Synthesis and Properties of the Poly(ε-caprolactone)-paclitaxel Prodrug

doi:10.6023/A15010055

Acta Chim. Sinica ›› 2015, Vol. 73 ›› Issue (4): 349-356.DOI: 10.6023/A15010055 Previous Articles Next Articles

Article

聚己内酯-紫杉醇高分子前药的合成及性能研究

杜征臻^a, 张琰^a, 叶金海^b, 徐衡^c, 郎美东^a

a 上海市先进聚合物材料重点实验室超细材料制备与应用教育部重点实验室华东理工大学材料科学与工程学院上海 200237;
b 南京医科大学口腔医学院南京 210029;
c 安徽省石油化工新材料协同创新中心安庆师范学院化学化工学院安庆 246011

投稿日期:2015-01-20 发布日期:2015-01-28
通讯作者: 张琰, 郎美东 E-mail:zhang_yan@ecust.edu.cn;mdlang@ecust.edu.cn
基金资助:
项目受国家自然科学基金(Nos. 21274039, 81371123)、上海市浦江人才计划(No. 14PJD014)和上海市基础研究重点(Nos. 12JC1403000, 12JC1403100)资助.

Synthesis and Properties of the Poly(ε-caprolactone)-paclitaxel Prodrug

Du Zhengzhen^a, Zhang Yan^a, Ye Jinhai^b, Xu Heng^c, Lang Meidong^a

a Shanghai Key Laboratory of Advanced Polymeric Materials, Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237;
b Institute of Stomatology, School of Stomatology, Nanjing Medical University, Nanjing 210029;
c Anhui Collaborative Innovation Center for Petrochemical New Materials, School of Chemistry and Chemical Engineering, Anqing Normal University, Anqing 246011

Received:2015-01-20 Published:2015-01-28
Supported by:
Project supported by the National Natural Science Foundation of China (Nos. 21274039, 81371123), the Shanghai Pujiang Program (No. 14PJD014) and the Basic Research Key Program Project of Commission of Science and Technology of Shanghai (Nos. 12JC1403000, 12JC1403100).

1. Synthesis and Properties of the Poly(ε-caprolactone)-paclitaxel Prodrug.PDF(291KB)

Abstract

This study presents a paclitaxel (PTX) based polymeric prodrug (FCPTX) using functionalized Pluronic-b-poly(ε-caprolactone) bearing carboxyl groups [pluronic-b-poly(ε-caprolactone-co-6-carboxylic-ε-caprolactone), Pluronic-b-P(CL-co-CCL), FC] as the substrate by a dicyclohexylcarbodiimide/4-dimethylaminopyridine-catalyzed (DCC/DMAP-catalyzed) esterification reaction. High Performance Liquid Chromatography (HPLC) and ¹H NMR were employed together to prove the successful reaction and confirmed the structure and composition of FCPTX. The result revealed that the 2'-OH of PTX participated in reaction and the PTX content in FCPTX was up to 18.3 wt%. The polymeric prodrug could self-assemble into micelles via an emulsion/solvent evaporation technique. Furthermore, the micelle was used as the nanomicellar carrier for delivery of free PTX. TEM and DLS were used to study the size and morphologies of the FCPTX micelles and PTX-loaded FCPTX (PTX/FCPTX) micelles. The results demonstrated that the two micelles were spherical spheres with narrow distribution and the size of PTX/FCPTX micelles was larger than that of FCPTX micelles due to the micellar core was enlarged by the loaded drug. The drug loading content (DLC) and drug loading efficiency (DLE) demonstrated that the great drug loading capability of FCPTX for free PTX which could be attributed to the fact that the excellent compatibility between drug and micellar core. The sustained in vitro release of PTX/FCPTX was due to that the forceful intermolecular interaction between conjugated PTX on the polymer and the encapsulated PTX, also, the forceful intermolecular interaction led to the high residual of PTX (only 33.0% total release after 72 h at pH 7.4). However, in the lower pH environment, the drug release was accelerated due to hydrolysis of ester bond and disaggregation of micelles. In vitro antitumor experiments showed that the cytotoxicity of the conjugated PTX was reduced due to that the 2'-OH of PTX was reacted and the drug activity was crippled. The PTX/FCPTX micelles revealed high antitumor activity due to the high cellular accumulation by micelle delivery. Subsequently, the great blood compatibility of FCPTX micelles and PTX/FCPTX micelles were obtained. All of the results demonstrated the use of the polymeric conjugated PTX as the core of the polymeric micelles afforded an ideal affinity site for free PTX and had a marvelous potential in combination chemotherapy.

