包载共轭亚油酸-紫杉醇的iRGD修饰的含溶血磷脂的温敏脂质体的细胞摄取和抗肿瘤药效

doi:10.5246/jcps.2019.02.012

中国药学(英文版) ›› 2019, Vol. 28 ›› Issue (2): 121-133.DOI: 10.5246/jcps.2019.02.012

包载共轭亚油酸-紫杉醇的iRGD修饰的含溶血磷脂的温敏脂质体的细胞摄取和抗肿瘤药效

郝艳丽^1,2, 钟婷^1,2, 杜若², 张华³, 刘碧林⁴, 张烜^1,2*

1. 北京大学医学部药学院分子药剂学与新释药系统北京市重点实验室, 北京 100191
2. 北京大学医学部药学院药剂学系, 北京 100191
3. 石河子大学药学院新疆植物药资源利用教育部重点实验室, 新疆石河子 832000
4. 重庆化工职业学院制药工程学院, 重庆 401228

收稿日期:2018-09-14 修回日期:2018-10-29 出版日期:2019-02-28 发布日期:2019-01-03
通讯作者: Tel./Fax: +86-010-82805765, E-mail: xuanzhang@bjmu.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81172992) and the National Key Research and Development Program of China (Grant No. 2017YFA0205600).

The cellular uptake and anti-tumor activity of conjugated linoleic acid-paclitaxel-loaded iRGD-modified lysolipid-containing thermosensitive liposomes

Yanli Hao^1,2, Ting Zhong^1,2, Ruo Du², Hua Zhang³, Bilin Liu⁴, Xuan Zhang^1,2*

1. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
3. Key Laboratory of Xinjiang Phytomedicine Resources and Utilization of Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832000, China
4. College of Pharmaceutical Engineering, Chongqing Chemical Industry Vocational College, Chongqing 401228, China

Received:2018-09-14 Revised:2018-10-29 Online:2019-02-28 Published:2019-01-03
Contact: Tel./Fax: +86-010-82805765, E-mail: xuanzhang@bjmu.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 81172992) and the National Key Research and Development Program of China (Grant No. 2017YFA0205600).

摘要/Abstract

摘要：

在本研究中, 我们制备了iRGD, CRGDK/RGPD/EC)修饰、含溶血磷脂的温敏脂质体(LTSL)载体系统用以递送共轭亚油酸-紫杉醇(CLA-PTX), 简称iRGD-LTSL-CLA-PTX。在B16-F10黑色素瘤细胞上评估了iRGD-LTSL-CLA-PTX的体外细胞摄取和体外细胞毒性。在荷B16-F10黑色素瘤的C57BL/6小鼠上评价了iRGD-LTSL-CLA-PTX的体内抗肿瘤作用。细胞摄取实验结果表明, 与SSL-CLA-PTX组相比, 在42 ºC分别孵育2、4和6 h, iRGD-LTSL-CLA-PTX给药组中CLA-PTX的细胞摄取分别增加2.05、3.31和4.83倍。体内抗肿瘤效果表明, 与CLA-PTX溶液、LTSL-CLA-PTX、LTSL-CLA-PTX(加热条件)和iRGD-LTSL-CLA-PTX相比, iRGD-LTSL-CLA-PTX(加热条件)可显着抑制B16-F10肿瘤的生长(P<0.01)。iRGD-LTSL-CLA-PTX对B16-F10黑素瘤的体外和体内抗肿瘤作用得到证实, 这是iRGD和LTSL共同作用的结果。

关键词: iRGD, 温敏脂质体, CLA-PTX, 抗肿瘤, 体外, 体内

Abstract:

