透明质酸修饰的载阿霉素多壁碳纳米管递药系统的制备及体外评价
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摘要
目的:制备透明质酸修饰的载阿霉素多壁碳纳米管主动靶向递药系统,并考察其对乳腺癌的抑制作用。方法:将阿霉素(DOX)通过π-π键相互作用负载于氨基化多壁碳纳米管(NH_2-MCNTs)上,构建被动递药系统(DOX-MCNTs);使用透明质酸(HA)对DOX-MCNTs进行修饰,构建主动靶向递药系统(HADOX-MCNTs)。对递药系统的粒径及Zeta电位、包封率、载药量及体外释放等进行了考察,采用人乳腺癌MDA-MB-231细胞进行了体外细胞摄取、细胞毒性和细胞划痕愈合评价。结果:HA-DOX-MCNTs的平均粒径为(349. 9±1. 5) nm; DOX-MCNTs对阿霉素的包封率为61. 2%,载药量为23. 4%; DOX-MCNTs经HA修饰后,DOX的释放量随着时间的延长持续提高,24 h释放率达到28. 6%;与DOX-MCNTs组相比,HA-DOXMCNTs组细胞摄取DOX的量更多; HA-DOX-MCNTs的细胞毒作用是DOX-MCNTs的3. 78倍; HA-DOX-MCNTs能够显著降低MDA-MB-231细胞的迁移能力。结论:HA修饰的载阿霉素多壁碳纳米管靶向递药系统制备成功,有用于肿瘤靶向治疗的潜力。
Objective: To develop a hyaluronic acid( HA)-modified doxorubicin( DOX)-loaded active targeting drug delivery system( HA-DOX-MCNTs) and investigate its inhibitory effect on breast cancer cells.Methods: DOX was loaded into the amino multi-walled carbon nanotubes( NH_2-MCNTs) by π-π stacking interactions to construct a passive targeting drug delivery system( DOX-MCNTs). Then,HA was used to modify DOX-MCNTs to construct an active targeting drug delivery system( HA-DOX-MCNTs). The particle size and zeta potential,encapsulation efficiency,drug loading,and in vitro release profiles of HA-DOX-MCNTs were evaluated; assay of in vitro cellular uptake,cytotoxicity and wound healing of HA-DOX-MCNTs was performed on MDA-MB-231 cells.Results: The average particle size of HA-DOX-MCNTs was( 349. 9 ± 1. 5) nm. The encapsulation efficiency of DOX-MCNTs was 61. 2%,and the drug-loading rate was 23. 4%. The release rate of DOX from HA-DOX-MCNTs( 28. 6% within 24 h) was higher than that from DOX-MCNTs. Higher cellular uptake efficiency of DOX was observed in the HA-DOX-MCNTs group compared with DOX-MCNTs group. HA-DOX-MCNTs displayed 2. 78 fold higher cytotoxicity than DOX-MCNTs against MDA-MB-231 cells in vitro. HA-DOX-MCNTs had stronger inhibitory effect on the migration of MDA-MB-231 cells than DOX-MCNTs. Conclusion: HA-modified DOX-loaded multiwalled carbon nanotube targeting drug delivery system has been successfully prepared,and it might be a potentialformulation for targeting cancer therapy.
Objective: To develop a hyaluronic acid( HA)-modified doxorubicin( DOX)-loaded active targeting drug delivery system( HA-DOX-MCNTs) and investigate its inhibitory effect on breast cancer cells.Methods: DOX was loaded into the amino multi-walled carbon nanotubes( NH_2-MCNTs) by π-π stacking interactions to construct a passive targeting drug delivery system( DOX-MCNTs). Then,HA was used to modify DOX-MCNTs to construct an active targeting drug delivery system( HA-DOX-MCNTs). The particle size and zeta potential,encapsulation efficiency,drug loading,and in vitro release profiles of HA-DOX-MCNTs were evaluated; assay of in vitro cellular uptake,cytotoxicity and wound healing of HA-DOX-MCNTs was performed on MDA-MB-231 cells.Results: The average particle size of HA-DOX-MCNTs was( 349. 9 ± 1. 5) nm. The encapsulation efficiency of DOX-MCNTs was 61. 2%,and the drug-loading rate was 23. 4%. The release rate of DOX from HA-DOX-MCNTs( 28. 6% within 24 h) was higher than that from DOX-MCNTs. Higher cellular uptake efficiency of DOX was observed in the HA-DOX-MCNTs group compared with DOX-MCNTs group. HA-DOX-MCNTs displayed 2. 78 fold higher cytotoxicity than DOX-MCNTs against MDA-MB-231 cells in vitro. HA-DOX-MCNTs had stronger inhibitory effect on the migration of MDA-MB-231 cells than DOX-MCNTs. Conclusion: HA-modified DOX-loaded multiwalled carbon nanotube targeting drug delivery system has been successfully prepared,and it might be a potentialformulation for targeting cancer therapy.
