Cationic Azobenzene Tag to Enhance Liposomal Prodrug Retention and Tumor-Targeting Prodrug Activation for Improved Antitumor Efficacy

In this study, we reported a cationic azobenzene (Azo) tag to increase the retention of camptothecin (CPT) prodrugs in liposomes driven by π-π stacking interaction between Azo. Compared with a cationic CPT prodrug without Azo, the liposome-encapsulating Azo-linked CPT prodrugs (AzoCPT-Lips) exhibited slower prodrug leakage in plasma and a longer blood circulation time in mice. The AzoCPT-Lips had a high encapsulation efficiency (95%), loading capacity (20%, by weight), and good storage stability. The AzoCPT was efficiently taken up by 4T1 tumor cells (100-fold higher than CPT) and readily converted into active CPT in the cytoplasm to exert 10-fold higher cytotoxicity than free CPT. More importantly, AzoCPT-Lips resulted in 5-20 times higher tumor distribution of active CPT than that of CPT solution or those in other tissues, which further led to more potent antitumor activity and lower toxicities in the 4T1 breast cancer xenograft. Such a cationic Azo tag represents an effective strategy for developing liposomal antitumor drugs with improved antitumor efficacy.