All-trans Retinoic Acid-Associated Low Molecular Weight Water-Soluble Chitosan Nanoparticles Based on Ion Complex

Dong-Gon Kim; Changyong Choi; Young-Il Jeong; Mi-Kyeong Jang; Jae-Woon Nah; Seong-Koo Kang; Moon-Soo Bang

Macromolecular Research, Vol.14, No.1, 66-72, February, 2006

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All-trans Retinoic Acid-Associated Low Molecular Weight Water-Soluble Chitosan Nanoparticles Based on Ion Complex

Dong-Gon Kim, Changyong Choi , Young-Il Jeong, Mi-Kyeong Jang , Jae-Woon Nah^†, Seong-Koo Kang¹, and Moon-Soo Bang²

Department of Polymer Science and Engineering, Sunchon National University, Jeonnam 540-742, Korea
¹Research Instrument Center, Sunchon National University, Jeonnam 540-742, Korea
²Division of Chemical Engineering, Kongju National University, Cheonan 330-717, Korea

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The purpose of this study is to develop novel nanoparticles based on polyion complex formation between low molecular weight water-soluble chitosan (LMWSC) and all-trans retinoic acid (atRA). LMWSC nanoparticles encapsulating atRA based on polyion complex were prepared by mixing of atRA into LMWSC aqueous solution using ultrasonication. In FTIR spectra, the carbonyl group of atRA at 1690 cm-1 disappeared or decreased when ion complexes were formed between LMWSC and atRA. In 1H NMR spectra, specific peaks of atRA disappeared when atRA-encapsulated LMWSC (RAC) nanoparticles were reconstituted into D2O while specific peaks both of atRA and LMWSC appeared in D2O/DMSO (1/3, v/v) mixture. XRD patterns also showed that the crystal peaks of atRA were disappeared by encapsulation into LMWSC nanoparticles. LMWSC nanoparticles encapsulating atRA have spherical shapes with particle size below 200 nm. The mechanism of encapsulation of atRA into LMWSC nanoparticles was thought to be an ion complex formation between LMWSC and atRA. LMWSC nanoparticles showed high atRA loading efficiency over 90% (w/w). AtRA was continuously released from nanoparticles over 10 days. In in vitro cell cytotoxicity test, free atRA showed higher cytotoxic effect against CT 26 colon carcinoma cell line on 1 day. However, RAC nanoparticles showed similar cytotoxicity against CT 26 cells on 2 day. These results suggest the potential for the introduction of LMWSC nanoparticles into various biomedical fields such as drug delivery.

Keywords:low molecular weight water-soluble chitosan;all-trans retinoic acid;polyion complex;nanoparticles;anticancer drug

[References]

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Lim SJ, Kim CK, Int. J. Pharm., 243, 135 (2002)
Choi Y, Kim SY, Kim SH, Lee KS, Kim C, Byun Y, Int. J. Pharm., 215, 67 (2001)
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[1] Hirano S, Polym. Int., 48, 732 (1999)

[2] Feranandez-Urrusuno R, Calvo P, Remunan-Lopez C, Vila-Jato JL, Alonso MJ, Pharm. Res., 16, 1576 (1999)

[3] Kotez AF, de Leeuw BJ, Lueben HL, deBoer AG, Verhoef JC, Junginger HE, Int. J. Pharm., 159, 243 (1997)

[4] Jang MK, Jeong YI, Cho CS, Yang SH, Kang YE, Nah JW, Bull. Korean Chem. Soc., 23, 914 (2002)

[5] Nah JW, Jang MK, J. Polym. Sci. A: Polym. Chem., 40(21), 3796 (2002)

[6] Lee M, Nah JW, Kwon Y, Koh JJ, Ko KS, Kim SW, Pharm. Res., 18, 427 (2001)

[7] Giannini F, Maestro R, Vukosa T, Vljevic T, Pomponi F, Boiocchi M, Int. J. Cancer, 70, 194 (1997)

[8] Krupitza G, Hulla W, Harant H, Dittrich E, Kallay E, Huber H, Int. J. Cancer, 61, 649 (1995)

[9] Huang EJ, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L, Gu LJ, Wang ZY, Blood, 72, 567 (1988)

[10] Conley BA, Egorin MJ, Sridaha R, Finley R, Hemady R, Wu S, Tait NS, Van Echo DA, Cancer Chem. Pharm., 39, 291 (1997)

[11] Frankel SR, Eardley A, Lauwers G, Weiss M, Warrell RP, Ann. Intern. Med., 117, 292 (1992)

[12] Muindi JRF, Frankel SR, Miller WH, Jakubowski A, Scheinberg DA, Young CW, Dmitrovsky E, Warrell RP, Blood, 79, 299 (1992)

[13] Achkar CC, Bentel JM, Boylan JF, Scher HI, Gudas LJ, Miller WH, Drug Metab. Dispos., 22, 451 (1994)

[14] Hirota T, Fujimoto T, Konno K, Sakakibara Y, Katano N, Tsurusawa M, Takitani K, Miyake M, Jap. J. Clin. Hemat., 38, 1170 (1997)

[15] Shelly RS, Jun HW, Price JC, Cadwallader DE, J. Pharm. Sci., 71, 904 (1982)

[16] Lehman PA, Slattery JT, Franz TJ, Percutaneous J. Invest. Dermatol., 91, 56 (1988)

[17] Szuts EZ, Harosi FI, Arch. Biochem. Biophys., 287, 297 (1991)

[18] Giordano GG, Refojo MF, Arroyo MH, Invest. Ophthalmol. Vis. Sci., 34, 2743 (1993)

[19] Extey EH, Giles FJ, Kantarjian H, O'Brien S, Cortes J, Freireich EJ, Lopez-Berestein G, Keating M, Clin. Observ. Interv. Ther., 94, 2230 (1999)

[20] Lim SJ, Kim CK, Int. J. Pharm., 243, 135 (2002)

[21] Choi Y, Kim SY, Kim SH, Lee KS, Kim C, Byun Y, Int. J. Pharm., 215, 67 (2001)

[22] Ezpeleta I, Irache JM, Stainmesse S, Chabenat C, Gueguen J, Popineau Y, Orecchioni AM, Int. J. Pharm., 131, 191 (1996)

[23] Thunemann AF, Beyermann J, Macromolecules, 33(18), 6878 (2000)

[24] Thunemann AF, Beyermann J, Kukula H, Macromolecules, 33(16), 5906 (2000)

[25] Rockley NL, Halley BA, Rockley MG, Nelson EC, Anal. Biochem., 133, 314 (1983)

[26] Nishiyama N, Kataoka K, J. Control. Release, 74, 83 (2001)

[27] Nishiyama N, Okazaki S, Cabral H, Miyamoto M, Kato Y, Sugiyama Y, Nishio K, Matsumura Y, Kataoka K, Cancer Res., 63, 8977 (2003)

[28] Gref R, Minamitake Y, Peracchia MT, Trubetskoy V, Torchilin V, Langer R, Science, 18, 1600 (1994)

[29] Lim SJ, Lee MK, Kim CK, J. Control. Release, 100, 53 (2004)