Antimalarial Polyethylene Glycol–Lumefantrine Conjugates: Synthesis and Effect of Linker Chemistry on Drug Release

ABSTRACT Polymer–drug conjugates have seen limited exploration in antimalarial therapy, despite their successful development for cancer and other diseases. With rising resistance and a critical shortage of first‐line treatments for severe malaria, innovative drug delivery strategies are urgently needed to maximize the currently available drugs. Building on our previous work that demonstrated a water‐soluble polymer–lumefantrine conjugate for the intravenous treatment of severe malaria, we investigated the influence of linker chemistry on drug release rate and kinetics of a new polyethylene glycol‐lumefantrine conjugate under conditions relevant to malaria pathophysiology. Four homologous aliphatic diacid linkers (succinic, glutaric, adipic, and dodecanedioic acids) containing 4, 5, 6, and 12 carbon atoms, respectively, were introduced between the polymer and the drug. The conjugates were structurally well‐defined and selectively cleaved at the ester bond under acidic conditions (pH 5.5), releasing only free lumefantrine, while remaining stable in human plasma (pH 7.4). Drug release rates were inversely proportional to linker length, with only the succinic acid‐linked conjugate, which exhibited an initial burst release, deviating from first‐order kinetic models. Complete inhibition of the Plasmodium falciparum NF54 strain was observed in vitro with a divalent variant of the succinic acid‐linked conjugate, underscoring its potential for effective therapeutic action.