Key words: ε-caprolactone, polymeric prodrug, paclitaxel, micelle

Cite this article

Du Zhengzhen, Zhang Yan, Ye Jinhai, Xu Heng, Lang Meidong. Synthesis and Properties of the Poly(ε-caprolactone)-paclitaxel Prodrug[J]. Acta Chim. Sinica, 2015, 73(4): 349-356.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

References

[1] Khandare, J.; Minko, T. Prog. Polym. Sci. 2006, 31, 359.
[2] Blencowe, C. A.; Russell, A. T.; Greco, F.; Hayes, W.; Thornthwaite, D. W. Polym. Chem. 2011, 2, 773.
[3] Wu, C.; Xie, J.; Quan, J.; Zhu, L. Acta Chim. Sinica 2011, 69, 843. (吴承尧, 谢建刚, 权静, 朱利民, 化学学报, 2011, 69, 843.)
[4] Wang, Z.; Luo, Y.; Zheng, Y.; Han, H.; Hong, X.; Jing, X. Chem. J. Chin. Univ. 2008, 29, 1671. (王占峰, 罗毅男, 郑勇辉, 韩海玲, 洪新雨, 景遐斌, 高等学校化学学报, 2008, 29, 1671.)
[5] Mura, S.; Zouhiri, F.; Lerondel, S.; Maksimenko, A.; Mougin, J.; Gueutin, C.; Brambilla, D.; Caron, J.; Sliwinski, E.; LePape, A.; Desmaele, D.; Couvreur, P. Bioconjugate Chem. 2013, 24, 1840.
[6] Li, G.; Liu, J.; Pang, Y.; Wang, R.; Mao, L.; Yan, D.; Zhu, X.; Sun, J. Biomacromolecules 2011, 12, 2016.
[7] Huang, P.; Wang, D.; Su, Y.; Huang, W.; Zhou, Y.; Cui, D.; Zhu, X.; Yan, D. J. Am. Chem. Soc. 2014, 136, 11748.
[8] Hu, X.; Li, J.; Lin, W.; Huang, Y.; Jing, X.; Xie, Z. RSC Adv. 2014, 4, 38405.
[9] Gu, Y.; Zhong, Y.; Meng, F.; Cheng, R.; Deng, C.; Zhong, Z. Biomacromolecules 2013, 14, 2772.
[10] Gong, J.; Huo, M.; Zhou, J.; Zhang, Y.; Peng, X.; Yu, D.; Zhang, H.; Li, J. Int. J. Pharm. 2009, 376, 161.
[11] Sang, C.; Kim, C.; Ick, C.; Hesson, C.; Seo, Y. J. Controlled Release 2003, 89, 437.
[12] Gelderblom, H.; Verweij, J.; Nooter, K.; Sparreboom, A. Eur. J. Cancer 2001, 37, 1590.
[13] Du, Z.; Zhang, Y.; Zhang, J.; Lang, M.-D. Acta Chim. Sinica 2014, 72, 609. (杜征臻, 张琰, 张静, 郎美东, 化学学报, 2014, 72, 609.)
[14] Sun, Y.; Dai, W.-F.; Zhang, Q.-C.; Zhang, Y.; Lang, M.-D. Acta Chim. Sinica 2009, 67, 1259. (孙琰, 戴炜枫, 张清醇, 张琰, 郎美东, 化学学报, 2009, 67, 1259.)
[15] Zhang, Y.; Li, J.; Du, Z.; Lang, M. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 188.
