pH值为5.8~6.5;
在另外一个具体的实施例中,步骤2)中京尼平的浓度为0.01-0.1mg/mL;在另外一个具体的实施例中,反应温度为37℃,pH值为7.0~7.8,优选7.4;在另外一个具体的实施例中,透析膜截留分子量为8000~12000Da,优选为10000Da。
本发明的第二个方面提供一种载有药物的复合纳米颗粒,所述载药纳米颗粒以如下方法制备,
(1)将CN和HBCOS分别溶于水中,将CN与HBCOS混合使CN与HBCOS的质量比为1:0.4-0.8,调节pH,形成复合纳米颗粒;
(2)加入京尼平,35℃~39℃反应24~72h,调pH后透析1~3天后冻干,得到交联后的复合纳米颗粒;
(3)将步骤2)中制备的复合纳米颗粒用超纯水复溶,调pH,加入药物,避光条件下室温摇晃12~15h后用超纯水透析,透析袋的截留分子量为8000~12000a,每8~15h换一次透析液;将透析袋里的样品冻干,得到载药复合纳米颗粒。
在一个优选的实施例中,所述的步骤1)中CN为浓度为0.5~1.5mg/mL,HBCOS的浓度为30-50mg/mL;在另外一个优选的实施例中,所述的CN与HBCOS的质量比为:1:0.4-0.8;在另外一个具体的实施例中,所述的pH值为5.8~6.5;
在另外一个具体的实施例中,步骤2)中京尼平的浓度为0.01-0.1mg/mL优选的0.05mg/mL;在另外一个具体的实施例中,反应温度为37℃,pH值为7.0~7.8,优选7.4;在另外一个具体的实施例中,透析膜分子粒径8000~12000Da,优选为10000Da。
在另外一个具体的实施例中,所述步骤3)中复合纳米颗粒溶解的终浓度为0.8~1.2mg/mL,优选为1mg/mL;在另外一个具体的实施方式中,所述的药物为化学药物,优选为抗肿瘤的化疗药物,最优选的为DOX;在另外一个具体的实施例中,所述的药物的终浓度为0.08~0.12mg/mL,优选为0.1mg/mL。
本发明的第三个方面提供一种温敏复合纳米颗粒的制备方法,所述的方法为:
(1)将CN和HBCOS分别溶于水中,将CN与HBCOS混合使CN与HBCOS的质量比为1:0.4-0.8,调节pH,形成复合纳米颗粒;
(2)加入京尼平,35℃~39℃反应24~72h,调pH后透析1~3天后冻干,得到交联后的复合纳米颗粒。
在一个优选的实施例中,所述的CN为浓度为0.5~1.5mg/mL,HBCOS的浓度为30-50mg/mL;在另外一个优选的实施例中,所述的CN与HBCOS的质量比为:1:0.4-0.8;在另外一个具体的实施例中,所述的pH值为5.8~6.5;
在另外一个具体的实施例中,步骤2)中京尼平的浓度为0.01-0.1mg/mL;在另外一个具体的实施例中,反应温度为37℃,pH值为7.0~7.8,优选7.4;在另外一个具体的实施例中,透析膜截留分子量为8000~12000Da,优选为10000Da。
本发明的第四个方面是提供一种载药的温敏复合纳米颗粒的制备方法,所述的方法为:
(1)将CN和HBCOS分别溶于水中,将CN与HBCOS混合使CN与HBCOS的质量比为1:0.4-0.8,调节pH,形成复合纳米颗粒;
(2)加入京尼平,35℃~39℃反应24~72h,调pH后透析1~3天后冻干,得到交联后的复合纳米颗粒;
(3)将步骤2)中制备的复合纳米颗粒用超纯水复溶,调pH,加入药物,避光条件下室温摇晃12~15h后用超纯水透析,透析袋的截留分子量为8000~12000a,每8~15h换一次透析液;将透析袋里的样品冻干,得到载药复合纳米颗粒。
在一个优选的实施例中,所述的步骤1)中CN为浓度为0.5~1.5mg/mL,HBCOS的浓度为30-50mg/mL;在另外一个优选的实施例中,所述的CN与HBCOS的质量比为:1:0.4-0.8;在另外一个具体的实施例中,所述的pH值为5.8~6.5;
在另外一个具体的实施例中,步骤2)中京尼平的浓度为0.01-0.1mg/mL优选的0.05mg/mL;在另外一个具体的实施例中,反应温度为37℃,pH值为7.0~7.8,优选7.4;在另外一个具体的实施例中,透析膜分子粒径8000~12000Da,优选为10000Da。
在另外一个具体的实施例中,所述步骤3)中复合纳米颗粒溶解的终浓度为0.8~1.2mg/mL,优选为1mg/mL;在另外一个具体的实施方式中,所述的药物为化学药物,优选为抗肿瘤的化疗药物,最优先的为DOX;在另外一个具体的实施例中,所述的药物的终浓度为0.08~0.12mg/mL,优选为0.1mg/mL。
本发明第五个方面是提供第一方面所述的温敏复合纳米颗粒或第三方面所述的温敏复合纳米颗粒的制备方法在制备药物组合物中的应用,具体的,所述的药物组合物中载有化学药物,优选的为抗肿瘤的化疗药物,更优选的为DOX。
本发明的有益效果为:
本发明首次利用CN和HBCOS溶解后加入交联剂京尼平,获得具有温度敏感的纳米颗粒,其本申请对于细胞具有低毒性和良好的生物相容性;
当获得的复合纳米颗粒作为载体与化疗药物混合制备获得载药复合纳米颗粒时,其具有良好的血液相容性以及温度敏感性;
