Angiopep-2修饰核-壳介孔二氧化硅脂质囊纳米粒的制备及体外评价

王国伟,费伟东,张蓉蓉,郭曼曼,徐骏军,李范珠

中国药学杂志 ›› 2015, Vol. 50 ›› Issue (9) : 775-783.

PDF(2191 KB)
PDF(2191 KB)
中国药学杂志 ›› 2015, Vol. 50 ›› Issue (9) : 775-783. DOI: 10.11669/cpj.2015.09.010
·论 著·

Angiopep-2修饰核-壳介孔二氧化硅脂质囊纳米粒的制备及体外评价

  • 王国伟,费伟东,张蓉蓉,郭曼曼,徐骏军,李范珠*
作者信息 +

Preparation and in Vitro Evaluation of Paclitaxel-loaded Core-Shell Structural Phospholipid-Functionalized Mesoporous Silica Nanoparticles Modified with Angiopep-2

  • WANG Guo-wei, FEI Wei-dong, ZHANG Rong-rong, GUO Man-man, XU Jun-jun, LI Fan-zhu*
Author information +
文章历史 +

摘要

目的 制备angiopep-2修饰核-壳结构介孔二氧化硅脂质囊纳米粒(ANG-MSN-LP),并进行体外评价。方法 采用Stober法制备介孔二氧化硅纳米粒(MSN),改进了溶液吸附法来制备载紫杉醇(PTX)的介孔二氧化硅纳米粒(MSN-PTX),然后以载紫杉醇的介孔二氧化硅纳米粒为核,运用自组装和薄膜水化法构建核-壳结构的angiopep-2修饰介孔二氧化硅脂质囊纳米粒(ANG-MSN-LP-PTX),透析袋法考察体外释药特性,噻唑蓝(MTT)法考察载体对人脑微毛细血管内皮细胞(HBMEC)和C6的细胞毒性,建立体外血脑屏障(BBB)模型研究载体对紫杉醇的跨膜转运能力和对C6细胞周期的影响。结果 介孔二氧化硅纳米粒粒径为(94.61±3.91) nm,比表面积(SBET)为425 m2·g-1,孔容积(Vp)为0.37 cm3·g-1,孔径3.5 nm。介孔二氧化硅纳米粒在紫杉醇的饱和溶液中反复吸附7次时达到平衡,载药量高达11.1%。Angiopep-2修饰介孔二氧化硅脂质囊纳米粒分布均一,无团聚现象,具有明显的核-壳结构,粒径(106.37±3.76) nm,并且在0~10 μg·mL-1范围内对HBMEC和C6细胞具有良好的安全性和生物相容性。Angiopep-2修饰介孔二氧化硅脂质囊纳米粒体外释药48 h内的累积释放率达到75.5%,突释现象降低,具有明显的缓释特性;跨膜血脑屏障转运12 h后,对紫杉醇转运率高达10.74%;在细胞周期实验中,使C6细胞滞留在G2-M期细胞数比例为(40.92±6.20)%,显著高于各对照组数倍。结论 Angiopep-2修饰介孔二氧化硅脂质囊纳米粒是一种优良的递药载体并有望应用于脑胶质瘤的治疗;反复饱和溶液吸附法可有效提高药物载药量,值得应用和借鉴。

Abstract

OBJECTIVE To prepare and evaluate the novel core-shell structural phospholipid-functionalized mesoporous silica nanoparticles (MSN-LP) modified with angiopep-2 (ANG-MSN-LP). METHODS Mesoporous silica nanoparticles (MSN) was synthesized by the modified Stober method. MSN-PTX was prepared by saturated solution adsorption method. ANG-MSN-LP was developed by selfassembly and film hydration method. By using dialysis bag method to investigate the in vitro drug release characteristics and MTT method to investigate the cytotoxicity on HBMEC and C6 cells. The transport ability and effects on cell cycle of the carrier was investigated by the BBB monolayer model. RESULTS MSN was synthesized with high specific surface area (SBET, 425 m2·g-1), cumulative pore volume (Vp, 0.37 cm3·g-1) and pore size(3.5 nm). PTX was highly encapsulated (drug loading efficiency up to 11.1%) into MSN. Results of in vitro release showed that about 75.5% of PTX released from ANG-MSN-LP-PTX after 48 h and burst release was effectively reduced compared with MSN-PTX or PTX solution, indicating pronounced sustained-release characteristics. The good biocompatibility and low toxicity of ANG-MSN-LP were evaluated by HBMEC and C6 cells. The transport ratio was 2.49% for PTX, 2.72% for MSN-PTX, 4.45% for MSN-LP-PTX and 10.74% for ANG-MSN-LP-PTX respectively. In addition, ANG-MSN-LP-PTX showed a higher cell number of G2-M phase of 40.92±6.20%. CONCLUSION ANG-MSN-LP is a prospective targeting drug delivery system for therapy of brain glioma. Meanwhile, saturated solution adsorption method can increase the drug loading efficiency highly.

