Development and evaluation of novel zein-based artemisinin sustained-release formulation for treating drug-resistant...

Artemisinin antimalarial drugs initially exhibited remarkable efficacy against Plasmodium falciparum. However, their poor solubility and low bioavailability necessitate high doses and lead to an extremely short in vivo half-life. These limitations not only drive the emergence of drug-resistant Plasmodium strains but also compromise long-term therapeutic outcomes. Herein, we report a zein-based sustained release formulation, wherein zein, a natural maize protein, serves as a biocompatible nanocarrier to effectively encapsulate artemisinin (ART). Notably, this nanocarrier formulation achieves a 200-fold enhancement in ART's water solubility, addressing a key bottleneck of ART-based therapies. In vitro assays confirm that the zein-based formulation allows for the sustained release of ART, which could help maintain therapeutic concentrations over extended periods and displayed different release rates and good dispersibility in both acid and basic environments. Importantly, in vitro evaluations also demonstrate that the nanoformulation exerts potent inhibitory effects against ART-resistant P. falciparum strains in both ring survival assay and recrudescence assay, attributed to the sustained maintenance of effective ART concentrations. In vivo studies, utilizing both rodent malaria models and humanized erythrocyte mouse models, further validate the nanoformulation's therapeutic potential. The zein nanocarrier significantly prolongs ART's in vivo half-life via its sustained-release capability, thereby maintaining effective blood concentrations over an extended duration. Compared to free ART, the nanoformulation exhibits superior efficacy in reducing parasitemia, preventing malaria recrudescence, and, most notably, overcoming ART resistance in drug-resistant Plasmodium infections. Collectively, these findings establish the zein-based nanocarrier as a promising strategy to optimize ART-based therapies by addressing solubility and pharmacokinetic limitations while effectively combating drug-resistant malaria.

Half of the world's population is at risk of malaria infection, and artemisinin (ART) turns out to be a powerful medicine for malaria control. The rapid emergence and global spread of resistance to ART have led to a significantly increasing clinical treatment failure rate worldwide. A critical limitation of ART is its extremely short blood half-life (~1 h), which results in rapid declines in plasma drug concentrations below therapeutic thresholds. Some parasites may switch into a "dormant" form, which is less sensitive to ART, resulting in recrudescence following treatment. Thus, developing a sustained-release formulation provides a promising solution to prolong the in vivo half-life of ART. Additionally, its relatively low solubility restricts its in vivo bioavailability, primarily due to the limited dissolution and absorption of the compound in aqueous biological environments. In this study, we prepared a zein-based sustained-release formulation of ART for oral and intraperitoneal administration. Our results indicate that this zein-based sustained release nanoformulation not only significantly improves ART's water solubility (a key barrier to its bioavailability) but also extends its in vivo half-life via controlled drug release. Importantly, the prolonged half-life ensures sustained therapeutic ART concentrations, directly enhancing the formulation's ability against ART-resistant P. falciparum strains. Collectively, these results highlight the formulation's substantial potential for clinical application in improving ART-based antimalarial therapy.