2.B.38. The Glycodendrimer Carrier (Glycodendrimer) Family
Fludarabine, a nucleoside analogue antimetabolite, has complicated pharmacokinetics requiring facilitated transmembrane transport and intracellular conversion to a triphosphate nucleotide form (Ara-FATP), causing it to be susceptible to emergence of drug resistance. Gorzkiewicz et al. 2018 tested a strategy to improve its clinical efficacy by direct delivery of Ara-FATP utilizing a biocompatible glycodendrimer nanocarrier system. They presented results of a proof-of-concept experiment in several in vitro-cultured leukemic cell lines (CCRF, THP-1, U937) using noncovalent complexes of maltose-modified poly(propyleneimine) dendrimer and fludarabine triphosphate. Ara-FATP had limited cytotoxic activity relative to free nucleoside (Ara-FA), but complexation with the glycodendrimer (which does not otherwise influence cellular metabolism) drastically increased its toxicity. Moreover, transport via hENT1 was a limiting step in Ara-FA toxicity, while complexation with dendrimer allowed Ara-FATP to kill cells even in the presence of a hENT1 inhibitor. Thus, the use of glycodendrimers for drug delivery allowed the circumvention of naturally occurring drug resistance due to decreased transporter activity. Complex formation did not change the advantageous multifactorial intracellular pharmacodynamics of Ara-FATP, preserving its high capability to inhibit DNA and RNA synthesis and induce apoptosis via the intrinsic pathway. In comparison to other nucleoside analogue drugs, fludarabine is an optimal candidate for maltose glycodendrimer-mediated drug delivery in antileukemic therapy.