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Polyamidoamine dendrimers with different surface charge as carriers in anticancer drug delivery

Abstract

Second-generation (G2) polyamidoamine (PAMAM) dendrimers are branched polymers containing 16 surface primary amine groups. Due to their structural properties, these polymers can be used as universal carriers in various drug delivery systems. Amine-terminated PAMAM dendrimers are characterized by a high positive surface charge, leading to effective but nonspecific interactions with negatively charged cell plasmatic membranes. To reduce the nonspecific internalization of PAMAM dendrimers, their primary amine groups are often modified by acetic or succinic anhydrides, polyethylene glycol derivatives and other compounds. In this work, the role of primary amine groups, which are localized on the surface of doxorubicin-conjugated (Dox) dendrimers, was studied with regard to their intracellular distribution and internalization rates using SKOV3 human ovarian adenocarcinoma cells. It was demonstrated that all Dox-labeled G2-derivatives containing different numbers of acetamide groups synthesized in this work show high rates of cellular uptake at 37°С. As expected, the conjugate carrying the maximum number of primary amine groups demonstrated the highest rates of binding and endocytosis. At the same time, the G2-Dox conjugate containing the maximum number of acetamide groups showed colocalization with LAMP2, a marker of lysosomes and late endosomes, as well as the highest level of cytotoxic activity against SKOV3 cells. We conclude that second-generation PAMAM dendrimers are characterized by varied pathways of internalization and intracellular distribution due to the number of primary amine groups on their surface and, as a consequence, a different surface charge.

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Abbreviations

PAMAM:

polyamidoamine dendrimers

G2:

second-generation polyamidoamine dendrimers

Dox:

doxorubicin

SKOV3:

human ovarian adenocarcinoma cells

G2-Dox:

doxorubicin-conjugated second-generation polyamidoamine dendrimers

LAMP2:

lysosomal and late endosomal marker

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Correspondence to N. G. Yabbarov.

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Original Russian Text © N.G. Yabbarov, E.D. Nikolskaya, O.A. Zhunina, I.G. Kondrasheva, I.A. Zamulaeva, E.S. Severin, 2017, published in Bioorganicheskaya Khimiya, 2017, Vol. 43, No. 2, pp. 180–188.

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Yabbarov, N.G., Nikolskaya, E.D., Zhunina, O.A. et al. Polyamidoamine dendrimers with different surface charge as carriers in anticancer drug delivery. Russ J Bioorg Chem 43, 155–162 (2017). https://doi.org/10.1134/S1068162017020182

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  • DOI: https://doi.org/10.1134/S1068162017020182

Keywords

  • dendrimers
  • doxorubicin
  • receptor-mediated endocytosis
  • acid-labile linker
  • antitumor drugs