由于CN容易被胰蛋白酶、胃蛋白酶、基质金属蛋白酶和组织蛋白酶B等水解,CN与其他材料复合后可以产生易于生物降解的材料。将HBCOS与CN通过静电相互作用结合得到复合纳米颗粒进行交联,可以得到稳定的温敏性复合纳米颗粒,可用于包埋DOX等抗肿瘤药物,实现载药纳米颗粒的温敏控制释放,治疗癌症。
附图说明
图1:复合纳米颗粒的温敏性:图1A,不同京尼平浓度的温敏检测;图1B,不同CN:HBCOS质量比构成的纳米颗粒温敏性检测。
图2复合纳米颗粒的稀释稳定性。
图3复合纳米颗粒的血液稳定性:图3A,纳米颗粒的血清稳定性;图3B,纳米颗粒的血液相容性。
图4载DOX复合纳米颗粒的响应释放。
图5载DOX复合纳米颗粒的抗癌活性:图5A,不同浓度的复合纳米颗粒的细胞毒性检测;图5B,负载DOX的复合纳米颗粒分别在37℃、42℃孵育24h后细胞存活率。
具体实施方式:
以下通过参考示范性实施例,本发明的目的和功能以及用于实现这些目的和功能的方法将得以阐明。然而,本发明并不受限于以下所公开的示范性实施例;可以通过不同形式来对其加以实现。说明书的实质仅仅是帮助相关领域技术人员综合理解本发明的具体细节。
实施例1羟丁基壳寡糖-酪蛋白酸钠聚电解质复合物的制备
1、CN-HBCOS复合纳米颗粒的制备
(1)溶解CN和HBCOS于水中,将1mg/mL的CN与HBCOS(40mg/mL)混合使CN与HBCOS的质量比为1:0.4-0.8,调pH至6.2,形成复合纳米颗粒。
(2)加入京尼平,使京尼平的浓度为0.01-0.1mg/mL,37℃反应48h,调pH至7.4后透析(10000Da)2天后冻干,得到交联后的复合纳米颗粒。
(3)温敏性检测
通过调整京尼平的浓度,观察复合纳米颗粒的温敏性,结果如图1A所示:通过比较复合纳米颗粒在37℃和42℃的粒径变化探究其温敏性,随着京尼平浓度的增加,复合纳米颗粒的温敏性先增加后下降,在京尼平浓度达到0.05mg/mL时其粒径变化最大,温敏性最强。
调整CN与HBCOS的质量比,观察纳米颗粒的温度敏感性,发现当HBCOS的浓度为0.4mg/mL时,复合纳米颗粒不具备温敏性;当HBCOS浓度达到0.5mg/mL以后,复合纳米颗粒出现温敏性(图1B)。
实施例2CN-HBCOS复合纳米颗粒的稳定性
1)稀释稳定性
通过测定复合纳米颗粒(CN:HBCOS=1:0.5,京尼平浓度为0.05mg/mL)在不同浓度和不同温度下的粒径来判断其在高度稀释下的稳定性情况。如图2所示,当复合纳米颗粒从1mg/mL稀释到0.1mg/mL之后,其粒径大小和温敏性均没有发现显著性差异。表明经过静电相互作用和共价交联形成的复合纳米颗粒的温敏性和稳定性不会受稀释过程的影响,可以在高稀释环境下发挥作用。
2)血清吸附实验
抗癌药物通过静脉注射需要保持其在血液中的稳定性。选择10%的胎牛血清来评估复合纳米颗粒在血清中的稳定性,以防止药物载体的非特异性蛋白质吸附。若纳米载体与血清蛋白发生吸附会导致纳米载体粒径的增加,因此采用动态光散射测定颗粒尺寸的变化进行稳定性评估。结果如图3A所示,复合纳米颗粒粒径在3天内没有增加,因此复合纳米颗粒在10%胎牛血清的存在下是稳定的。
3)溶血试验
评价复合纳米颗粒的血液相容性。溶血率表示与血液接触的物质破坏红细胞膜的程度,溶血率值越小,说明生物材料的血液相容性越好。将红细胞与不同浓度的复合纳米颗粒共孵育1h,结果如图3B所示,在所有的浓度范围内,复合纳米颗粒的溶血率均为负值。与其他研究人员采用PEG材料得到的结果类似。证明复合纳米颗粒具有良好的血液相容性。
实施例3载药CN-HBCOS复合纳米颗粒的制备
1)将实施例1制备获得的复合纳米颗粒用超纯水复溶至1mg/mL,调pH至7.4,加入4mg/mL的DOX使其浓度为0.1mg/mL,避光条件下室温摇晃12h后用500mL超纯水透析24h,透析袋的截留分子量为10000Da,每12h换一次透析液。将透析袋里的样品冻干,得到载DOX复合纳米颗粒。
2)纳米颗粒对药物包封率检测
表1复合纳米对DOX的包封
*CN的浓度为1mg/mL
复合纳米对DOX具有良好的包封率和载药量。
实施例4载药复合纳米颗粒温敏释放检测
对上述载DOX复合纳米颗粒进行释放测定,发现其释放动力学曲线具有温度响应特性,在高温下释放速率和释放量显著增加。
将载DOX复合纳米颗粒溶解于10mmol/L的磷酸盐缓冲液(pH7.4)中得到浓度为1mg/mL的溶液,取4mL样品置于透析袋(10000Da)中进行透析,透析液分别为pH 7.4和5.5的10mmol/L的磷酸盐缓冲液(透析体积为60mL),透析温度分别为37℃和42℃。分别于0.5、1、2、3、4、6、8小时取样3mL进行测定,测定波长为485nm。每次取样后加入同体积同pH的新鲜透析液。结果如图4所示,在37℃,pH 7.4时复合纳米载体中的药物在8小时内缓慢释放至36.5%。当温度从37℃增加到42℃,在pH 7.4条件下8小时内累积释放比从36.5%增加到41.0%,表明载药复合纳米颗粒可以对外部温度刺激作出反应,具有温敏性,因此在更高的温度下增强了药物的释放。