Products Cited in Publications Worldwide Cytarabine and dexamethasone-PAMAM dendrimer di-conjugate sensitizes human acute myeloid leukemia cells to apoptotic cell death

Cytarabine and dexamethasone-PAMAM dendrimer di-conjugate sensitizes human acute myeloid leukemia cells to apoptotic cell death

Wrobel, Konrad; Deregowska, Anna; Betlej, Gabriela; Walczak, Malgorzata; Wnuk, Maciej; Lewinska, Anna; Wolowiec, Stanislaw

DOI:

Abstract

Polyamidoamine (PAMAM) dendrimers are widely used as a part of drug delivery systems (DDS) to improve anticancer drug bioavailability. In the present study, monophosphates of nucleosides, anti-nucleosides (cytarabine, C and fludarabine, F) and synthetic glucocorticoid dexamethasone (D) were attached to the third generation (G3) PAMAM dendrimer via phosphamide pH-sensitive linker. Conjugates were found to be stable at neutral pH, whereas acid-triggered hydrolysis of phosphamide bond was observed at pH 5. The anticancer action of selected biotinylated mono- and di-conjugates, namely CP-, FP-, DP-CP- and DP-FP-PAMAM dendrimers was then compared to cytotoxic activity of free drugs using four cellular models of leukemia in vitro, i.e., K-562, LAMA-84, THP-1 and HL-60 cells. Ten nM DP-CP-conjugate lowered metabolic activity, caused G0/G1 cell cycle arrest and induced apoptotic cell death in HL-60 cells compared to non-cytotoxic and non-cytostatic action of free drugs when used at the same concentration 10 nM CP-, DP-FP- and FP-conjugates also promoted a decrease in metabolic activity in K-562, LAMA-84, and THP-1 and HL-60 cells, resp., however, without a sign of cytotoxicit. In conclusion, we show that the anticancer potential of CP and FP in leukemia cells may be enhanced by the conjugation with PAMAM dendrimers, especially in the presence of DP in selected exptl. settings.

Keywords

PAMAM G3 dendrimer conjugates ; Cytarabine ; Fludarabine ; Dexamethasone ; pH-cleavable linker ; Leukemia cell apoptosis

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