目的 基于肿瘤细胞的同源靶向性,拟构建一种脑胶质瘤U251细胞膜包覆介孔二氧化硅纳米粒(mesoporous silica nanoparticles,MSN)的仿生递药系统(U251/MSN),以化疗药物多柔比星(doxorubicin,DOX)为模型药物,初步评价其在胶质瘤靶向治疗中的应用可能。方法 使用共挤出法制备U251/MSN-DOX。对纳米粒的粒径、电位、形态进行表征;测定其载药量与包封率;考察纳米粒的细胞毒性、比较包膜前后纳米粒以及不同细胞膜仿生纳米粒在胶质瘤细胞U251中的摄取差异;并通过构建体外血脑屏障(brain-blood barrier,BBB)模型考察仿生纳米粒的跨膜转运效率。结果 仿生纳米粒U251/MSN呈球形,可观察到明显的“核壳”结构,粒径为(135.70±3.85)nm,载药量为(18.57±2.17)%,包封率为(64.99±2.52)%,细胞实验表明,U251/MSN-DOX细胞毒性低,且较MSN-DOX以及非同源细胞膜纳米粒具备更强的靶向性和跨BBB效率。结论 胶质瘤细胞膜可通过共挤出法有效包覆在MSN表面,制备的仿生纳米粒具有良好的靶向性和跨BBB能力,显示出在肿瘤靶向,特别是脑部肿瘤靶向递药领域的应用价值。
Abstract
OBJECTIVE To construct a biomimetic delivery system (U251/MSN-DOX), and assess its application of glioma targeted therapy. METHODS U251 cell membrane was coated on the surface of mesoporous silica nanoparticles(MSN) by co-extrusion to prepare cell membrane biomimetic nanoparticles U251/MSN-DOX. The particle size, potential and morphology were characterized. The physical characteristics, loading content (LC) and encapsulation efficiency (EE) of these nanoparticles were determined. Their toxicity of normal cells was investigated. Their cellular uptake of different formulations in U251 was studied by flow cytometry and fluorescence confocal microscope. Additionally, we assessed the transmembrane transport efficiency of nanoparticles via in vitro BBB. RESULTS The cell membrane-coated nanoparticles U251/MSN were spherical, and a distinct "core-shell" structure could be observed. The particle size was (135.70±3.85) nm, the LC was (18.57±2.17)%, and the EE was (64.99±2.52)%. The cell experiment showed that U251/MSN had low cytotoxicity and U251/MSN-DOX exhibited stronger cellular uptake ability and BBB transporting efficiency. CONCLUSION The glioma cell membrane can be coated on the surface of MSN to construct biomimetic nanoparticles U251/MSN. The biomimetic nanoparticles not only are capable of targeting the homologous tumor cells, but also show the enhanced ability to penetrate BBB, which indicate potential applications in the field of tumor targeted drug delivery especially in brain tumor.
关键词
胶质瘤 /
细胞膜仿生递药系统 /
介孔二氧化硅纳米粒 /
血脑屏障 /
靶向
{{custom_keyword}} /
Key words
glioma /
cell membrane-coated drug delivery system /
mesoporous silica nanoparticles /
blood-brain barrier /
targeting
{{custom_keyword}} /
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] RASMUSSEN B K, HANSEN S, LAURSEN R J, et al. Epidemiology of glioma:clinical characteristics, symptoms, and predictors of glioma patients grade Ⅰ-Ⅳ in the the danish neuro-oncology registry[J]. J Neuro-Oncol, 2017, 135 (3):571-579.
[2] MADDAHI Y, ZAREINIA K, GAN L S, et al. Treatment of glioma using neuroarm surgical system[J]. Biomed Res Int, 2016:9734512.
[3] KARIM R, PALAZZO C, EVRARD B, et al. Nanocarriers for the treatment of glioblastoma multiforme:current state-of-the-art. [J]. J Controlled Release, 2016, 227:23-37.
[4] ZHANG H, ZHANG W, ZHOU Y, et al. Dual functional mesoporous silicon nanoparticles enhance the radiosensitivity of VPA in glioblastoma[J]. Transl Oncol, 2017, 10 (2):229-240.
[5] ABUL B, SARWAR B, SUNIL K P, et al. Functionalized mesoporous silica nanoparticles in anticancer therapeutics[J]. Seminars Cancer Biol, 2019. Doi:10. 1016/j. semcancer. 2019. 08. 022.
[6] BENEZRA M, PENATE-MEDINA O, ZANZONICO P B, et al. Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma[J]. J Clin Invest, 2011, 121 (7):2768-2780.
[7] MO J, HE L, MA B, et al. Tailoring particle size of mesoporous silica nanosystem to antagonize glioblastoma and overcome blood-brain barrier[J]. ACS Appl Mater Interfaces, 2016, 8 (11):6811-6825.