同时,在释放初期,DOX的释放速率在42℃更快。在生理条件下(pH 7.4),复合纳米颗粒所带的负电荷较多,和DOX的静电相互作用较强,释放较弱。然而,在肿瘤组织或核内体/溶酶体(pH 6.5-5.0)所表现的酸性介质中,复合纳米颗粒中CN所带-COO-减少,同时HBCOS开始质子化,由此导致复合纳米颗粒与DOX的静电相互减弱,促进DOX的释放。在37℃,pH 5.5时,载药复合纳米颗粒中DOX在8小时内的释放达到46.9%,显著高于同等温度下pH 7.4时的释放程度,证明了低pH条件下质子的置换会促进DOX的释放,表现出pH响应性。复合纳米颗粒的温度响应在低pH下表现的更明显,在pH5.5时,42℃下载药纳米颗粒中的DOX会释放的更加迅速,在8小时内的释放也更加彻底,达到62.0%。
实施例5载DOX复合纳米颗粒与肿瘤细胞共孵育发现其抗肿瘤活性具有温度响应性
采用CCK-8试验评估复合纳米载体和载DOX复合纳米颗粒在结肠癌细胞HT-29细胞系中的体外细胞毒性。
将HT-29细胞以每孔2×104个细胞的密度接种于96孔培养板中,培养48h。然后用不同浓度的复合纳米载体(2-0.125mg/mL)处理细胞。孵育24h后,向每个孔中加入10μL的CCK-8溶液,孵育1h后用酶标仪在450nm和650nm下测定HBCOS处理和未处理(对照)样品的吸光度。用相对细胞活力评价细胞毒性,对照组为100%。
将载DOX复合纳米颗粒溶在pH7.4的磷酸缓冲液中溶解至包埋的DOX浓度为100μg/mL。加入到细胞培养基中使其浓度分别为10-0.625μg/mL,分别于37℃和42℃培养箱中培养24h后采用CCK-8测定细胞活性。结果如图5所示。
在测定载药复合纳米颗粒的体外抗癌活性之前,我们先测定了不同浓度复合纳米颗粒对结肠癌细胞HT-29细胞的细胞毒性。结果如图5A所示,在加入不同浓度的复合纳米颗粒以后,所有细胞活性仍保持在95%以上,表明复合纳米颗粒作为药物载体对细胞具有低毒性和良好的生物相容性。我们对载DOX复合纳米颗粒在不同温度下对HT-29细胞的细胞毒性也进行了评估。图5B显示了负载DOX的复合纳米颗粒分别在37℃、42℃孵育24h后细胞存活率。结果发现,载药纳米颗粒对HT-29细胞的毒性具有明显的浓度依赖性。HT-29细胞在37℃和42℃孵育24小时后细胞活性均高于90%,表明温度自身对细胞活性没有抑制作用。在DOX浓度较低(0.625μg/mL)时,不同温度下的细胞活性没有明显差异;当DOX浓度增加,42℃条件下孵育的载DOX的复合纳米颗粒对HT-29细胞的毒性显著高于在37℃条件下孵育的载药颗粒。这表明当温度高于复合纳米材料的相变温度时,载DOX的复合纳米颗粒的细胞毒性显著增强。这与载DOX复合纳米颗粒的释放曲线结果相一致,高温下较高的细胞毒性归因于DOX从复合纳米颗粒中更快地释放。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于此。在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,包括各个技术特征以任何其它的合适方式进行组合,这些简单变型和组合同样应当视为本发明所公开的内容,均属于本发明的保护范围。
Claims (10)
1.一种温敏复合纳米颗粒的制备方法,所述的纳米颗粒由羟丁基壳聚糖HBCOS和酪蛋白酸钠CN组成,具体由如下方法制备:
(1)将CN和HBCOS分别溶于水中,将CN与HBCOS混合使CN与HBCOS的质量比为1:0.4-0.8,调节pH,形成复合纳米颗粒;
(2)加入京尼平,35℃~39反应24~72h,调pH后透析1~3天后冻干,得到交联后的复合纳米颗粒。
2.根据权利要求1所述的温敏复合纳颗粒的制备方法,其中步骤1),所述的CN为浓度为0.5~1.5mg/mL,HBCOS的浓度为30-50mg/mL,所述的CN与HBCOS的质量比为:1:0.4-0.8;所述的pH值为5.8~6.5。
3.根据权利要求1或2所述的复合纳米颗粒的制备方法,其中步骤2)中京尼平的浓度为0.01-0.1mg/mL;pH值为7.0~7.8。
4.一种载药复合纳米颗粒的制备方法,所述载药复合纳米颗粒以如下方法制备,
(1)将CN和HBCOS分别溶于水中,将CN与HBCOS混合使CN与HBCOS的质量比为1:0.4-0.8,调节pH,形成复合纳米颗粒;
(2)加入京尼平,35℃~39反应24~72h,调pH后透析1~3天后冻干,得到交联后的复合纳米颗粒;
(3)将步骤(2)中制备的复合纳米颗粒用超纯水复溶,调pH,加入药物,避光条件下室温摇晃12~15h后用超纯水透析,每8~15h换一次透析液;将透析袋里的样品冻干,得到载药复合纳米颗粒。
5.根据权利要求4所述的载药复合纳米颗粒的制备方法,其中所述的步骤1)中CN为浓度为0.5~1.5mg/mL,HBCOS的浓度为30-50mg/mL;所述的CN与HBCOS的质量比为:1:0.4-0.8;所述的pH值为5.8~6.5。
6.根据权利要求4或5所述的载药复合纳米颗粒的制备方法,其中步骤2)中京尼平的浓度为0.01-0.1mg/mL,反应温度为37°C,pH值为7.0~7.8。
