Abstract
Acetylshikonin (AS) has demonstrated antitumor potential. However, the development of therapeutic applications utilizing AS is inhibited by its poor solubility in water. In the present work, polyamidoamine (PAMAM) dendrimers and their PEGylated derivatives were employed to increase the solubility of AS. A distinct color transition was observed during the encapsulation of AS suggesting strong intermolecular forces between PAMAM and AS. Ultraviolet–visible, high-performance liquid chromatography, and 1H NMR were used to verify the interaction between PAMAM and AS. The maximum amount of combined AS to each PAMAM molecule was determined. The cytotoxicity of AS nanoparticles was evaluated against leukemia (K562) and breast cancer (SK-BR-3) cell lines; the AS nanoparticles were shown to effectively inhibit tumor cells.
Similar content being viewed by others
References
Papageorgiou VP. Naturally occurring isohexenylnaphthazarin pigments: a new class of drugs. Planta Med. 1980;38(03):193–203.
Hayashi M. Pharmacological studies of Shikon and Tooki. (2) Pharmacological effects of the pigment components, shikonin and acetylshikonin. Nihon yakurigaku zasshi. Folia pharmacol Jpn. 1977;73(2):193–203.
Sankawa U, Ebizuka Y, Miyazaki T, Isomura Y, Otsuka H. Antitumor activity of shikonin and its derivatives. Chem Pharm Bull. 1977;25(9):2392.
Papageorgiou VP, Assimopoulou AN, Samanidou V, Papadoyannis I. Recent advances in chemistry, biology and biotechnology of alkannins and shikonins. Curr Org Chem. 2006;10(16):2123–42.
Chang YS, Kuo SC, Weng SH, Jan SC, Ko FN, Teng CM. Inhibition of platelet aggregation by shikonin derivatives isolated from Arnebia euchroma. Planta Med. 1993;59(05):401–4.
Staniforth V, Wang SY, Shyur LF, Yang NS. Shikonins, phytocompounds from Lithospermum erythrorhizon, inhibit the transcriptional activation of human tumor necrosis factor α promoter in vivo. J Biol Chem. 2004;279(7):5877–85.
Lee HJ, Lee HJ, Magesh V, Nam D, Lee EO, Ahn KS, et al. Shikonin, acetylshikonin, and isobutyroylshikonin inhibit VEGF-induced angiogenesis and suppress tumor growth in lewis lung carcinoma-bearing mice. Yakugaku Zasshi. 2008;128(11):1681–8.
Zeng Y, Liu G, Zhou LM. Inhibitory effect of acetylshikonin on human gastric carcinoma cell line SGC-7901 in vitro and in vivo. World J Gastroenterol. 2009;15(15):1816.
Rajasekar S, Park DJ, Park C, Park S, Park YH, Kim ST, et al. In vitro and in vivo anticancer effects of Lithospermum erythrorhizon extract on B16F10 murine melanoma. J Ethnopharmacol. 2012;144:335–45.
Svenson S, Tomalia DA. Dendrimers in biomedical applications—reflections on the field. Adv Drug Deliv Rev. 2012;57:2106–29.
Yiyun C, Tongwen X. Dendrimers as potential drug carriers. Part I. Solubilization of non-steroidal anti-inflammatory drugs in the presence of polyamidoamine dendrimers. Eur J Med Chem. 2005;40(11):1188–92.
D’Emanuele A, Attwood D. Dendrimer–drug interactions. Adv Drug Deliv Rev. 2005;57(15):2147–62.
Maingi V, Kumar MVS, Maiti PK. PAMAM dendrimer–drug interactions: effect of pH on the binding and release pattern. J Phys Chem B. 2012;116(14):4370–6.
Gupta U, Agashe HB, Asthana A, Jain N. Dendrimers: novel polymeric nanoarchitectures for solubility enhancement. Biomacromolecules. 2006;7(3):649–58.
Zhao L, Wu Q, Cheng Y, Zhang J, Wu J, Xu T. High-throughput screening of dendrimer-binding drugs. J Am Chem Soc. 2010;132(38):13182–4.
Malik N, Wiwattanapatapee R, Klopsch R, Lorenz K, Frey H, Weener J, et al. Dendrimers: relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of 125I-labelled polyamidoamine dendrimers in vivo. J Control Release. 2000;65(1):133–48.
Bhadra D, Bhadra S, Jain S, Jain N. A PEGylated dendritic nanoparticulate carrier of fluorouracil. Int J Pharm. 2003;257(1):111–24.
Luo D, Haverstick K, Belcheva N, Han E, Saltzman WM. Poly(ethylene glycol)-conjugated PAMAM dendrimer for biocompatible, high-efficiency DNA delivery. Macromolecules. 2002;35(9):3456–62.
Jiang YY, Tang GT, Zhang LH, Kong SY, Zhu SJ, Pei YY. PEGylated PAMAM dendrimers as a potential drug delivery carrier: in vitro and in vivo comparative evaluation of covalently conjugated drug and noncovalent drug inclusion complex. J Drug Target. 2010;18(5):389–403.
Rundle R, Foster JF, Baldwin R. On the nature of the starch—iodine complex 1. J Am Chem Soc. 1944;66(12):2116–20.
Kontogiannopoulos KN, Assimopoulou AN, Hatziantoniou S, Karatasos K, Demetzos C, Papageorgiou VP. Chimeric advanced drug delivery nano systems (chi-aDDnSs) for shikonin combining dendritic and liposomal technology. Int J Pharm. 2011;422:381–9.
Malam Y, Loizidou M, Seifalian AM. Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. Trends Pharmacol Sci. 2009;30(11):592–9.
Gullotti E, Yeo Y. Extracellularly activated nanocarriers: a new paradigm of tumor targeted drug delivery. Mol Pharm. 2009;6(4):1041–51.
Utreja S, Khopade A, Jain N. Lipoprotein-mimicking biovectorized systems for methotrexate delivery. Pharm Acta Helv. 1999;73(6):275–9.
Cho MH, Paik YS, Hahn TR. Physical stability of shikonin derivatives from the roots of Lithospermum erythrorhizon cultivated in Korea. J Agric Food Chem. 1999;47(10):4117–20.
Majoros IJ, Myc A, Thomas T, Mehta CB, Baker JR. PAMAM dendrimer-based multifunctional conjugate for cancer therapy: synthesis, characterization, and functionality. Biomacromolecules. 2006;7(2):572–9.
Buczkowski A, Sekowski S, Grala A, Palecz D, Milowska K, Urbaniak P, et al. Interaction between PAMAM-NH2 G4 dendrimer and 5-fluorouracil in aqueous solution. Int J Pharm. 2011;408(1):266–70.
Acknowledgments
This work was supported by the Natural Science Foundation of Jiangsu Province grant (no. BK2011771) and the Fundamental Research Funds for the Central Universities (no. JKQ2011019).
Author information
Authors and Affiliations
Corresponding authors
Additional information
Jianqing Peng, Wen Zhou, and Xinyi Xia contributed equally to this work.
Rights and permissions
About this article
Cite this article
Peng, J., Zhou, W., Xia, X. et al. Encapsulation of Acetylshikonin by Polyamidoamine Dendrimers for Preparing Prominent Nanoparticles. AAPS PharmSciTech 15, 425–433 (2014). https://doi.org/10.1208/s12249-014-0074-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1208/s12249-014-0074-2