[8] JIAO X X, HU C L, HE M, et al. Preparation and in vitro evaluation of angiopep-2-modifed brain-targeting polypeptide micelles [J]. Acad J Sec Mil Univ(第二军医大学学报), 2018, 39(4): 411-419.
[9] MONACO I, CAMORANI S, COLECCHIA D, et al. Aptamer functionalization of nanosystems for glioblastoma targeting through the blood-brain barrier[J]. J Med Chem, 2017, 60 (10):4510-4516.
[10] SU J, SUN H, MENG Q, et al. Enhanced blood suspensibility and laser-activated tumor-specific drug release of theranostic mesoporous silica nanoparticles by functionalizing with erythrocyte membranes[J]. Theranostics, 2017, 7 (3):523-537.
[11] YOO J W, IRVINE D J, DISCHER D E, et al. Bio-inspired, bioengineered and biomimetic drug delivery carriers[J]. Nat Rev Drug Dis, 2011, 10 (7):521-535.
[12] FANG R H, JIANG Y, FANG J C, et al. Cell membrane-derived nanomaterials for biomedical applications[J]. Biomaterials, 2017, 128:69-83.
[13] SU J, SUN H, MENG Q, et al. Long circulation red-blood-cell-mimetic nanoparticles with peptide-enhanced tumor penetration for simultaneously inhibiting growth and lung metastasis of breast cancer[J]. Adv Funct Mater, 2016, 26 (8):1243-1252.
[14] HU C M J, FANG R H, WANG K C, et al. Nanoparticle biointerfacing by platelet membrane cloaking[J]. Nature, 2015, 526 (7571):118-121.
[15] PARODI A, QUATTROCCHI N, VAN DE VEN A L, et al. Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions[J]. Nat Nanotechnol, 2013, 8 (1):61-68.
[16] BOSE R J, PAULMURUGAN R, MOON J, et al. Cell membrane-coated nanocarriers:the emerging targeted delivery system for cancer theranostics[J]. Drug Dis Today, 2018, 23 (4):891-899.
[17] KHALDOYANIDI S K, GLINSKY V V, SIKORA L, et al. MDA-MB-435 human breast carcinoma cell homo-and heterotypic adhesion under flow conditions is mediated in part by Thomsen-Friedenreich antigen-galectin-3 interactions[J]. J Biol Chem, 2003, 278 (6):4127-4134.
[18] SUN H, SU J, MENG Q, et al. Cancer-cell-biomimetic nanoparticles for targeted therapy of homotypic tumors[J]. Adv Mater, 2016, 28 (43):9581-9588.
[19] LI S Y, CHENG H, QIU W X, et al. Cancer cell membrane-coated biomimetic platform for tumor targeted photodynamic therapy and hypoxia-amplified bioreductive therapy[J]. Biomaterials, 2017, 142:149-161.
[20] MAJETI R, CHAO M P, ALIZADEH A A, et al. CD47 Is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells[J]. Cell, 2009, 138 (2):286-299.
[21] CAO H Q, DAN Z L, HE X Y, et al. Liposomes coated with isolated macrophage membrane can target lung metastasis of breast cancer [J]. ACS Nano, 2016,10(8):7738-7748.
[22] WANG L S, WU L C, LU S Y, et al. Biofunctionalized phospholipid-capped mesoporous silica nanoshuttles for targeted drug delivery:improved water suspensibility and decreased nonspecific protein binding[J]. ACS Nano, 2010, 4(8):4371-4379.
[23] BOUCHOUCHA M, C-GAUDREAULT R, FORTIN M A, et al. Mesoporous silica nanoparticles: selective surface functionalization for optimal relaxometric and drug loading performances[J]. Adv Funct Mater, 2014, 24(37):5911-5923.
[24] LIU W, WANG F, ZHU Y, et al. Galactosylated chitosan-functionalized mesoporous silica nanoparticle loading by calcium leucovorin for colon cancer cell-targeted drug delivery[J]. Molecules, 2018, 23(12):3082.
[25] HAN N, WANG Y, BAI J L, et al. Facile synthesis of the lipid bilayer coated mesoporous silica nanocomposites and their application in drug delivery[J]. Microporous and Mesoporous Materials, 2015, 219:209-218.
[26] SU J H, SUN H P,MENG Q S,et al. Enhanced blood suspensibility and laser-activated tumor-specific drug release of theranostic mesoporous silica nanoparticles by functionalizing with erythrocyte membranes[J]. Theranostics, 2017,7(3):523-537.
[27] SUN H P, SU J H, MENG Q S, et al. Cancer-cell-biomimetic nanoparticles for targeted therapy of homotypic tumors[J]. Adv Mater, 2016, 28(43):9581-9588.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
基金
国家自然科学基金面上项目资助(81472349);上海市科委自然科学基金项目资助(14ZR1433300);上海交通大学医工交叉项目资助(0507N17014);松江区科技攻关项目资助(18sjkjgg33);国家自然科学基金青年科学基金资助(81703051)
{{custom_fund}}
PDF(6292 KB)
