Preparation and anticancer activity evaluation of self-assembled paclitaxel conjugated MPEG-PCL micelles on 4T1 cells

Yun Sung Lee; Hyun Joo Kim; Dae Hyeok Yang; Heung Jae Chun

Journal of Industrial and Engineering Chemistry, Vol.71, 369-377, March, 2019

DOI10.1016/j.jiec.2018.11.048 Export Citation

Preparation and anticancer activity evaluation of self-assembled paclitaxel conjugated MPEG-PCL micelles on 4T1 cells

Yun Sung Lee^{1, 2}, Hyun Joo Kim², Dae Hyeok Yang², and Heung Jae Chun^{1, 2, †}

¹Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
²Institute of Cell & Tissue Engineering, Department of Biomedical Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea

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In this study, we prepared self-assembled micelles with methoxy poly(ethylene glycol)-b-poly (ε-caprolactone) (MPEG-PCL) for paclitaxel (PTX) delivery. MPEG-PCL was synthesized by ring-opening polymerization in which the hydroxyl group was substituted for a carboxyl group by succinic anhydride. PTX was then coupled to carboxylated MPEG-PCL through esterification (MPEG-PCL-PTX). MPEG-PCLPTX micelles were prepared by a solvent evaporation method. Conjugation of PTX to MPEG-PCL-PTX was confirmed by 1H NMR. MPEG-PCL-PTX micelles self-assembled into micellar nanoparticles at concentrations above 2.5 x 10-2 mg/mL, as evaluated by fluorescence spectrometry. DLS and TEM analyses revealed that the micelles were globular in shape with an average size of 111 nm. The drug release studies under three pH conditions demonstrated that PTX release from MPEG-PCL-PTX micelles was entirely dependent upon the hydrolysis of ester bond between PTX and MPEG-PCL copolymer, therefore, no severe initial burst release but pH sensitive profile was observed. In vitro tests with the 4T1 cell line showed that conjugation of PTX to MPEG-PCL led to improved cellular uptake and apoptosis compared to free PTX, supporting the feasibility of using the micelles as drug carriers for cancer therapy.

Keywords:Poly(ethylene glycol)-b-poly;(ε-caprolactone) (MPEG-PCL);Paclitaxel (PTX);MPEG-PCL-PTX;4T1 cell line;Cancer therapy

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[Referenced By]

[1] Walsh V, Goodman J, Soc. Sci. Med., 49, 1215 (1999)

[2] Spencer CM, Faulds D, Drugs, 48, 794 (1994)

[3] Gill PS, Tulpule A, Espina BM, Cabriales S, Bresnahan J, Ilaw M, Louie S, Gustafson NF, Brown MA, Orcutt C, Winograd B, Scadden DT, J. Clin. Oncol., 17, 1876 (1999)

[4] Weiss RB, Donehower RC, Wiernik PH, Ohnuma T, Gralla RJ, Trump DL, Baker JR, Echo DAV, Hoff DDV, Leyland-Jones B, J. Clin. Oncol., 8, 1263 (1990)

[5] Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A, Tao C, De T, Beals B, Dykes D, Noker P, Yao R, Labao E, Hawkins M, Soon-Shiong P, Clin.Cancer.Res., 12, 1317 (2006)

[6] Adams ML, Lavasanifar A, Kwon GS, J. Pharm. Sci., 92, 1343 (2003)

[7] Chiellini E, Solaro R, Adv. Mater., 8(4), 305 (1996)

[8] Ma P, Mumper RJ, J. Nanomed. Nanotechnol., 4, 100016 (2013)

[9] Abedalwafa M, Wang F, Wang L, Li C, Rev. Adv. Mater. Sci., 34, 123 (2012)

[10] Allen C, Yu Y, Maysinger D, Eisenberg A, Bioconjug. Chem., 9, 564 (1998)

[11] Nasongkla N, Shuai X, Ai H, Weinberg BD, Pink J, Boothman DA, Gao J, Angew. Chem.-Int. Edit., 43, 6323 (2004)

[12] Knop K, Hoogenboom R, Fischer D, Schubert US, Angew. Chem.-Int. Edit., 49, 6288 (2010)

[13] Klibanov AL, Maruyama K, Beckerleg AM, Torchilin VP, Huang L, Biochim. Biophys. Acta, 1062, 142 (1991)

[14] Moghimi SM, Hunter AC, Murray JC, Pharmacol. Rev., 53, 283 (2001)

[15] Danafar H, Cogent Med., 3, 114241 (2016)

[16] Wang C, Wang Y, Wang Y, Fan M, Luo F, Qian Z, Int. J. Pharm., 414, 251 (2011)

[17] Xin H, Chen L, Gu J, Ren X, wei Z, Luo J, Chen Y, Jiang X, Sha X, Fang X, Int. J. Pharm., 402, 238 (2010)

[18] Sohn JS, Jin JI, Hess M, Jo BW, Polym. Chem., 1, 778 (2010)

[19] Delplace V, Couvreur P, Nicolas J, Polym. Chem., 5, 1529 (2014)

[20] Kim MS, Hyun H, Cho YH, Seo KS, Jang WY, Kim SK, Khang G, Lee HB, Polym. Bull., 55(3), 149 (2005)

[21] Kalyanasundaram K, Thomas JK, J. Am. Chem. Soc., 99, 2039 (1977)

[22] Li Z, Liu GJ, Law SJ, Sells T, Biomacromolecules, 3(5), 984 (2002)

[23] Sugahara SI, Kajiki M, Kuriyama H, Kobayashi TR, Biol. Pharm. Bull., 25, 632 (2002)

[24] Cha EJ, Kim JE, Ahn CH, Eur. J. Pharm. Sci., 38, 341 (2009)

[25] Yan J, Ye Z, Luo H, Chen M, Zhou Y, Tan W, Xiao Y, Zhang Y, Lang M, Polym. Chem., 2, 1331 (2011)

[26] Chang L, Liu J, Zhang J, Deng L, Dong A, Polym. Chem., 4, 1430 (2013)

[27] Nam JP, Park JK, Son DH, Kim TH, Park SJ, Park SC, Choi C, Jang MK, Nah JW, Colloids Surf. B: Biointerfaces, 120, 168 (2014)

[28] Huo Q, Zhu J, Niu Y, Shi H, Gong Y, Li Y, Song H, Liu Y, Int. J. Nanomedicine, 12, 8631 (2017)

[29] Urbano B, Silva P, Olea AF, Fuentes I, Martinez F, J. Chil. Chem. Soc., 53, 1507 (2008)

[30] Gao W, Chan JM, Farokhzad OC, Mol. Pharm., 7, 1913 (2010)

[31] Wei H, Zhuo RX, Zhang XZ, Prog. Polym. Sci, 38, 503 (2013)

[32] Howard MD, Ponta A, Eckman A, Jay M, Bae Y, Pharm. Res., 28, 2435 (2011)

[33] Rivolta I, Panariti A, Lettiero B, Sesana S, Gasco P, Gasco MR, Masserini M, Miserocchi G, J. Physiol. Pharmacol., 62, 45 (2011)

[34] Yoo KD, Kim GH, Noh DI, Jang JW, Shim YB, Chun HJ, Macromol. Res., 21(1), 108 (2013)

[35] Rieger AM, Nelson KL, Konowalchuk JD, Barreda DR, J. Vis. Exp., 50, 2597 (2011)