In the present study, we prepared the iRGD-modified lysolipid-containing thermosensitive liposomes (LTSL) containing conjugated linoleic acid-paclitaxel (CLA-PTX), also known as iRGD-LTSL-CLA-PTX. The in vitro cellular uptake and invitro cytotoxicity of iRGD-LTSL-CLA-PTX were evaluated in B16-F10 melanoma cells. The in vivo anti-tumor effect of iRGD-LTSL-CLA-PTX was investigated using B16-F10 tumor-bearing C57BL/6 mice. The results of the cellular uptake experimentindicated that the increased cellular uptake of CLA-PTX in the iRGD-LTSL-CLA-PTX-treated groups was 2.05-, 3.31- or 4.83-foldcompared with that in the SSL-CLA-PTX group after a 2-, 4- or 6-h incubation at 42°C, respectively. The in vivo antitumor results showed that iRGD-LTSL-CLA-PTX/heat significantly inhibited the growth of B16-F10 tumors compared with the CLA-PTX solution (LTSL-CLA-PTX, LTSL-CLA-PTX/heat and iRGD-LTSL-CLA-PTX) (P<0.01). In conclusion, the antitumor effect of iRGD-LTSL-CLA-PTX was confirmed on B16-F10 melanoma in vitro and in vivo, which was induced by both the effect of iRGD and LTSL.

Key words: iRGD, Lysolipid-containing thermosensitive liposomes, CLA-PTX, Antitumor effect, In vitro, In vivo

中图分类号:

R943

Supporting:

郝艳丽, 钟婷, 杜若, 张华, 刘碧林, 张烜. 包载共轭亚油酸-紫杉醇的iRGD修饰的含溶血磷脂的温敏脂质体的细胞摄取和抗肿瘤药效[J]. 中国药学(英文版), 2019, 28(2): 121-133.

Yanli Hao, Ting Zhong, Ruo Du, Hua Zhang, Bilin Liu, Xuan Zhang. The cellular uptake and anti-tumor activity of conjugated linoleic acid-paclitaxel-loaded iRGD-modified lysolipid-containing thermosensitive liposomes[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(2): 121-133.

参考文献

[1] Shi, J.J.; Kantoff, P.W.; Wooster, R.; Farokhzad, O.C. Cancer nanomedicine: progress, challenges and opportunities. Nat. Rev. Cancer. 2017, 17, 20-37.

[2] Rowland, A.; Dias, M.M.; Wiese, M.D.; Kichenadasse, G.; Mckinnon, R.A.; Karapetis, C.S.; Sorich, M.J. Reply: Comment on ‘Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer’. Br. J. Cancer. 2015, 113, 1635.

[3] Deshpande, P.; Jhaveri, A.; Pattni, B.; Biswas, S.; Torchilin, V. Transferrin and octaarginine modified dual-functional liposomes with improved cancer cell targeting and enhanced intracellular delivery for the treatment of ovarian cancer. Drug Deliv. 2018, 25, 517-532.

[4] Sharma, R.; Mody, N.; Kushwah, V.; Jain, S.; Vyas, S.P. C-Type lectin receptor(s)-targeted nanoliposomes: an intelligent approach for effective cancer immunotherapy. Nanomedicine (Lond). 2017, 12, 1945-1959.

[5] Zhao, B.J.; Ke, X.Y.; Huang, Y.; Chen, X.M.; Zhao, X.; Zhao, B.X.; Lu W.L.; Lou, J.N.; Zhang, X.; Zhang, Q. The antiangiogenic efficacy of NGR-modified PEG-DSPE micelles containing paclitaxel (NGR-M-PTX) for the treatment of glioma in rats. J. Drug Target. 2011, 19, 382-390.

[6] Luo, L.M.; Huang, Y.; Zhao, B.X.; Zhao, X.; Duan, Y.; Du, R.; Yu, K.F.; Song, P.; Zhao, Y.; Zhang, X.; Zhang, Q. Anti-tumor and anti-angiogenic effect of metronomic cyclic NGR-modified liposomes containing paclitaxel. Biomaterials. 2013, 34, 1102-1114.

[7] Huang, D.; Zhang, S.; Zhong, T.; Ren, W.; Yao, X.; Guo, Y.; Duan, X.C.; Yin, Y.F.; Zhang, S.S.; Zhang, X. Multi-targeting NGR-modified liposomes recognizing glioma tumor cells and vasculogenic mimicry for improving anti-glioma therapy. Oncotarget. 2016, 7, 43616-43628.

