암 치료를 위한 Poly(ethylene glycol)-Doxorubicin/SPION 자성 나노입자의 제조 및 특성분석

김유경; 이선민; 김단비; 노강민; 오근상; 조성훈; 최은표; 김규표; 허강무; Yugyeong Kim; Seonmin Lee; Danbee Kim; Kangmin Noh; Keun Sang Oh; Sunghoon Cho; Eunpyo Choi; Kyu-pyo Kim; Kang Moo Huh

Polymer(Korea), Vol.42, No.6, 1059-1067, November, 2018

DOI10.7317/pk.2018.42.6.1059 Export Citation

암 치료를 위한 Poly(ethylene glycol)-Doxorubicin/SPION 자성 나노입자의 제조 및 특성분석

Preparation and Characterization of Poly(ethylene glycol)-Doxorubicin/SPION Magnetic Nanoparticles for Cancer Therapy

김유경¹, 이선민², 김단비², 노강민¹, 오근상¹, 조성훈³, 최은표^{3, 4}, 김규표^{2, †}, 허강무^{1, †}

¹충남대학교 고분자공학과
²서울아산병원 의생명연구소
³전남대학교 로봇연구소 마이크로의료로봇센터
⁴전남대학교 기계공학부

Yugyeong Kim¹, Seonmin Lee², Danbee Kim², Kangmin Noh¹, Keun Sang Oh¹, Sunghoon Cho³, Eunpyo Choi^{3, 4}, Kyu-pyo Kim^{2, †}, and Kang Moo Huh^{1, †}

¹Dept. of Polymer Science and Engineering, Chungnam National University, 99 Daehakro, Yuseonggu, Daejeon 34134, Korea
²Asan Medical center, Biomedical Research Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
³Medical Microrobot Center, Robot Research Initiative, Chonnam National University, Gwangju 61011, Korea
⁴Department of Mechanical Engineering, Chonnam National University, Gwangju 61186, Korea

E-mail:,

초록

본 연구에서는 친수성 poly(ethylene glycol)(PEG)와 소수성 항암제인 독소루비신(DOX)의 화학적 결합에 의해 합성된 PEG-DOX conjugate를 이용하여 암 진단 및 치료가 가능한 자성 나노입자를 제조하고자 하였다. 양친매성 PEG-DOX는 수용액 내에서 자기조립 특성을 보이고, 10 nm 내외의 자성 나노입자(SPION)에 대해 높은 봉입능 및 봉입률을 보였다. 제조된 PEG-DOX/SPION 나노입자는 ~100 nm의 균일한 사이즈 분포를 가지며 phantom 실험을 통해 조영제로서의 가능성을 확인하였다. 세포독성평가에서 DOX에 비해 낮은 독성을 보였고 최대내성용량(MTD) 평가실험에서 사망 개체가 발생하지 않았다. 결과적으로, 고함량의 항암제와 SPION으로 구성된 본 나노입자 시스템은 낮은 독성, MR 조영 특성, 수동적 및 자성 표적화능 등 다양한 생기능성을 기반으로 암 진단 및 치료에 유용한 테라그노스틱 제형에 응용될 수 있을 것으로 기대한다.

In this study, an amphiphilic polymer-drug conjugate was synthesized by chemical conjugation of a hydrophilic polymer poly(ethylene glycol) (PEG) with a hydrophobic anticancer agent, doxorubicin (DOX), to prepare magnetic nanoparticles for cancer diagnosis and therapy. The amphiphilic PEG-DOX polymer could self-assemble in the aqueous solution to form nanoparticles (NPs) and efficiently encapsulated superparamagnetic iron oxide nanoparticles (SPION) with high loading capacity and loading efficiency. The resulting SPION encapsulated PEG-DOX (PEG-DOX/SPION) NPs were observed to have an average size of ~100 nm with a narrow and unimodal size distribution and demonstrated the characteristic of MR contrast agent from the phantom experiments. In the toxicity assessment, PEG-DOX/SPION NPs showed lower toxicity than pristine DOX, and no mortality was detected at the maximum MTD. As a result, these magnetic NPs with high contents of DOX and SPION could be utilized as a theragnostic formulation for efficient cancer diagnosis and therapy, due to their diverse potential capacities properties, such as low toxicity, MR imaging character, passive and magnetic targeting properties, and so on.

