D-α-生育酚-聚(2-乙基-2-口恶唑啉)琥珀酸酯修饰siRNA脂质复合物的构建及初步评价

苏红,韩姝,孙瑞阳,吕静,文路乔,黄守震,徐缓

中国药学杂志 ›› 2018, Vol. 53 ›› Issue (9) : 713-718.

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中国药学杂志 ›› 2018, Vol. 53 ›› Issue (9) : 713-718. DOI: 10.11669/cpj.2018.09.011
论著

D-α-生育酚-聚(2-乙基-2-口恶唑啉)琥珀酸酯修饰siRNA脂质复合物的构建及初步评价

  • 苏红,韩姝,孙瑞阳,吕静,文路乔,黄守震,徐缓*
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Construction and Preliminary Evaluation of Lipid Complex of siRNA Modified by D-α-tocopheryl Poly (2-ethyl-2-oxazoline) Succinate

  • SU Hong, HAN Shu, SUN Rui-yang, LÜ Jing, WEN Lu-qiao, HUANG Shou-zhen, XU Huan*
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摘要

目的 制备D-α-生育酚-聚(2-乙基-2-唑啉)琥珀酸酯【D-α-tocopheryl poly (2-ethyl-2-oxazoline) succinate, TPOS】修饰小干扰RNA(small interfering RNA,siRNA)脂质复合物(TPOS-L/siRNA)。方法 以普通siRNA脂质复合物(CLs/siRNA)和PEG修饰CLs/siRNA(PEG-L/siRNA)为对照,对TPOS-L/siRNA的包封率、形态、稳定性、体外释放、细胞摄取等进行评价。结果 根据正负电荷的静电吸引作用通过直接混合方法等体积混合空白CLs 和siRNA,得到CLs/siRNA。CLs/siRNA具有脂质双分子层结构,包封率为(86.68±1.41)%,粒径小于200 nm。TPOS或PEG-DSPE修饰后,对CLs/siRNA包封率和粒径基本无影响,而且均能赋予脂质复合物良好的稳定性;同时TPOS-L/siRNA具有较好的pH敏感性,能够响应微酸环境,细胞摄取明显增强。结论 TPOS能够构建良好的siRNA载体,并能增加该纳米载体的稳定性和pH敏感性。

Abstract

OBJECTIVE To prepare small interfering RNA(siRNA) lipid complexes (TPOS-L/siRNA) modified by D-α-tocopheryl poly (2-ethyl-2-oxazoline) succinate (TPOS).METHODS The conventional siRNA lipid complexes (CLs/siRNA) and PEGylated CLs/siRNA (PEG-L/siRNA) were used as controls. CLs/siRNA was prepared by mixing blank CLs and siRNA directly of equal volume according to the electrostatic interaction of positive and negative charges. The encapsulation efficiency, morphology, stability, in vitro release and cell uptake of TPOS-L/siRNA were investigated.RESULTS The CLs/siRNA had obvious lipid bilayer structure, the encapsulation efficiency (EE) was (86.68±1.41)%, and the particle size of CLs/siRNA was less than 200 nm. The modification with TPOS or PEG-DSPE had no significant effect on the EE and particle size of CLs/siRNA, which could endow the lipid complexes with good stability. In addtion, TPOS-L/siRNA had good pH-sensitive property, and could respond to slightly acidic environment, which significantly enhanced the cell uptake.CONCLUSION TPOS can construct good siRNA carrier and increase the stability and pH sensitivity of the nanocarrier.

关键词

小干扰RNA / D-α-生育酚-聚(2-乙基-2-口恶唑啉)琥珀酸酯 / pH敏感 / 脂质复合物

Key words

siRNA / D-α-tocopherol-poly(2-ethyl-2-oxazoline) succinate / pH-sensitive / lipid complex

引用本文

导出引用
苏红,韩姝,孙瑞阳,吕静,文路乔,黄守震,徐缓. D-α-生育酚-聚(2-乙基-2-口恶唑啉)琥珀酸酯修饰siRNA脂质复合物的构建及初步评价[J]. 中国药学杂志, 2018, 53(9): 713-718 https://doi.org/10.11669/cpj.2018.09.011
SU Hong, HAN Shu, SUN Rui-yang, Lü Jing, WEN Lu-qiao, HUANG Shou-zhen, XU Huan. Construction and Preliminary Evaluation of Lipid Complex of siRNA Modified by D-α-tocopheryl Poly (2-ethyl-2-oxazoline) Succinate[J]. Chinese Pharmaceutical Journal, 2018, 53(9): 713-718 https://doi.org/10.11669/cpj.2018.09.011
中图分类号: R944. 1   