[8] Zhao, B.X.; Zhao, Y.; Huang, Y.; Luo, L.M.; Song, P.; Wang, X.; Chen, S.; Yu, K.F.; Zhang, X.; Zhang. Q. The efficiency of tumor-specific pH-responsive peptide-modified polymeric micelles containing paclitaxel. Biomaterials. 2012, 33, 2508-2520.

[9] Zhao, Y.; Ren, W.; Zhong, T.; Zhang, S.; Huang, D.; Guo, Y.; Yao, X.; Wang, C.; Zhang, W.Q.; Zhang, X.; Zhang, Q. Tumor-specific pH-responsive peptide-modified pH-sensitive liposomes containing doxorubicin for enhancing glioma targeting and anti-tumor activity. J. Control. Release. 2016, 222, 56-66.

[10] Zheng, X.C.; Ren, W.; Zhang, S.; Zhong, T.; Duan, X.C.; Yin, Y.F.; Xu, M.Q.; Hao, Y.L.; Li, Z.T.; Li, H.; Liu, M.; Li Z.Y.; Zhang, X. The theranostic efficiency of tumor-specific, pH-responsive, peptide-modified, liposome-containing paclitaxel and superparamagnetic iron oxide nanoparticles. Int. J. Nanomedicine. 2018, 13, 1495-1504.

[11] Yu, K.F.; Zhang, W.Q.; Luo, L.M.; Song, P.; Li, D.; Du, R.; Ren, W.; Huang, D.; Lu, W.L.; Zhang, X.; Zhang, Q. The antitumor activity of a doxorubicin loaded, iRGD-modified sterically-stabilized liposome on B16-F10 melanoma cells: in vitro and in vivo evaluation. Int. J. Nanomedicine. 2013, 8, 2473-2485.

[12] Du, R.; Zhong, T.; Zhang, W.Q.; Song, P.; Song, W.D.; Zhao, Y.; Wang, C.; Tang, Y.Q.; Zhang, X.; Zhang, Q. Antitumor effect of iRGD-modified liposomes containing conjugated linoleic acid-paclitaxel (CLA-PTX) on B16-F10 melanoma. Int. J. Nanomedicine. 2014, 24, 3091-3105.

[13] Wang, C.; Wang, X.; Zhong, T.; Zhao, Y.; Zhang, W.Q.; Ren, W.; Huang, D.; Zhang, S.; Guo, Y.; Yao, X.; Tang, Y.Q.; Zhang, X.; Zhang, Q. The antitumor activity of tumor-homing peptide-modified thermosensitive liposomes containing doxorubicin on MCF-7/ADR: in vitro and in vivo. Int. J. Nanomedicine. 2015, 10, 2229-2248.

[14] Zhang, W.Q.; Yu, K.F.; Zhong, T.; Luo, L.M.; Du, R.; Ren, W.; Huang, D.; Song, P.; Li, D.; Zhao, Y.; Wang, C.; Zhang, X. Does ligand-receptor mediated competitive effect or penetrating effect of iRGD peptide when co-administration with iRGD-modified SSL? J. Drug Target. 2015, 23, 897-909.

[15] Sugahara, K.N.; Teesalu, T.; Karmali, P.P.; Kotamraju, V.R.; Agemy, L.; Girard, O.M.; Hanahan, D.; Mattrey, R.F.; Ruoslahti, E. Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell. 2009, 16, 510-520.

[16] Ma, L.J.; Chen, Q.B.; Ma, P.P.; Han, M.K.; Xu, Z.G.; Kang, Y.J.; Xiao, B.; Merlin. D. iRGD-functionalized PEGylated nanoparticles for enhanced colon tumor accumulation and targeted drug delivery. Nanomedicine. 2017, 12, 1991-2006.

[17] Zhang, J.; Wang, S.; Deng, Z.T.; Li, L.; Tan, G.H.; Liu, X.; Zheng, H.R.; Yan, F. Ultrasound-Triggered Drug Delivery for Breast Tumor Therapy Through iRGD-Targeted Paclitaxel-Loaded Liposome-Microbubble Complexes. J. Biomed. Nanotechnol. 2018, 14, 1384-1395.

