Abstract
In this study, we synthesized deoxycholic acid (DA)-conjugated dextran (DexDA) and prepared doxorubicin (DOX)-encapsulated nanoparticles using DexDA conjugates. Since DexDA conjugates have amphiphilic properties, they will show self-aggregation behavior at aqueous environment. To approve self-aggregation behavior, critical aggregation concentration value of DexDA conjugates was evaluated using fluorescence spectroscopy. DOX-incorporated DexDA nanoparticles were less than 200 nm. The higher substitution degree of DA and higher drug feeding ratio resulted in increased particle size. Drug release was decreased by increase of substitution degree value of DA and increase of drug feeding ratio. At in vitro cytotoxicity test using DOX-resistant CT26 colon carcinoma cells, higher antitumor activity was obtained with DOX-incorporated nanoparticles compared to free DOX. Fluorescence microscopic observation verified this result, i.e. nanoparticles were properly entered into tumors cells and maintained longer compared to DOX itself. These results suggested that DOX-incorporated DexDA nanoparticles are promising vehicles for antitumor drug delivery.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Akiyoshi, K., Kobayashi, S., Shichibe, S., Mix, D., Baudys, M., Kim, S. W., and Sunamoto, J., Self-assembled hydrogel nanoparticle of cholesterol-bearing pullulan as a carrier of protein drugs: complexation and stabilization of insulin. J. Control. Release, 54, 313–320 (1998).
Allémann, E., Gurny, R., and Doelker, E., Drug-loaded nanoparticles-preparation methods and drug targeting issues. Eur. J. Pharm. Biopharm., 39, 173–191 (1993).
Bennis, S., Chapey, C., Couvreur, P., and Robert, J., Enhanced cytotoxicity of doxorubicin encapsulated in polyisohexylcyanoacrylate nanospheres against multidrug-resistant tumour cells in culture. Eur. J. Cancer, 30A, 89–93 (1994).
Dreher, M. R., Liu, W., Michelich, C. R., Dewhirst, M. W., Yuan, F., and Chilkoti, A., Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J. Natl. Cancer Inst., 98, 335–344 (2006).
Estey, E., Thall, P. F., Mehta, K., Rosenblum, M., Brewer, T., Jr., Simmons, V., Cabanillas, F., Kurzrock, R., and Lopez-Berestein, G., Alterations in tretinoin pharmacokinetics following administration of liposomal all-trans retinoic acid. Blood, 87, 3650–3654. (1996)
Gianni, L., Dombernowsky, P., Sledge, G., Martin, M., Amadori, D., Arbuck, S. G., Ravdin, P., Brown, M., Messina, M., Tuck, D., Weil, C., and Winograd, B., Cardiac function following combination therapy with paclitaxel and doxorubicin: an analysis of 657 women with advanced breast cancer. Ann. Oncol., 12, 1067–1073 (2001).
Gref, R., Minamitake, Y., Peracchia, M. T., Trubetskoy, V., Torchilin, V., and Langer, R., Biodegradable long-circulating polymeric nanospheres. Science, 263, 1600–1603 (1994).
Ichinose, K., Tomiyama, N., Nakashima, M., Ohya, Y., Ichikawa, M., Ouchi, T., and Kanematsu, T., Antitumor activity of dextran derivatives immobilizing platinum complex (II). Anticancer Drugs, 11, 33–38 (2000).
Jeong, Y. I., Cheon, J. B., Kim, S. H., Nah, J. W., Lee, Y. M., Sung, Y. K., Akaike, T., and Cho, C. S., Clonazepam release from core-shell type nanoparticles in vitro. J. Control. Release., 51, 169–178 (1998).
Jeong, Y. I., Shim, Y. H., Kim, C., Lim, G. T., Choi, K. C., and Yoon, C., Effect of cryoprotectants on the reconstitution of surfactant-free nanoparticles of poly(DL-lactide-co-glycolide). J. Microencapsul., 22, 593–601 (2005).
Jeong, Y. I., Choi, K. C., and Song, C. E., Doxorubicin Release from Core-Shell Type Nanoparticles of Poly(DL-lactideco-glycolide)-Grafted Dextran. Arch. Pharm. Res., 29, 712–719 (2006).
Jung, S. W., Jeong, Y. I., Kim, Y. H., Choi, K. C., and Kim, S. H., Drug release from core-shell type nanoparticles of poly(DL-lactide-co-glycolide)-grafted dextran. J. Microencapsul., 22, 901–911 (2005).
