A novel cascade strategy using a nanonized targeted prodrug for enhanced oral delivery efficiency

Abstract It is a great challenge to improve the oral bioavailability for BCS class IV drugs because they have low solubility and poor permeability. However, nanonization and intestinal transporter-targeted prodrugs can increase the solubility and permeability, respectively. Hence, an “increased solubility and improved permeability” cascade strategy was proposed to enhance the dissolution rate and permeability for BCS class IV drugs. In this study, acyclovir glutarate (AG), a prodrug of acyclovir, was synthesized to improve intestinal permeability by targeting monocarboxylate transporter 1 (MCT 1), an intestinal influx transporter. Then, AG was formulated as AG nanoneedles (AGNNs) to improve dissolution behavior. AG was demonstrated to exhibit greatly higher cellular uptake efficiency and permeability than acyclovir due to the MCT 1-mediated active transport. Furthermore, intact AGNNs were also demonstrated to be endocytosed by enterocytes and to be transcytosed potentially. In addition, oral pharmacokinetics showed that the AUC0–24h of AGNNs was 1.89-fold to that of acyclovir. Collectively, these results confirmed that nanonized MCT 1-targeted prodrugs enhanced the oral bioavailability of acyclovir in a cascade manner. Our findings propose a promising strategy to develop BCS class IV drugs and have significant implications for a wide range of such drugs for high oral delivery efficiency.