Abstract
Polymeric nanoscale materials able to target and accumulate in the tumor microenvironment (TME) offer promising routes for a safer delivery of anticancer drugs. By reaching their targets before significant amounts of drug are released, such materials can reduce off-target side effects and maximize drug concentration in the TME. However, poor drug loading capacity and inefficient nanomaterial penetration into the tumor can limit their therapeutic efficacy. Herein, we provide a novel approach to achieve high loading profiles while ensuring fast and efficient drug penetration in the tumor. This is achieved by co-polymerizing light-sensitive paclitaxel with monomers responsive to tumor-associated enzymes, and assembling the resulting di-block copolymers into spherical micelles. While light exposure enables paclitaxel to decouple from the polymeric backbone into light-activated micelles, enzymatic digestion in the TME initiates its burst release. Through a series of in vitro cytotoxicity assays, we demonstrate that these light-switch micelles hold greater potency than covalently linked, non-triggered micelles, and enable therapeutic profiles comparable to that of the free drug.