Keywords:polymer-drug conjugate;PEG;doxorubicin;SPION;cancer diagnosis and therapy

[References]

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Jo SD, Ku SH, Won YY, Kim SH, Kwon IC, Theranostics, 6, 1362 (2016)
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[Referenced By]

[1] Urruticoechea A, Alemany R, Balart J, Villanueva A, Vinals F, Capella G, Curr. Pharm. Des., 16, 3 (2010)

[2] Maeda H, Greish K, Fang J, Adv. Polym. Sci., 193, 103 (2006)

[3] Chatterjee K, Zhang J, Honbo N, Karliner JS, Cardiol., 115, 155 (2010)

[4] Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL, J. Mol. Cell. Cardiol., 52, 1213 (2012)

[5] Volkova M, Russell R, Curr. Cardiol. Rev., 7, 214 (2011)

[6] Cho K, Wang X, Nie S, Chen ZG, Shin DM, Clin. Cancer Res., 14, 1310 (2008)

[7] Cho KJ, Tissue Eng. Regen. Med., 5, 172 (2008)

[8] Wilczewska AZ, Niemirowicz K, Markiewicz KH, Car H, Pharmacol. Rep., 64, 1020 (2012)

[9] Khandare J, Minko T, Prog. Polym. Sci, 31, 359 (2006)

[10] Mahato R, Tai W, Cheng K, Adv. Drug Deliv. Rev., 63, 659 (2011)

[11] Larson N, Ghandehari H, Chem. Mater., 24, 840 (2012)

[12] Kopecek J, Adv. Drug Deliv. Rev., 65, 49 (2013)

[13] Turecek PL, Bossard MJ, Schoetens F, Ivens IA, J. Pharm. Sci., 105, 460 (2016)

[14] Yokoyama M, Miyauchi M, Yamada N, Okano T, Sakurai Y, Kataoka K, Inoue S, Cancer Res., 50, 1693 (1990)

[15] Veronese FM, Schiavon O, Pasut G, Mendichi R, Andersson L, Tsirk A, Ford H, Wu G, Kneller S, Davies J, Duncan R, Bioconjugate Chem., 16, 775 (2005)

[16] Wang H, He J, Cao D, Zhang M, Li F, Tam KC, Ni P, Polym. Chem., 6, 4809 (2015)

[17] Pechar M, Braunova A, Ulrich K, J. Bioact. Compat. Polym., 20, 319 (2005)

[18] Fang J, Nakamura H, Maeda H, Adv. Drug Deliv. Rev., 63, 136 (2011)

[19] Krasia-Christoforou T, Georgiou TK, J. Mater. Chem. B, 1, 3002 (2013)

[20] Mulens V, Morales MDP, Barber DF, Int. Sch. Res. Notices, 2013, 14 (2013)

[21] Lee DE, Koo H, Sun IC, Ryu JH, Kim K, Kwon IC, Chem. Soc. Rev., 41, 2656 (2012)

[22] Jo SD, Ku SH, Won YY, Kim SH, Kwon IC, Theranostics, 6, 1362 (2016)

[23] Thomas R, Park IK, Jeong YY, Int. J. Mol. Sci., 14(8), 15910 (2013)

[24] Revia RA, Zhang M, Mater. Today, 19, 157 (2016)

[25] Yuk SH, Oh KS, Cho SH, Lee BS, Kim SY, Kwak BK, Kim K, Kwon IC, Biomacromolecules, 12(6), 2335 (2011)

[26] Lee H, Lee E, Kim DK, Jang NK, Jeong YY, Jon S, J. Am. Chem. Soc., 128(22), 7383 (2006)

[27] Gnanaprakash G, Yyappan SA, Jayakumar T, Philip J, Raj B, Nanotechnology, 17, 5851 (2006)

[28] Zhang Y, Huang Y, Zhao W, Lu J, Zhang P, Zhang X, Li J, Gao X, Venkataramanan R, Li S, AAPS J., 16, 1282 (2014)

[29] Gautier J, Allard-Vannier E, Munnier E, Souce M, Chourpa I, J. Control. Release, 169, 48 (2013)

[30] Gautier J, Munnier E, Douziech-Eyrolles L, Paillard A, Dubois P, Chourpa L, Analyst, 138, 7354 (2013)

[31] Bachur NR, Friedman RD, Holenbeck RG, Cancer Chemother. Pharmacol., 12, 5 (1984)

[32] Fiallo M, Laigle A, Garnier-Suillerot A, Amirand C, Dallini J, Chinsky L, Duquesne M, Jolles B, Sureau F, Turpin P, Vigny P, Biochim. Biophys. Acta, 1177, 236 (1993)

[33] Ha DC, Lee HY, Son YW, Yuk SH, Choi YW, Kwak BK, Shin BC, Cho CW, Cho SH, Nanoscale Res. Lett., 9, 38 (2014)

[34] Reddy AM, Kwak BK, Shim HJ, Ahn C, Lee HS, Suh YJ, Park ES, J. Korean Med. Sci., 25, 211 (2010)