关键词

介孔二氧化硅 / angiopep-2 / 溶液吸附法 / 血脑屏障 / 脑胶质瘤 / 体外评价

Key words

mesoporous silica nanoparticles / angiopep-2

引用本文

导出引用
王国伟,费伟东,张蓉蓉,郭曼曼,徐骏军,李范珠. Angiopep-2修饰核-壳介孔二氧化硅脂质囊纳米粒的制备及体外评价[J]. 中国药学杂志, 2015, 50(9): 775-783 https://doi.org/10.11669/cpj.2015.09.010
WANG Guo-wei, FEI Wei-dong, ZHANG Rong-rong, GUO Man-man, XU Jun-jun, LI Fan-zhu. Preparation and in Vitro Evaluation of Paclitaxel-loaded Core-Shell Structural Phospholipid-Functionalized Mesoporous Silica Nanoparticles Modified with Angiopep-2[J]. Chinese Pharmaceutical Journal, 2015, 50(9): 775-783 https://doi.org/10.11669/cpj.2015.09.010
中图分类号: R944   

参考文献

[1] ALLARD E, PASSIRANI C, BENOIT J P. Convection-enhanced delivery of nanoparticles for the treatment for brain tumors . Biomaterials, 2009,30(12):2302-2318.
[2] OSTROM Q T, BAUCHET L, DAVIS F G, et al. The epidemiology of glioma in adults: A “state of the science” review . Neuro Oncol, 2014, 16(17):896-913.
[3] GAN C W, FENG S S. Transferrin-conjugated nanoparticles of poly(lactide)-D-alpha-tocopheryl polyethylene glycol succinate diblock copolymer for targeted drug delivery across the blood-brain barrier . Biomaterials, 2010, 31(30):7748-7757.
[4] HUANG R Q, MA H J, GUO Y B, et al. Angiopep-Conjugated Nanoparticles for Targeted Long-Term Gene Therapy of Parkinson′s disease . Pharm Res, 2013, 30(10):2549-2559.
[5] DEMEULE M, RGINA A, CHC, et al. Identification and design of peptides as a new drug delivery system for the brain . J Pharmacol Exp Ther, 2008, 324(3):1064-1072.
[6] REN J, SHEN S, WANG D, et al. The targeted delivery of anticancer drugs to brain glioma by PEGylated oxidized multi-walled carbon nanotubes modified with angiopep-2 . Biomaterials, 2012,33(11):3324-3333.
[7] NIU D C, LIU Z J, LI Y S, et al. Monodispersed and Ordered Large-Pore Mesoporous Silica Nanospheres with Tunable Pore Structure for Magnetic Functionalization and Gene Delivery . Adv Mater, 2014,26(29):4947-4953.
[8] WU S H, MOU C Y, LIN H P. Synthesis of mesoporous silica nanoparticles . Chem Soc Rev, 2013, 42(9):3862-3875.
[9] 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 . ACS Nano, 2010,4(8):4371-4379.
TENG I T, CHANG Y J, WANG L S, et al. Phospholipid- functionalized mesoporous silica nanocarriers for selective photodynamic therapy of cancer . Biomaterials, 2013,34(30):7462-7470.
ZHANG Z, MCGORON AJ, CRUMPLER ET, et al. Co-culture based blood-brain barrier in vitro model, a tissue engineering approach using immortalized cell lines for drug transport study . Appl Biochem Biotechnol, 2011,163(2):278-295.
DU JU, LU W L, YING X, et al. Dual-targeting topotecan liposomes modified with tamoxifen and wheat germ agglutinin significantly improve drug transport across the blood-brain barrier and survival of brain tumor-bearing animals . Mol Pharm, 2009, 6(3):905-917.
REN J F, SHEN S, WANG D G, et al. The targeted delivery of anticancer drugs to brain glioma by PEGylated oxidized multi-walled carbon nanotubes modified with angiopep-2 . Biomaterials,2012, 33(11):3324-3333.
JULIE T, ANNE-LISE T, LAURENT D, et al. Steric Stabilization of Lipid/Polymer Particle Assemblies by Poly(ethylene glycol)-Lipids . Biomacromolecules,2007,8(11):3651-3660.
LIANG L, LIN S W, DAI W B, et al. Novel cathepsin B-sensitive paclitaxel conjugate: Higher water solubility, better efficacy and lower toxicity . J Controlled Release, 2012, 160(3):618-629.
RGINA A, DEMEULE M, CHC, et al. Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2. Br J Pharmacol, 2008, 155(2):185-197.
HUWYLER J, WU D F. Brain drug delivery of small molecules using immunoliposomes . Proc Natl Acad Sci USA,1996, 93(24):14164-14169.
HAO N J, YANG H H, LI L F, et al. The shape effect of mesoporous silica nanoparticles on intracellular reactive oxygen species in A375 cells . New J Chem, 2014, 38(9):4258-4266.
FISICHELLA M, DABBOUE H, BHATTACHARYYA S, et al. Uptake of Functionalized Mesoporous Silica Nanoparticles by Human Cancer Cells. J Nanosci Nanotechnol, 2010, 10(4):2314-2324.
ROBERTS A D, ZHANG H. Poorly water-soluble drug nanoparticles via solvent evaporation in water-soluble porous polymers . Int J Pharm, 2013, 447(1-2):251-250.
YONCHEVA K, POPOVA M, SZEGEDI A, et al. Functionalized mesoporous silica nanoparticles for oral delivery of budesonide . J Solid State Chem, 2014, 211(12):154-161.

基金

国家自然科学基金资助项目(81274089、81473361);浙江省自然科学基金资助项目(LZ13H280001)
PDF(2191 KB)

Accesses

Citation

Detail

段落导航
相关文章

/