플루페나민산이 담지된 키토산 나노입자의 제조 및 항암 효과

안준혁; 나재운; 정경원; Jun-Hyuk Anh; Jae-Woon Nah; Gyeong-Won Jeong

Polymer(Korea), Vol.45, No.5, 680-687, September, 2021

DOI10.7317/pk.2021.45.5.680 Export Citation

플루페나민산이 담지된 키토산 나노입자의 제조 및 항암 효과

Preparation and Anticancer Effect of Flufenamic Acid-loaded Chitosan Nanoparticle

안준혁, 나재운 ^†, 정경원^{1, †}

순천대학교 공과대학 고분자공학과
¹조선이공대학교 생명환경화공과

Jun-Hyuk Anh, Jae-Woon Nah^†, and Gyeong-Won Jeong^{1, †}

Department of Polymer Science and Engineering, Sunchon National University, 255 Jungang-ro, Suncheon, Jeonnam 57922, Korea
¹Department of Bioenvironmental & Chemical Engineering, Chosun College of Science and Technology, Gwangju 61453, Korea

E-mail:,

초록

플루페나민산(flufenamic acid, FA)은 방광암 치료 약물로 잘 알려져 있으나, 자체 사용 시 체내의 면역반응과 약물 내성으로 인해 그 치료 효과가 반감하는 문제점을 갖고 있다. 이러한 문제를 해결하기 위해 본 연구에서는 core-shell 형태의 구조의 나노입자를 제조하고 소수성 core 내부에 FA를 담지하여 그 치료 효과를 극대화하고자 하였다. 친수성 고분자 low molecular weight water-soluble chitosan(LMWSC)에 소수성 물질 lauric acid(LA)를 화학적 개질을 통해 LMWSC-g-LA(LMLA)를 합성하였고, 1H NMR 분석을 통해 합성되었음을 확인하였다. 또한, FA가 담지된 LMLA(LMLAF) 나노입자는 투석법에 의해 제조하였으며, 이를 DLS, UV-vis spectrophotometer, fluorophotometer 그리고 TEM를 이용하여 다양한 물리·화학적 특성을 분석함으로써 합성된 LMLA가 FA 약물 전달체로서 사용 가능함을 입증하였다. 또한, LMLA 및 LMLAF의 세포 독성 및 항암 효과를 다양한 세포에서 MTT assay를 이용하여 확인한 결과 독성이 없으며 높은 항암 효과를 확인하였다. 이러한 결과를 통해 LMLAF 나노입자는 체내에 안전함과 동시에 방광암 치료 효율을 극대화할 수 있는 항암 제제로 사용이 가능할 것으로 사료된다.

Flufenamic acid (FA) is well known as a bladder cancer treatment drug, but when used by itself, its therapeutic effect is halved due to the immune response and drug resistance in the body. To solve this problem, in this study, nanoparticles with a core-shell structure were prepared and FA was encapsulated at the hydrophobic core to maximize the therapeutic effect. LMWSC-g-LA (LMLA) was synthesized by chemical modification of the hydrophobic substance lauric acid (LA) in the hydrophilic polymer low molecular weight water-soluble chitosan (LMWSC), and it was confirmed that the synthesis was successful through 1H NMR analysis. In addition, FA-encapsulated LMLA (LMLAF) nanoparticles were prepared by dialysis method, and utilization of LMLA as FA drug delivery carrier has proven by various physicochemical properties analysis using DLS, UV-vis spectrophotometer, fluorophotometer, and TEM. Moreover, results of the cytotoxicity and anticancer effects of LMLA and LMLAF using MTT assay in various cells showed non-toxic and high anticancer effects. These results suggest that LMLAF nanoparticles can be used as an anticancer agent because they can maximize bladder cancer treatment efficiency while being safe in the body.

Keywords:low molecular weight water-soluble chitosan;flufenamic acid;nanoparticle;drug delivery system;anticancer effect

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[1] Michel L, Rassaf T, Totzeck M, J. Thora. Dis., 10, S4282 (2018)

[2] Wang J, Zheng Y, Zhao M, Front. Pharmacol., 7, 533 (2016)

[3] Allahyari H, Heidari S, Ghamgosha M, Saffarian P, Amani J, Tumour Biology., 39, 1010428317692226 2017.

[4] Kundranda MN, Niu J, Drug Des. Devel. Ther., 9, 3767 (2015)

[5] Silva EF, Bazoni RF, Ramos EB, Rocha MS, Biopolymers., 107, e22998 (2017)

[6] Behnam B, Rezazadehkermani M, Ahmadzadeh S, Mokhtarzadeh A, Nematollahi-Mahani SN, Pardakhty A, Artif. Cells Nanomed. Biotechnol., 46, 118 (2018)

[7] Aboian MS, Yu JF, Gautam A, Sze CH, Yang JK, et al., Biomed. Microdevices, 18, 98 (2016)

[8] Meredith AM, Dass CR, J. Pharm. Pharmacol., 68, 729 (2016)

[9] Saraiva CR, Praca C, Ferreira R, Santos T, Ferreira L, Bernardino L, J. Control. Release, 235, 34 (2016)

[10] Matoba T, Koga JI, Nakano K, Egashira K, Tsutsui H, J. Cardiology., 70, 206 (2017)

[11] Mangal S, Gao W, Li T, Zhou QT, Acta Pharmacol. Sin., 38, 782 (2017)

[12] Park J, Choi Y, Chang H, Um W, Ryu JH, Kwon IC, Theranostics., 9, 8073 (2019)

[13] Baetke SC, Lammers T, Kiessling F, Brit. J. Radiol., 88, 201502 (2015)

[14] Jeong GW, Park SC, Choi C, Nam JP, Kim TH, Choi SK, Park JK, Nah JW, Int. J. Pharm., 488, 165 (2015)

[15] Mammeri M, Chevillot A, Thomas M, Polack B, Julien C, et al., Exp. Parasitol., 194, 1 (2018)

[16] Ribeiro JCV, Vieira RS, Melo IM, Araujo VMA, Lima V, Sci. World J., 8639898 2017.

[17] Matica MA, Aachmann FL, Tondervik A, Sletta H, Ostafe V, Int. J. Mol. Sci., 20, 5889 (2019)

[18] Cheung RC, Ng TB, Wong JH, Chan WY, Mar. Drugs., 13, 5156 (2015)

[19] Shahid UII, Butola BS, Int. J. Biol. Macromol., 121, 905 (2019)

[20] Jang MJ, Kim DG, Jeong YI, Jang MK, Nah JW, Polym. Korea, 31(6), 555 (2007)

[21] Guinamard R, Simard C, Del Negro C, Pharmacol. Ther., 138, 272 (2013)

[22] Sun H, Wei Y, Deng H, Xiong Q, Li M, Lahiri J, Fang Y, Sci. Rep., 4, 4934 (2014)

[23] Smolkova R, Zelenak V, Smolko L, Sabolova D, Kuchar J, Gyepes R, J. Inorg. Biochem., 177, 143 (2017)

[24] Malinovskaja-Gomez K, Labouta HI, Schneider M, Hirvonen J, Laaksonen T, Eur. J. Pharm. Sci., 89, 154 (2016)

[25] Matsumoto R, Tsuda M, Yoshida K, Tanino M, Kimura T, Nishihara H, Abe T, Shinohara N, Nonomura K, Tanaka S, Sci. Rep., 6, 34625 (2016)

[26] Hendriks CM, Penning TM, Zang T, Wiemuth D, Grunder S, Sanhueza IA, Schoenebeck F, Bolm C, Bioorganic Med. Chem. Lett., 25, 4437 (2015)