Atom-efficient and self-delivered prodrug based on methylene blue and doxorubicin for tumor combination therapy

Abstract

Traditional cancer treatments often lead to significant side effects and exhibit limited circulation within the body. To address these issues, considerable efforts have been directed towards developing drug delivery systems and prodrug strategies. However, the inclusion of supplementary carrier materials and protective groups complicates the clinical transition process. Here, we introduce a prodrug nano-assembly formed by conjugating methylene blue (MB) and doxorubicin (DOX) through a urea linkage. Notably, the resulting MB-DOX structure incorporates only 1.9 % additional atoms compared to clinical MB and DOX. This formulation effectively masks the cytotoxicity of DOX and eliminates the photosensitivity of MB. Moreover, the amphiphilic nature of MB-DOX facilitates self-assembly into nanostructures without requiring additional carriers, realizing self-delivery. Upon accumulation at the tumor site, light-induced cleavage of the urea bond releases therapeutic MB and DOX, enabling combined photodynamic therapy and chemotherapy with minimal adverse effects. Crucially, our design fulfills self-delivery and reduces the side effects of MB and DOX by simply introducing a urea linkage, eliminating the necessity for carrier materials and bulk protective groups, and holding promise for expediting the clinical translation of prodrugs.