[18] Hu, H.; Wan, J.L.; Huang, X.T.; Tang, Y.X.; Xiao, C.; Xu, H.B.; Yang, X.L.; Li, Z.F. iRGD-decorated reduction-responsive nanoclusters for targeted drug delivery. Nanoscale. 2018, 10, 10514-10527.

[19] Yang, Y.Y.; Wang, X.F.; Liao, G.C.; Liu, X.Q.; Chen, Q.L.; Li, H.M.; Lu, L.; Zhao, P.; Yu, Z.Q. iRGD-decorated red shift emissive carbon nanodots for tumor targeting fluorescence imaging. J. Colloid. Interface Sci. 2018, 509, 515-521.

[20] Liu, D.; Yang, F.; Xiong, F.; Gu, N. The smart drug delivery system and its clinical potential. Theranostics. 2016, 6, 1306.

[21] Unezaki, S.; Maruyama, K.; Takahashi, N.; Koyama, M.; Yuda, T.; Suginaka, A.; Iwatsuru, M. Enhanced delivery and antitumor activity of doxorubicin using long-circulating thermosensitive liposomes containing amphipathic polyethylene glycol in combination with local hyperthermia. Pharm. Res. 1994, 11, 1180-1185.

[22] Koning, G.A.; Eggermont, A.M.; Lindner, L.H.; ten Hagen, T.L. Hyperthermia and thermosensitive liposomes for improved delivery of chemotherapeutic drugs to solid tumors. Pharm. Res. 2010, 27, 1750-1754.

[23] Singh, N.K.; Lee, D.S. In situ gelling pH-and temperature-sensitive biodegradable block copolymer hydrogels for drug delivery. J. Control. Release. 2014, 193, 214-227.

[24] Needham, D.; Anyarambhatla, G.; Kong, G.; Dewhirst, M.W. A new temperature-sensitive liposome for use with mild hyperthermia: characterization and testing in a human tumor xenograft model. Cancer Res. 2000, 60, 1197-1201.

[25] Landon, C.D.; Park, J.Y.; Needham, D.; Dewhirst, M.W. Nanoscale drug delivery and hyperthermia: the materials design and preclinical and clinical testing of low temperature-sensitive liposomes used in combination with mild hyperthermia in the treatment of local cancer. Open Nanomed J. 2011, 3, 38-64.

[26] Needham, D.; Park, J.Y.; Wright, A.M.; Tong, J. Materials characterization of the low temperature sensitive liposome (LTSL): effects of the lipid composition, lysolipid and DSPE-PEG2000) on the thermal transition and release of doxorubicin. Faraday Discuss. 2013, 161, 515-534; discussion 563-589.

[27] Sadeghi, N.; Deckers, R.; Ozbakir, B.; Akthar, S.; Kok, R.J.; Lammers, T.; Storm, G. Influence of cholesterol inclusion on the doxorubicin release characteristics of lysolipid-based thermosensitive liposomes. Int. J. Pharm. 2018, 548, 778-782.

[28] Banno, B.; Ickenstein, L.M.; Chiu, G.N.; Bally, M.B.; Thewalt, J.; Brief, E.; Wasan, E.K. The functional roles of poly (ethylene glycol)-lipid and lysolipid in the drug retention and release from lysolipid-containing thermosensitive liposomes in vitro and in vivo. J. Pharm. Sci. 2010, 99, 2295-2308.

[29] VanOsdol, J.; Ektate, K.; Ramasamy, S.; Maples, D.; Collins, W.; Malayer, J.; Ranjan, A. Sequential HIFU heating and nanobubble encapsulation provide efficient drug penetration from stealth and temperature sensitive liposomes in colon cancer. J. Control. Release. 2017, 247, 55-63.

[30] Dou, Y.N.; Chaudary, N.; Chang, M.C.; Dunne, M.; Huang, H.; Jaffray, D.A.; Milosevic, M.; Allen, C. Tumor microenvironment determines response to a heat-activated thermosensitive liposome formulation of cisplatin in cervical carcinoma. J. Control. Release. 2017, 262, 182-191.

