Molecular recognition-driven supramolecular nanoassembly of a hydrophobic uracil prodrug and hydrophilic cytarabine for precise combination treatment of solid and non-solid tumors.

Combination chemotherapy has shown distinct therapeutic advantages over monotherapy in clinical cancer treatment, especially for two chemotherapeutic drugs with different mechanisms of action. However, how to achieve efficient co-delivery of two or more drugs with different physicochemical and pharmacokinetic properties for synergistic therapy is still a huge challenge. In particular, it is even more difficult to efficiently co-deliver a hydrophilic drug and a hydrophobic drug into one nanosystem. Herein, inspired by the natural Watson-Crick base pair molecular recognition in nucleic acids, a reduction-sensitive uracil prodrug of doxorubicin (U-SS-DOX) is synthesized and performs supramolecular co-assembly with cytarabine (Ara-C). Interestingly, the hydrophilic Ara-C molecules could readily co-assemble with U-SS-DOX, and multiple hydrogen bonds are found in the nanoassembly with an ultra-high drug loading rate. Moreover, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) is used as a fluorescent probe to investigate the pharmacokinetics of U : C NPs. It turns out that the DiR-labeled U : C NPs significantly prolong the systemic circulation and promote the tumor-specific accumulation of DiR when compared with DiR solution. Furthermore, the supramolecular nanoassembly demonstrates potent satisfactory therapeutic effects in treating both solid and non-solid tumors in vivo . This study provides a novel molecular co-assembly nanoplatform for efficient co-delivery of hydrophilic and hydrophobic drugs.