Balancing Chemical and Supramolecular Stability in OEGylated Supramolecular Polymers for Systemic Drug Delivery.

The chemical conjugation of poly(ethylene glycol) (PEG) to therapeutic agents, known as PEGylation, is a well-established strategy for enhancing drug solubility, chemical stability, and pharmacokinetics. Here, we report on a class of supramolecular polymeric prodrugs by utilizing oligo(ethylene glycol) (OEG) to modify the hydrophobic anticancer drug camptothecin (CPT). These OEGylated prodrugs, despite their low molecular weight, spontaneously self-assemble into therapeutic supramolecular polymers (SPs) with a tubular morphology, featuring a dense OEG coating on the surface. By designing biodegradable linkers with varying chemical stabilities, we investigated how the release kinetics of CPT influence the in vitro and in vivo performance of these SPs. Our findings demonstrate that self-assembling prodrugs (SAPDs) with a self-immolative disulfanyl-ethyl carbonate (etcSS) linker exhibit a faster drug release rate than those with a reducible disulfanyl butyrate (buSS) linker, leading to higher potency and significantly improved antitumor efficacy. Notably, two stable tubular SPs, Tubustecan () and , outperformed irinotecan─a clinically approved CPT prodrug─in a colon cancer model, achieving enhanced tumor growth inhibition and prolonged animal survival. These results highlight the potential of supramolecular OEGylation as an important strategy for engineering drug-based supramolecular polymers and underscore the critical role of chemical stability vs supramolecular stability in optimizing supramolecular prodrug design.