[31] Wang, Z.Y.; Zhang, H.; Yang, Y.; Xie, X.Y.; Yang, Y.F.; Li, Z.P.; Li, Y.; Gong, W.; Yu, F.L.; Yang, Z.B.; Li, M.Y.; Mei, X.G. Preparation, characterization, and efficacy of thermosensitive liposomes containing paclitaxel. Drug Deliv. 2016, 23, 1222-1231.

[32] Ke, X.Y.; Zhao, B.J.; Zhao, X.; Wang, Y.; Huang, Y.; Chen, X.M.; Zhao, B.X.; Zhao, S.S.; Zhang, X.; Zhang, Q. The therapeutic efficacy of conjugated linoleic acid-paclitaxel on glioma in the rat. Biomaterials. 2010, 31, 5855-5864.

[33] Li, D.; Yang, K.; Li, J.S.; Ke, X.Y.; Duan, Y.; Du, R.; Song, P.; Yu, K.F.; Ren, W.; Huang, D.; Li, X.H.; Hu, X.; Zhang, X.; Zhang, Q. Antitumor efficacy of a novel CLA-PTX microemulsion against brain tumors: in vitro and in vivo findings. Int. J. Nanomedicine. 2012, 7, 6105-6114.

[34] Zhong, T.; Yao, X.; Zhang, S.; Guo, Y.; Duan, X.C.; Ren, W.; Huang, D.; Yin, Y.F.; Zhang, X. A self-assembling nanomedicine of conjugated linoleic acid-paclitaxel conjugate (CLA-PTX) with higher drug loading and carrier-free characteristic. Sci. Rep. 2016, 6, 36614.

[35] Al-Ahmady, Z.S.; Scudamore, C.L.; Kostarelos, K. Triggered doxorubicin release in solid tumors from thermosensitive liposome-peptide hybrids: Critical parameters and therapeutic efficacy. Int. J. Cancer. 2015, 137, 731-743.

[36] De, Smet. M.; Langereis, S.; van den Bosch, S.; Grüll, H. Temperature-sensitive liposomes for doxorubicin delivery under MRI guidance. J. Control. Release. 2010, 143, 120-127.

[37] Hong, S.S.; Choi, J.Y.; Kim, J.O.; Lee, M.K.; Kim, S.H.; Lim, S.J. Development of paclitaxel-loaded liposomal nanocarrier stabilized by triglyceride incorporation. Int. J. Nanomedicine. 2016, 11, 4465-4477.

[38] Zhang, S.; Li, Z.T.; Liu, M.; Wang, J.R.; Xu, M.Q.; Li, Z.Y.; Duan, X.C.; Hao, Y.L.; Zheng, X.C.; Li, H.; Feng, Z.H.; Zhang, X. Anti-tumour activity of low molecular weight heparin doxorubicin nanoparticles for histone H1 high-expressive prostate cancer PC-3M cells. J. Control Release. 2018 Dec 21. pii: S0168-3659(18)30737-5. doi: 10.1016/j.jconrel.2018.12.034.

[39] Duan, X.C.; Yao, X.; Zhang, S.; Xu, M.Q.; Hao, Y.L.; Li, Z.T.; Zheng, X.C.; Liu, M.; Li, Z.Y.; Li, H.; Wang, J.R.; Feng, Z.H.; Zhang, X. Antitumor activity of the bioreductive prodrug 3-(2-nitrophenyl) propionic acid-paclitaxel nanoparticles (NPPA-PTX NPs) on MDa-MB-231 cells: in vitro and in vivo. Int. J. Nanomedicine. 2019, 14, 195-204.

[40] Deng, Z.T.; Xiao, Y.; Pan, M.; Li, F.; Duan, W.L.; Meng, L.; Liu, X.; Yan, F.; Zheng, H. Hyperthermia-triggered drug delivery from iRGD-modified temperature-sensitive liposomes enhances the anti-tumor efficacy using high intensity focused ultrasound. J. Control. Release. 2016, 243, 333-341.