[16] Lei, Z.-L.; Liu, Y.-L. Acta Chim. Sinica 2006, 64, 2403. (雷忠利, 刘亚兰, 化学学报, 2006, 64, 2403.)
[17] Ru, M.; Dai, W.-F.; Du, Z.-Z.; Lang, M.-D. Acta Chim. Sinica 2008, 66, 1884. (茹敏良, 戴炜枫, 杜征臻, 郎美东, 化学学报, 2008, 66, 1884.)
[18] Yuan, M.; Xiao, Y.; Le, V.; Wei, C.; Fu, Y.; Liu, J.; Lang, M. Colloids Surf., A 2014, 457, 116.
[19] Yan, J.; Ye, Z.; Chen, M.; Liu, Z.; Xiao, Y.; Zhang, Y.; Zhou, Y.; Tan, W.; Lang, M. Biomacromolecules 2011, 12, 2562.
[20] Lu, J.; Chuan, X.; Zhang, H.; Dai, W.; Wang, X.; Wang, X.; Zhang, Q. Int. J. Pharm. 2014, 471, 525.
[21] Ayala, V.; Herrera, A.; Latorre-Esteves, M.; Torres-Lugo, M.; Rinaldi, C. J. Nanopart. Res. 2013, 15, 1.
[22] Yang, D.; Liu, X.; Jiang, X.; Liu, Y.; Ying, W.; Wang, H.; Bai, H.; Taylor, W. D.; Wang, Y.; Clamme, J.-P.; Co, E.; Chivukula, P.; Tsang, K. Y.; Jin, Y.; Yu, L. J. Controlled Release 2012, 161, 124.
[23] Gu, G.; Xia, H.; Hu, Q.; Liu, Z.; Jiang, M.; Kang, T.; Miao, D.; Tu, Y.; Pang, Z.; Song, Q.; Yao, L.; Chen, H.; Gao, X.; Chen, J. Biomaterials 2013, 34, 196.
[24] Dubey, N.; Shukla, J.; Hazari, P. P.; Varshney, R.; Ganeshpurkar, A.; Mishra, A. K.; Trivedi, P.; Bandopadhaya, G. P. Hell. J. Nucl. Med. 2011, 15, 9.
[25] Raveendran, R.; Bhuvaneshwar, G.; Sharma, C. P. J. Biomater. Appl. 2013, 27, 811.
[26] Huo, M.; Zhang, Y.; Zhou, J.; Zou, A.; Yu, D.; Wu, Y.; Li, J.; Li, H. Int. J. Pharm. 2010, 394, 162.
[27] Hou, L.; Fan, Y.; Yao, J.; Zhou, J.; Li, C.; Fang, Z.; Zhang, Q. Carbohydr. Polym. 2011, 86, 1157.
[28] Mao, C.; Liang, C. X.; Mao, Y. Q.; Li, L.; Hou, X. M.; Shen, J. Colloids Surf., B 2009, 74, 362.
[29] Xia, H.; Gao, X.; Gu, G.; Liu, Z.; Zeng, N.; Hu, Q.; Song, Q.; Yao, L.; Pang, Z.; Jiang, X.; Chen, J.; Chen, H. Biomaterials 2011, 32, 9888.
[30] Wen, Z.; Yan, Z.; Hu, K.; Pang, Z.; Cheng, X.; Guo, L.; Zhang, Q.; Jiang, X.; Fang, L.; Lai, R. J. Controlled Release 2011, 151, 131.

聚己内酯-紫杉醇高分子前药的合成及性能研究

Synthesis and Properties of the Poly(ε-caprolactone)-paclitaxel Prodrug

PDF

Supporting Info.