7.根据权利要求6所述的载药复合纳米颗粒的制备方法,其中所述步骤3)中复合纳米颗粒溶解的终浓度为0.8~1.2mg/mL;所述的药物为化学药物。
8.权利要求1-3任一项所述的方法制备获得的温敏复合纳米颗粒。
9.权利要求4-7任一项所述的方法制备获得的载药复合纳米颗粒。
10.权利要求1-3任一项所述的方法、权利要求4-7任一项所述的方法、权利要求8所述的温敏复合纳米颗粒或者权利要求9所述的载药复合纳米颗粒在制备治疗肿瘤的药物中的应用。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310583091.5A CN116459232B (zh) | 2023-05-23 | 2023-05-23 | 一种温敏载药复合纳米颗粒的制备及应用 |
NL2037729A NL2037729A (en) | 2023-05-23 | 2024-05-21 | Preparation and applications of temperature-sensitive drug-loading composite nanoparticles |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310583091.5A CN116459232B (zh) | 2023-05-23 | 2023-05-23 | 一种温敏载药复合纳米颗粒的制备及应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN116459232A true CN116459232A (zh) | 2023-07-21 |
CN116459232B CN116459232B (zh) | 2023-10-24 |
Family
ID=87173839
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310583091.5A Active CN116459232B (zh) | 2023-05-23 | 2023-05-23 | 一种温敏载药复合纳米颗粒的制备及应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN116459232B (zh) |
NL (1) | NL2037729A (zh) |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101284884A (zh) * | 2008-02-19 | 2008-10-15 | 上海其胜生物材料技术研究所有限公司 | 一种温敏性壳聚糖衍生物-羟丁基壳聚糖的制备方法 |
CN103494775A (zh) * | 2013-09-17 | 2014-01-08 | 南昌大学 | 京尼平交联壳聚糖载药微球的制备方法 |
CN103705938A (zh) * | 2013-12-26 | 2014-04-09 | 南京农业大学 | 一种耐胃酸的多肽-多糖纳米颗粒及其制备方法 |
CN105381472A (zh) * | 2015-12-08 | 2016-03-09 | 华南农业大学 | 月见草素b-酪蛋白磷酸肽-壳聚糖纳米粒及制备方法与应用 |
CN108310460A (zh) * | 2018-02-02 | 2018-07-24 | 武汉大学 | 可注射高强度温敏性改性甲壳素基水凝胶及其制备方法和应用 |
CN112159533A (zh) * | 2020-09-24 | 2021-01-01 | 长春工业大学 | 一种酪蛋白酸钠/羧甲基壳聚糖导电粘韧水凝胶及其制备方法 |
CN114868916A (zh) * | 2022-03-18 | 2022-08-09 | 江南大学 | 姜黄素/抗坏血酸稳定化核-壳粒子及其制备方法 |
WO2022227700A1 (zh) * | 2021-04-27 | 2022-11-03 | 江苏大学 | 负载生物活性成分的蛋白肽-多糖纳米颗粒的超声波制备方法 |
-
2023
- 2023-05-23 CN CN202310583091.5A patent/CN116459232B/zh active Active
-
2024
- 2024-05-21 NL NL2037729A patent/NL2037729A/en unknown
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101284884A (zh) * | 2008-02-19 | 2008-10-15 | 上海其胜生物材料技术研究所有限公司 | 一种温敏性壳聚糖衍生物-羟丁基壳聚糖的制备方法 |
CN103494775A (zh) * | 2013-09-17 | 2014-01-08 | 南昌大学 | 京尼平交联壳聚糖载药微球的制备方法 |