包载共轭亚油酸-紫杉醇的iRGD修饰的含溶血磷脂的温敏脂质体的细胞摄取和抗肿瘤药效

The cellular uptake and anti-tumor activity of conjugated linoleic acid-paclitaxel-loaded iRGD-modified lysolipid-containing thermosensitive liposomes

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	拓文静, 华若辰, 李星玥, 宋继红, 卢闻. 基于不同种属细胞体外血脑屏障模型的药物渗透性比较[J]. 中国药学(英文版), 2023, 32(4): 237-249.
[2]	阳丽梅, 王丽满, 黄旭慧, 庄捷. 华法林通过调控Gas6/Axl/PI3K/Akt/NF-κB通路影响肺癌细胞株的增殖和凋亡[J]. 中国药学(英文版), 2023, 32(3): 190-199.
[3]	刘良裕, 杨宇珂, 杜肖, 吴桐, 王建农. 白英中三个未被报道的甾体糖苷生物碱及其抗肿瘤活性[J]. 中国药学(英文版), 2022, 31(3): 192-201.
[4]	许士琪, 朱礼岩, 郝超, 刘文倩, 陈成龙, 陈泳怡, 刘爱芹. 一种新型含氨基酸基团替加氟前药的合成及其抗肿瘤活性评价[J]. 中国药学(英文版), 2021, 30(9): 743-753.
[5]	黄聪, 吴霭琳, 海沙尔江·吾守尔, 徐子悦, 张逸晨, 管晓东, 史录文. 中国浙江省级医保报销对于靶向抗肿瘤药使用的影响: 一项带对照的间断时间序列分析[J]. 中国药学(英文版), 2021, 30(7): 590-597.
[6]	汪子翔, 张宜凡, 杜望春, 陈群力, 姚虹, 赵梅. 天然产物通过调节活性氧水平防治肿瘤的研究进展[J]. 中国药学(英文版), 2021, 30(6): 455-467.
[7]	宋慧慧, 向卓, 薛淑一, 苗青, 赵丽艳, 李明春. 白头翁皂苷及其单体抗肿瘤作用及机制的研究进展[J]. 中国药学(英文版), 2021, 30(5): 381-392.
[8]	刘曼, 张爽, 李卓越, 王光雪, 王景茹, 张烜. 氧化锌纳米粒的制备与表征[J]. 中国药学(英文版), 2020, 29(9): 617-625.
[9]	李承群, 牛霞, 牟家慧, 王晓梅, 苏瑾, 李桂玲. APT011缓释微球的制备及体外评价[J]. 中国药学(英文版), 2020, 29(8): 554-563.
[10]	周北斗, 俞紫涵, 童玉贵, 李佳莉, 黄堡城, 魏蓉蓉, 翁智敏, 王欣, 阮志鹏, 林健, 许彩红, 刘建波. 异戊烯基和香叶基取代的呫吨酮的合成与生物活性研究[J]. 中国药学(英文版), 2020, 29(8): 564-576.
[11]	刘晓昕, 覃小雅, 李子圆, 范田园. 掺杂型超顺磁性氧化铁纳米簇的微波辅助制备及体外表征[J]. 中国药学(英文版), 2020, 29(3): 153-160.
[12]	余飞, 周文莉, 阚家义, 彭灿. 11种盐酸小檗碱片剂在不同溶出度介质中溶出度曲线特征的比较[J]. 中国药学(英文版), 2020, 29(2): 102-112.
[13]	程文文, 张冬梅, 郑强, 李中军, 孟祥豹. 新型组蛋白去乙酰化酶抑制剂的设计、合成及活性评价: 含硫锌离子结合基团的发现 [J]. 中国药学(英文版), 2019, 28(6): 408-421.
[14]	周北斗, 王欣, 翁智敏, 黄堡城, 马泽通, 于博, 阮丽琴, 胡栋宝. 氧杂蒽酮的合成和抗肿瘤、抑制酪氨酸酶和抑制血小板聚集活性研究[J]. 中国药学(英文版), 2019, 28(4): 247-256.
[15]	卢东渤, 陈宇, 刘姗, 郭超, 李霞, 李中军, 孟祥豹. 茚[1, 2-b]并吲哚衍生物的合成、双重抑制拓扑异构酶I和II及逆转多重耐药等生物活性研究[J]. 中国药学(英文版), 2019, 28(11): 786-801.