Synthesis and Properties of the Poly(ε-caprolactone)-paclitaxel Prodrug
Received date: 2015-01-20
Online 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).
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
Du Zhengzhen , Zhang Yan , Ye Jinhai , Xu Heng , Lang Meidong . Synthesis and Properties of the Poly(ε-caprolactone)-paclitaxel Prodrug[J]. Acta Chimica Sinica, 2015 , 73(4) : 349 -356 . DOI: 10.6023/A15010055
[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.
/
| 〈 |
|
〉 |
