Self-Emulsifying Hydrophobic Prodrug Conjugate That Enables the Oral Co-Administration and Programmable Release of Dual Antitumor Drugs

The oral delivery of chemotherapeutics has the potential to revolutionize anticancer medicine but has had limited clinical success as a consequence of delivery challenges. The reconstruction of molecular structures will modulate the physicochemical properties of parent drugs and thereby should facilitate the incorporation of prodrugs into appropriate delivery platforms. Herein we investigated the possibility of combining a drug reconstruction strategy with a self-emulsifying drug delivery system (SEDDS) for the simultaneous oral co-delivery of two antitumor agents. To demonstrate this concept, we constructed a hydrophobic heterodimeric prodrug 1 comprised of 7-ethyl-10-hydroxy-camptothecin (SN38) and capsaicin via a short succinic acid linker with the intent of alleviating the polarity of both drugs. Compound 1 was miscible with polysorbate 80 (Tween 80) and formed a transparent solution (termed 1-SEDDS) upon blending with water. Interestingly, the resulting 1-SEDDS nanomedicine was stable in the acidic environment of the gastrointestinal (GI) tract but concurrently released dual therapeutically active drugs in the small intestine that is neutral. Finally, in vivo studies showed that orally administered 1-SEDDS outperformed intravenously injected CPT-11, a clinically approved SN38 prodrug, in terms of its antitumor effect. Collectively, these results provided a novel heterodimeric prodrug design strategy for the oral administration of dual anticancer therapeutics in the form of a single platform. Further extending this concept to other potent chemotherapeutics could significantly enhance the potential of SEDDS-based platforms for combination cancer therapies.