Abstract
An anthracycline drug, adriamycin, was chemically conjugated onto the backbone of glycol chitosan via an acid-labile cis-aconityl linkage. The physicochemical characteristics of the glycol chitosan–adriamycin (GC–ADR) conjugates were investigated by dynamic light scattering, atomic force microscopy, and fluorescence spectroscopy. The GC–ADR conjugates were capable of forming nano-sized self-aggregates in an aqueous medium, when the adriamycin content in the conjugate was in the range of 2.0–5.0 wt.%. The self-aggregates were spherical in shape, and had mean diameters of 238–304 nm, depending on the adriamycin content. The critical aggregation concentrations of the conjugates, estimated by the fluorescence quenching method, were as low as 1.0–2.5×10−2 mg/ml. The size of self-aggregates was not affected by the polymer concentration in the range from 50 to 2,000 μg/ml, and was maintained up to 8 days in phosphate-buffered saline (pH 7.4), indicating high colloidal stability. The release of adriamycin from self-aggregates was significantly dependent on the pH of the medium due to the cis-aconityl linkage; e.g., the amount of adriamycin released for 4 days was 7.3±0.3% at pH 7, whereas it was 29.3±1.9% at pH 4. The cell viability results demonstrated that free adriamycin shows more potent cytotoxicity than the conjugates, primarily attributed to the sustained release of adriamycin from self-aggregates. In conclusion, the self-aggregates, formed by GC–ADR conjugates, might be useful for the site-specific delivery of adriamycin in a sustained manner.
Similar content being viewed by others
References
Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, Monconduit M, Hulin C, Caillot D, Bouabdallah R, Voillat L, Sotto JJ, Grosbois B, Bataille R (2003) N Engl J Med 349:2495
Matesich SM, Shapiro CL (2003) Semin Oncol 30:740
Ku Y, Iwasaki T, Tominaga M, Fukumoto T, Takahashi T, Kido M, Ogata S, Takahashi M, Kuroda Y, Matsumoto S, Obara H (2004) Ann Surg 239:53
Speth PA, van Hoesel QG, Haanen C (1988) Clin Pharmacokinet 15:15
Bally MB, Nayar R, Masin D, Cullis PR, Mayer LD (1990) Cancer Chemother Pharmacol 27:13
Duncan R (1999) Pharm Sci Technol Today 2:441
Shiah JG, Sun Y, Kopečková P, Peterson CM, Straight RC, Kopeček J (2001) J Control Release 74:249
Satchi-Fainaro R, Hailu H, Davies JW, Summerford C, Duncan R (2003) Bioconjug Chem 14:797
Etrych T, Jelínková M, Říhová B, Ulbrich K (2001) J Control Release 73:89
Shiah JG, Dvořák M, Kopečková P, Sun Y, Peterson CM, Kopeček J (2001) Eur J Cancer 37:131
Matsumura Y, Maeda H (1986) Cancer Res 46:6387
Maeda H, Wu J, Sawa T, Matsumura Y, Hori K (2000) J Control Release 65:271
Rapoport N, Pitt WG, Sun H, Nelson JL (2003) J Control Release 91:85
Adams ML, Lavasanifar A, Kwon GS (2003) J Pharm Sci 92:1343
Lee SC, Kim C, Kwon IC, Chung H, Jeong SY (2003) J Control Release 89:437
Otsuka H, Nagasaki Y, Kataoka K (2003) Adv Drug Deliv Rev 55:403
Gref R, Minamitake Y, Peracchia MT, Trubetskoy V, Torchilin V, Langer R (1994) Science 263:1600
Nakanishi T, Fukushima S, Okamoto K, Suzuki M, Matsumura Y, Yokoyama M, Okano T, Sakurai Y, Kataoka K (2001) J Control Release 74:295
Lee SC, Chang Y, Yoon J, Kim C, Kwon IC, Kim Y, Jeong SY (1999) Macromolecules 32:1847
Kim C, Lee SC, Kang SW, Kwon IC, Kim YH, Jeong SY (2000) Langmuir 16:4792
Huh KM, Lee KY, Kwon IC, Kim YH, Kim C, Jeong SY (2000) Langmuir 16:10566
Nishikawa T, Akiyoshi K, Sunamoto J (1996) J Am Chem Soc 118:6110
Lee KY, Kim JH, Kwon IC, Jeong SY (2000) Colloid Polym Sci 278:1216
Na K, Bae YH (2002) Pharm Res 19:681
Na K, Lee ES, Bae YH (2003) J Control Release 87:3
Kwon S, Park JH, Chung H, Kwon IC, Jeong SY, Kim I (2003) Langmuir 19:10188
Park JH, Kwon S, Nam J, Park R, Chung H, Seo SB, Kim I, Kwon IC, Jeong SY (2004) J Control Release 95:579
Son YJ, Jang J, Cho YW, Chung H, Park R, Kwon IC, Kim I, Park JY, Seo SB, Park CR, Jeong SY (2003) J Control Release 91:135
Nogusa H, Yano T, Okuno S, Hamana H, Inoue K (1995) Chem Pharm Bull 43:1931
Harada A, Kataoka K (1995) Macromolecules 28:5294
Harada A, Kataoka K (1998) Macromolecules 31:288
Hudecz F, Ross H, Price MR, Baldwin RW (1990) Bioconjug Chem 1:197
Wirth M, Fuchs A, Wolf M, Ertl B, Gabor F (1998) Pharm Res 15:1031
Haas M, Moolenaar F, Elsinga A, Van der Wouden EA, de Jong PE, Meijer DK, de Zeeuw D (2002) J Drug Target 10:81
Shen WC, Ryser HJP (1981) Biochem Biophys Res Commun 102:1048
Kratz F, Beyer U, Schutte MT (1999) Crit Rev Ther Drug Carrier Syst 16:245
Yang HM, Reisfeld RA (1988) Proc Natl Acad Sci U S A 85:1189
Gaal D, Hudecz F (1998) Eur J Cancer 34:155
Kwon GS, Naito M, Yokoyama M, Okano T, Sakurai Y, Kataoka K (1995) Pharm Res 12:192
Saha SK, Krishnamoorthy G, Dogra SK (1999) J Photochem Photobiol A Chem 121:191
Cramb DT, Beck SC (2000) J Photochem Photobiol A Chem 134:87
Lee KY, Jo WH, Kwon IC, Kim Y, Jeong SY (1998) Langmuir 14:2329
Na K, Park K, Kim SW, Bae YH (2000) J Control Release 69:225
Dillman RO, Johnson DE, Shawler DL, Koziol JA (1988) Cancer Res 48:6097
Lavie E, Hirschberg DL, Schreiber G, Thos K, Hill L, Hellstrom I, Hellstrom KE (1991) Cancer Immunol Immunother 33:223
Yoo HS, Lee EA, Park TG (2002) J Control Release 82:17
Yoo HS, Lee KH, Oh JE, Park TG (2000) J Control Release 68:419
Acknowledgements
This study was supported by the Ministry of Science and Technology and the Ministry of Commerce, Industry and Energy, Korea.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Park, J.H., Cho, Y.W., Son, Y.J. et al. Preparation and characterization of self-assembled nanoparticles based on glycol chitosan bearing adriamycin. Colloid Polym Sci 284, 763–770 (2006). https://doi.org/10.1007/s00396-005-1438-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00396-005-1438-7