Kataoka, K., Kwon, G. S., Yokoyama, M., Okano, T., and Sakurai, Y., Block copolymer micelles as vehicles for drug delivery. J. Control. Release, 24, 119–132 (1993).
Konan, Y. N., Gurny, R., and Allémann, E., Preparation and characterization of sterile and freeze-dried sub-200 nm nanoparticles. Int. J. Pharm., 233, 239–252 (2002).
Kreuter, J., Nanoparticle-based drug delivery system. J. Control. Release, 16, 169–176 (1991).
Kwon, G. S., Naito, M., Yokoyama, M., Okano, T., Sakurai, Y., and Kataoka, K., Polymeric micelles based on AB block copolymers of poly(ethylene oxide) and poly(β-benzyl Laspartate). Langmuir, 9, 945–949 (1993).
La, S. B., Okano, T., and Kataoka, K., Preparation and characterization of the micelle-forming polymeric drug indomethacin-incorporated poly(ethylene oxide)-poly(-benzyl L-aspartate) block copolymer micelles. J. Pharm. Sci., 85, 85–90 (1996).
Lehn, J. M., Supramolecular chemistry. Science, 260, 1762–1763 (1993).
Mehvar, R., Recent trends in the use of polysaccharides for improved delivery of therapeutic agents: pharmacokinetic and pharmacodynamic perspectives. Curr. Pharm. Biotechnol., 4, 283–302 (2003).
Molteni, L., Dextran and inulin conjugates as drug carriers. Methods Enzymol., 112, 285–298 (1985).
Nishikawa, T., Akiyoshi, K., and Sunamoto, J., Supramolecular assembly between nanoparticles of hydrophobized polysaccharide and soluble protein complexation between the selfaggregate of cholesterol-bearing pullulan and á-chymotrypsin. Macromolecules, 27, 7654–7659 (1994).
Sakai, M., Imai, T., Ohtake, H., Azuma, H., and Otagiri, M., Simultaneous use of sodium deoxycholate and dipotassium glycyrrhizinate enhances the cellular transport of poorly absorbed compounds across Caco-2 cell monolayers. J. Pharm. Pharmacol., 51, 27–33 (1999).
Sugahara, S., Kajiki, M., Kuriyama, H., and Kobayashi, T. R., Complete regression of xenografted human carcinomas by a paclitaxel-carboxymethyl dextran conjugate (AZ10992). J. Control. Release, 117, 40–50 (2007).
Van Dijk-Wolthuis, W. N. E., Franssen, O., Talsma, H., Van Steenbergen, M. J., Kettenes-Van den Bosch, J. J., and Hennink, W. E., Synthesis, characterization, and polymerization of glycidyl methacrylate derivatized dextran. Macromolecules, 28, 6317–6322 (1995).
Walsh, M. T. and Atkinson, D., Physical properties of apoprotein B in mixed micelles with sodium deoxycholate and in a vesicle with dimyristoyl phosphatidylcholine. J. Lipid Res., 27, 316–325 (1986).
Watanabe, E., Sudo, R., Takahashi, M., and Hayashi, M., Evaluation of absorbability of poorly water-soluble drugs: validity of the use of additives. Biol. Pharm. Bull., 23, 838–843 (2000).
Wilhelm, M., Zaho, C. L., Wang, Y., Xu, R., Winnik, M. A., Mura, J. L., Riess, G., and Croucher, M. D., Poly(styreneethylene oxide) block copolymer micelle formation in water: a fluorescence probe study. Macromolecules, 24, 1033–1040 (1991).
Yokoyama, M., Okano, T., Sakurai, Y., Ekimoto, H., Shibazaki, C., and Kataoka, K., Toxicity and antitumor activity against solid tumors of micelleforming polymeric anticancer drug and its extremely long circulation in blood. Cancer Res., 51, 3229–3236 (1991).
Zimmermann, E., Müller, R. H., and Mäder, K., Influence of different parameters on reconstitution of lyophilized SLN Int. J. Pharm., 196, 211–213 (2000).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jeong, YI., Chung, KD. & Choi, K.C. Doxorubicin release from self-assembled nanoparticles of deoxycholic acid-conjugated dextran. Arch. Pharm. Res. 34, 159–167 (2011). https://doi.org/10.1007/s12272-011-0119-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-011-0119-y