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    2020-08-18


    Grant support
    This study was supported by Helse Vest, the University of Bergen, the Norwegian Cancer Society, the Research Council of Norway, Bergen Research Foundation, by the Dutch Cancer Society (‘KWF Kankerbestrijding’: www.kwf.nl), contract number UM-13-5782 granted to RA and by Biocenter Finland (grant to AS).
    Conflict of interest statement
    There are no conflicts of interest to disclose.
    Author contribution
    ILT, CK, AR designed and planned study.
    ILT, HFB, JT gathered clinical samples and collected patient data.
    SA, MH performed steroid analysis.
    KEF, ISH performed fat distribution analysis.
    TS performed RNA sequencing.
    ILT, KEF, AJ, TS, ES, CK, AR performed data analyses.
    ILT, CK, AR interpreted data, prepared figures and tables and wrote the manuscript.
    References
    [23] P. Maurovich-Horvat, J. Massaro, C.S. Fox, F. Moselewski, C.J. O'Donnell, U. Hoffmann, Comparison of anthropometric, area- and volume-based assessment of abdominal subcutaneous and visceral adipose tissue volumes using multi-detector computed tomography, Int. J. Obes. 31 (2007) 500–506.
    [37] K. Ito, Y. Miki, T. Suzuki, K.M. McNamara, H. Sasano, In situ androgen and Alternariol biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production, Endocr. Relat. Cancer 23 (2016) R323–R335.
    Contents lists available at ScienceDirect
    European Polymer Journal
    journal homepage: www.elsevier.com/locate/europolj
    Blood-compatible, stable micelles of sodium alginate – Curcumin bioconjugate for anti-cancer applications 
    T
    Dorota Lachowicza, Alicja Karabaszb, Monika Bzowskab, Michał Szuwarzyńskia, Anna Karewiczc, , Maria Nowakowskac
    a AGH University of Science and Technology, Academic Centre for Materials and Nanotechnology, al. A. Mickiewicza 30, 30-059 Krakow, Poland
    b Department of Cell Biochemistry, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland
    c Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Kraków, Poland
    Keywords:
    Curcumin
    Sodium alginate
    Bioconjugate
    Cross-linked micelles
    Anti-cancer activity 
    The bioconjugate of alginate and curcumin (AA-CUR) was synthesized in a simple, one-step process and used to prepare the stable calcium cross-linked spherical micelles serving as a delivery vehicle for curcumin. Above its critical micelle concentration (0.6 mg/ml) AA-CUR forms colloidally stable micelles of ca. 200 nm. Prolonged, well controlled release of curcumin was observed from the AA-CUR micelles cross-linked with calcium ions for 5 h under the physiological conditions. To assess the safety of applying the bioconjugate into the bloodstream for possible anti-cancer applications, the interaction between AA-CUR and cells isolated from human blood was analyzed. No red cells aggregation or hemolysis was observed. AA-CUR was also shown to have no significant cytotoxicity to the human Peripheral Blood Mononuclear Cells (PBMC) isolated from peripheral blood of healthy donors and to the mouse primary brain endothelial cells. To evaluate the efficiency of the obtained bioconjugate in the anti-cancer therapy, the micellar solution of AA-CUR was tested against various cancer cells lines: mammary carcinoma 4T1, melanoma B16F10 and colon carcinoma CT26-CEA and MC38-CEA. The bioconjugate at the concentration of 0.7 mg/ml decreased the viability of cancer cells by ca. 80%. The cellular uptake of AA-CUR was rapid and the highest micelles accumulation was detected within 1 h after treatment. The AA-CUR micellar system can serve as an effective and safe delivery vehicle for curcumin.
    1. Introduction
    Low solubility and low stability in aqueous media are limiting fac-tors in applying a number of biologically active compounds as drugs. There are various approaches to mitigate these problems. One of them is to synthesize the bioconjugate of biologically active compound with polymer. Properly chosen macromolecules can serve as carriers, sig-nificantly increasing the water solubility of the bound active com-pound, which would be otherwise too hydrophobic or unstable to be delivered efficiently to the human body. This idea has been widely explored in literature, as various polymeric conjugates of biologically active compounds were developed and studied [1–4].
    Curcumin, a natural polyphenol obtained from turmeric, is well known for its anti-inflammatory, anti-oxidant and anticancer activities. Its bioavailability, however, is low, mostly due to its high hydro-phobicity resulting in low solubility in aqueous media, and its physi-cochemical and biological instability [5–7]. As a solution to this pro-blem various micro- and nanocarriers have been proposed, including