引文
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[15] KIM S,PARK J,YOUN YS,et al. Hoechst 33258-conjugated hyaluronated fullerene for efficient photodynamic tumor therapy and necrotic tumor targeting[J]. J Bioact Compat Pol,2015,30(3):275-288.
[2] LIN CY,JAVADI M,BELNAP DM,et al. Ultrasound sensitive e Liposomes containing doxorubicin for drug targeting therapy[J].Nanomedicine,2014,10(1):67-76.
[3]陶磊,申夏夏,朱利民.含乳糖酸修饰的多壁碳纳米管复合载药体系的合成及表征[J].功能高分子学报,2014,27(4):392-398.
[4] HOU L,YUAN Y,REN J. In vitro and in vivo comparative study of the phototherapy anticancer activity of hyaluronic acid-modified single-walled carbon nanotubes,graphene oxide,and fullerene[J]. J Nanopart Res,2017,19(8):286-303.
[5]田佳,刘思思,黎雁英,等.叶酸-壳聚糖-碳纳米管-顺铂复合物对卵巢癌细胞的体外抑瘤效应[J].临床与实验病理学杂志,2016,32(6):669-673.
[6] LI Z,DE BALB,SOARES DCF,et al. Functionalized singlewalled carbon nanotubes:cellular uptake,biodistribution and applications in drug delivery[J]. Int J Pharmaceut,2017,524(1-2):41-54.
[7] BRAHMACHARI S,GHOSH M,DUTTA S,et al. Biotinylated amphiphile-single walled carbon nanotube conjugate for targetspecific delivery to cancer cells[J]. J Mater Chem B,2014,2(9):1160-1173.
[8] LI JC,HE Y,SUN WJ,et al. Hyaluronic acid-modified hydrothermally synthesized iron oxide nanoparticles for targeted tumor MR imaging[J]. Biomaterials,2014,35(11):3666-3677.
[9]傅超萍,张黎明.基于透明质酸的抗肿瘤药物载体研究进展[J].高分子通报. 2019,2:103-111.
[10] SINGH BK,VERMA K,PANIGRAHI L,et al. Integrating radiologist feedback with computer aided diagnostic systems for breast cancer risk prediction in ultrasonic images:an experimental investigation in machine learning paradigm[J]. Expert Syst Appl,2017,90:209-223.
[11]彭文绣,杜小莉.乳腺癌靶向治疗新药ribociclib[J].中国新药杂志,2018,27(1):8-11.
[12] KANG B,LI J,CHANG S,et al. Tracking of drug release from carbon nanotube vehicles in living cells[J]. Small,2012,8(5):777-782.
[13] CALAF GM,PONCE-CUSI R,ABRCA-QUINONES J. Effect of curcumin on the cell surface markers CD44 and CD24 in breast cancer[J]. Oncol Rep,2018,39(6):2741-2748.
[14] MO Y,WANG H,LIU J,et al. Controlled release and targeted delivery to cancer cells of doxorubicin from polysaccharide-functionalised single-walled carbon nanotubes[J]. J Mater Chem B,2015,3(9):1846-1855.
[15] KIM S,PARK J,YOUN YS,et al. Hoechst 33258-conjugated hyaluronated fullerene for efficient photodynamic tumor therapy and necrotic tumor targeting[J]. J Bioact Compat Pol,2015,30(3):275-288.