CN103705938A (zh) * | 2013-12-26 | 2014-04-09 | 南京农业大学 | 一种耐胃酸的多肽-多糖纳米颗粒及其制备方法 |
CN105381472A (zh) * | 2015-12-08 | 2016-03-09 | 华南农业大学 | 月见草素b-酪蛋白磷酸肽-壳聚糖纳米粒及制备方法与应用 |
CN108310460A (zh) * | 2018-02-02 | 2018-07-24 | 武汉大学 | 可注射高强度温敏性改性甲壳素基水凝胶及其制备方法和应用 |
CN112159533A (zh) * | 2020-09-24 | 2021-01-01 | 长春工业大学 | 一种酪蛋白酸钠/羧甲基壳聚糖导电粘韧水凝胶及其制备方法 |
WO2022227700A1 (zh) * | 2021-04-27 | 2022-11-03 | 江苏大学 | 负载生物活性成分的蛋白肽-多糖纳米颗粒的超声波制备方法 |
CN114868916A (zh) * | 2022-03-18 | 2022-08-09 | 江南大学 | 姜黄素/抗坏血酸稳定化核-壳粒子及其制备方法 |
Non-Patent Citations (2)
Title |
---|
WEI Y, 等: "Structure formation in pH-sensitive hydrogels composed of sodium caseinate and N, O-carboxymethyl chitosan", INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, vol. 89, pages 353, XP029601592, DOI: 10.1016/j.ijbiomac.2016.04.081 * |
王广宇: "酪蛋白/壳聚糖复合水凝胶的制备及性能研究", 《中国优秀硕士学位论文全文数据库(工程科技Ⅰ辑)》, vol. 2023, pages 1 - 62 * |
Also Published As
Publication number | Publication date |
---|---|
NL2037729A (en) | 2024-06-11 |
CN116459232B (zh) | 2023-10-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Wang et al. | pH-Controlled drug delivery with hybrid aerogel of chitosan, carboxymethyl cellulose and graphene oxide as the carrier | |
Polk et al. | Controlled release of albumin from chitosan-alginate microcapsules | |
Wu et al. | Chitosan nanoparticles as a novel delivery system for ammonium glycyrrhizinate | |
Deng et al. | Green preparation process, characterization and antitumor effects of doxorubicin–BSA–dextran nanoparticles | |
Tian et al. | Diselenide-crosslinked zwitterionic nanogels with dual redox-labile properties for controlled drug release | |
Barbari et al. | RETRACTED ARTICLE: A novel nanoemulsion-based method to produce ultrasmall, water-dispersible nanoparticles from chitosan, surface modified with cell-penetrating peptide for oral delivery of proteins and peptides | |
Trusek et al. | Graphene oxide as a potential drug carrier–Chemical carrier activation, drug attachment and its enzymatic controlled release | |
WO2012153286A1 (en) | Polymeric nanoparticles for drug delivery | |
Verma et al. | Release kinetics from bio-polymeric nanoparticles encapsulating protein synthesis inhibitor-cycloheximide, for possible therapeutic applications | |