参考文献

[1] HAUSSECKER D. Current issues of RNAi therapeutics delivery and development[J] . J Controlled Release, 2014, 195:49-54.
[2] OZPOLAT B, SOOD A K, LOPEZ-BERESTEIN G. Liposomal siRNA nanocarriers for cancer therapy[J] . Adv Drug Deliv Rev, 2014, 66(1):110-116.
[3] CHAKRABORTY C. Potentiality of small interfering RNAs (siRNA) as recent therapeutic targets for gene-silencing[J] . Curr Drug Targets, 2007, 8(3):469-482.
[4] HOERTER J A, WALTER N G. Chemical modification resolves the asymmetry of siRNA strand degradation in human blood serum[J] . RNA,2007, 13(11):1887-1893.
[5] LU J J, LANGER R, CHEN J. A novel mechanism is involved in cationic lipid-mediated functional siRNA delivery[J] . Mol Pharm, 2009, 6(3):763-771.
[6] DASS C R, CHOONG P F M. Selective gene delivery for cancer therapy using cationic liposomes:in vivo proof of applicability[J] . J Controlled Release, 2006, 113(2):155-163.
[7] WANG T, UPPONI J R, TORCHILIN V P. Design of multifunctional non-viral gene vectors to overcome physiological barriers: dilemmas and strategies[J] . Int J Pharm, 2012, 427(1):3-20.
[8] REMAUT K, LUCAS B, BRAECKMANS K, et al. Pegylation of liposomes favours the endosomal degradation of the delivered phosphodiester oligonucleotides[J] . J Controlled Release, 2007, 117(2):256-266.
[9] ZHANG D, XU H, HU M N, et al. "PEG dilemma" for liposomes and its solving approaches[J] . Acta Pharm Sin (药学学报), 2015, 50(3):252-260.
[10] WANG C H, HSIUE G H. Synthesis and characterization of temperature-and pH-sensitive hydrogels based on poly(2-ethyl-2-oxazoline) and poly(D,L-lactide)[J] . J Polym Sci:Part A:Polym Chem, 2002, 40(8):1112-1121.
[11] YUE H X, WANG X C, XU H. Synthesis and application of 2-oxazoline polymer in drug delivery systems:a review[J] . Chin Pharm J (中国药学杂志), 2017, 52(9):713-720.
[12] VIEGAS T X, BENTLEY M D, HARRIS J M, et al. Polyoxazoline:chemistry, properties, and applications in drug delivery[J] . Bioconju Chem, 2011, 22(5):976-986.
[13] XU H, ZHANG W, LI Y, et al. The bifunctional liposomes constructed by poly(2-ethyl-oxazoline)-cholesteryl methyl carbonate:an effectual approach to enhance liposomal circulation time, pH-sensitivity and endosomal escape[J] . Pharm Res, 2014, 31(11):3038-3050.
[14] XU H, HU M N, YU X, et al. Design and evaluation of pH-sensitive liposomes constructed by poly(2-ethyl-2-oxazoline)-cholesterol hemisuccinate for doxorubicin delivery[J] . Eur J Pharm Biopharm, 2015, 91:66-74.
[15] ZHANG D, LI J Y, WANG X C, et al. Preparation and evaluation of doxorubicin hydrochloride liposomes modified by poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate[J] . Acta Pharm Sin (药学学报), 2015, 50(9):1174-1179.
[16] ZHANG Y, LI H M, SUN J, et al. DC-Chol/DOPE cationic liposomes: a comparative study of the influence factors on plasmid pDNA and siRNA gene delivery[J] . Int J Pharm, 2010, 390(2):198-207.
[17] KIM H K, DAVAA E, MYUNG C S, et al. Enhanced siRNA delivery using cationic liposomes with new polyarginine-conjugated PEG-lipid[J] . Int J Pharm, 2010, 392(1):141-147.
[18] YANG S Y, CHEN X J. Advance in the research of cationic liposome carriers for gene delivery[J] . Chin J New Drug (中国新药杂志), 2010, 19(20):1866-1870.
[19] YANG Y F, XIE X Y, YANG Y, et al. A review on the influences of size and surface charge of liposome on its targeted drug delivery in vivo[J] . Acta Pharm Sin (药学学报), 2013, 48(11):1644-1650.
[20] YANG Y F, XIE X Y, YANG Y, et al. A review on the influences of size and surface charge of liposome on its targeted drug delivery in vivo[J] . Acta Pharm Sin(药学学报), 2013, 48(11):1644-1650.
[21] TAGALAKIS A D, LEE D H D, BIENEMANN A S, et al. Multifunctional, self-assembling anionic peptide-lipid nanocomplexes for targeted siRNA delivery[J] . Biomaterials, 2014, 35(29):8406-8415.
[22] NGUYEN L T, ATOBE K, BARICHELLO J M, et al. Complex formation with plasmid DNA increases the cytotoxicity of cationic liposomes[J] . Biol Pharm Bull, 2007, 30(4):751-757.
[23] LV H T, ZHANG S B, WANG B, et al. Toxicity of cationic lipids and cationic polymers in gene delivery[J] . J Controlled Release, 2006, 114(1):100-109.
[24] ZHI D F, WANG B, CUI S H, et al. Comparison of two kinds of cationic vectors-mediated gene delivery[J] . Acta Pharm Sin (药学学报), 2009, 44(5):553-557.

基金

国家自然科学基金项目资助(81102394);辽宁省自然科学基金项目资助(20170540575)

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