Knowledge

Cited

Abstract

Cite this article

share this article

References

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	Chenyu Liao, Shanwei Guo, Meiwei Huang, Yong Guo, Qing-Yun Chen, Chao Liu, Yunwen Zhang. Synthesis and Properties of Fluoroether Phosphocholine [J]. Acta Chimica Sinica, 2024, 82(1): 46-52.
[2]	Zhao Weiwei, Wang Yilin. Development of Surfactant Application in Wastewater Treatment [J]. Acta Chim. Sinica, 2019, 77(8): 717-728.
[3]	Zhang Bei, Chang Baisong, Sun Taolei. Synthesis and Study of Hypoxia-Responsive Micelles Based on Hyaluronic Acid [J]. Acta Chim. Sinica, 2018, 76(1): 35-42.
[4]	Sha Min, Zhang Ding, Pan Renming, Xing Ping, Jiang Biao. Synthesis and Properties Study of Novel Branched Fluorinated Surfactants with CF₃CF₂CF₂C(CF₃)₂ Group [J]. Acta Chim. Sinica, 2015, 73(5): 395-402.
[5]	Hu Qi, Li Yuxiang, Wang Jingyuan, Li Yapeng. Synthetic of pH-Sensitive PEG-b-PHEMA(His) Polymers andthe Study of Micelle [J]. Acta Chim. Sinica, 2015, 73(5): 416-422.
[6]	Ding Yanchun, Yu Yanlei, Wei Jia. Synthesis and Self-assembly Behavior of Photo-responsive Diblock Copolymers with Different Hydrophilic/Hydrophobic Ratios [J]. Acta Chimica Sinica, 2014, 72(5): 602-608.
[7]	Zhu Hua, Li Nan, Lin Xinfeng, Hong Ye, Yang Zhi. Design and Synthesis of ¹¹¹In-CCPM-RGD Nanoparticles for Dual-modality Molecular Imaging [J]. Acta Chimica Sinica, 2014, 72(4): 427-432.
[8]	Xia Binkai, Li Weihua, Qiu Feng. Self-assembling Behaviors of Symmetric Diblock Copolymers in C Homopolymers [J]. Acta Chimica Sinica, 2014, 72(1): 30-34.
[9]	Fan Cunhua, Yang Yiqun, Zhao Wei, Xiao Yu, Luo Jing, Liu Xiaoya. Research on Amphiphilic Copolymer MIP Micelles Electrochemical Sensor [J]. Acta Chimica Sinica, 2013, 71(06): 934-940.
[10]	Wang Liquan, Lin Jiaping, Zhang Qian. Dissipative Particle Dynamics Simulation on Self-Assembly of Comb-Coil Copolymers [J]. Acta Chimica Sinica, 2013, 71(06): 913-919.
[11]	Zhao Zhiyong, Wu Fen, Yang Zhongqiang, Liu Dongsheng, Fan Qing-Hua. Synthesis and Self-Assembly of DNA-Aliphatic Polyether Dendron Hybrids [J]. Acta Chimica Sinica, 2013, 71(04): 549-554.
[12]	Liu Zhaohui, Fang Xiaoliang, Chen Cheng, Zheng Nanfeng. Pd Nanoparticles Encapsulated in Hollow Mesoporous Aluminosilica Nanospheres as an Efficient Catalyst for Multistep Reactions and Size-Selective Hydrogenation [J]. Acta Chimica Sinica, 2013, 71(03): 334-338.
[13]	Chen Dongdong, Wang Lin, Sun Junqi. High Efficient Loading of Hydrophobic Molecules in Layer-by-Layer Assembled Microgel Films with the Assistance of Surfactant Micelles [J]. Acta Chimica Sinica, 2012, 70(17): 1779-1784.
[14]	Chu Zonglin, Zhang Yongmin, Han Yugui, Wang Hongyan, Li Bin, Feng Yujun. Shear Banding Transition of Wormlike Micelles Formed by a C₂₂-Tailed Cationic Surfactant [J]. Acta Chimica Sinica, 2012, 70(14): 1551-1554.
[15]	Yang Youqiang, Sun Qingqing, Zhang Canyang, Guo Xindong, Zhang Lijuan, Wen Xiufang. Synthesis of pH-Sensitive Amphiphilic Copolymer Brush by the Combination of ARGET ATRP with ROP and Its Self-Assembly Behavior [J]. Acta Chimica Sinica, 2012, 70(04): 505-511.