Hellmers et al. | Characterization and in vitro cytotoxicity of doxorubicin-loaded γ-polyglutamic acid-chitosan composite nanoparticles | |
Dang et al. | Characterization and biocompatibility of injectable microspheres-loaded hydrogel for methotrexate delivery | |
Shi et al. | Preparation of glucose responsive polyelectrolyte capsules with shell crosslinking via the layer-by-layer technique and sustained release of insulin | |
Chen et al. | Overcoming multidrug resistance of breast cancer cells by the micellar doxorubicin nanoparticles of mPEG-PCL-graft-cellulose | |
Wu et al. | A novel methotrexate delivery system based on chitosan-methotrexate covalently conjugated nanoparticles | |
Xing et al. | Topotecan hydrochloride liposomes incorporated into thermosensitive hydrogel for sustained and efficient in situ therapy of H22 tumor in Kunming mice | |
Shikida et al. | Arginine-conjugated chitosan nanoparticles for topical arginine release in wounds | |
Zashikhina et al. | Multilayered particles based on biopolyelectrolytes as potential peptide delivery systems | |
Liu et al. | Surface charge switchable and core cross-linked polyurethane micelles as a reduction-triggered drug delivery system for cancer therapy | |
Pourmadadi et al. | Synthesis and characterization of biological macromolecules double emulsion based on carboxymethylcellulose/gelatin hydrogel incorporated with ZIF-8 as metal organic frameworks for sustained anti-cancer drug release | |
CN116459232B (zh) | 一种温敏载药复合纳米颗粒的制备及应用 | |
CN116459231B (zh) | 一种温敏载药核壳纳米颗粒的制备及应用 | |
Sarkar et al. | Development and in-vitro characterisation of chitosan loaded paclitaxel nanoparticle | |
Abolhasani et al. | Development and characterization of chitosan nanoparticles containing an indanonic tricyclic spiroisoxazoline derivative using ion-gelation method: an in vitro study | |
Yu et al. | Release of paclitaxel from pH sensitive and biodegradable dextran based hydrogels | |
Esfahani et al. | Optimized preparation of lysozyme loaded dextran-chitosan nanoparticles using D-optimal design |
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 |