Perivascular nanocarrier aggregation as a drug reservoir augments tumor drug delivery and treatment efficacy

Anticancer nanomedicines must overcome a series of physiological and pathological barriers to reach the site of action, and this often leads to low overall therapeutic efficiency. Herein, we present tumor acidity regulated rapid aggregation of nanocarriers around tumor blood vessels to construct drug reservoirs for on-demand drug delivery. We designed two nanocarriers, one that protonates extremely quickly to expose click reactive groups on its surface and that subsequently reacted with the other noncarrier via click chemistry to rapidly form agglomerates as drug reservoirs. In proof-of-concept experiments, vascular disrupting agent combretastatin A4 (CA4) and hypoxia-activated prodrug PR-104A were loaded into the two nanocarriers, respectively. CA4 was enriched near blood vessels while PR-104A diffused deep into tumors and was activated by profound hypoxia levels induced by CA4. This combination produced effective adaptive therapy for tumors with different hypoxia levels.