Toward Glioblastoma Treatment with High Spatiotemporal Precision: Controlling Temozolomide Release from Upconverting Nanoparticles Using Near-Infrared Light

As the first-line chemotherapeutic for glioblastoma multiforme (GBM), Temozolomide (TMZ) suffers from rapid degradation in physiological fluid, making it difficult to deliver sufficient doses of active TMZ to GBM tumors without inducing severe side effects. By protecting TMZ and then controlling its release using an external stimulus, we can prevent its premature degradation, thereby increasing its active concentration at the tumor site. Here, we present a near-infrared (NIR) controlled system in which TMZ is protected within a polymer before its on-demand release. NIR light is preferable, given its high penetration depth and noncarcinogenicity, but ultraviolet (UV) light is required to cleave chemical bonds. Upconverting nanoparticles (UCNPs) overcome this challenge as they convert NIR to UV, a property of the rare-earth lanthanides of which they are comprised. In this work, we coat UCNPs with poly(acrylic acid) (PAA) conjugated to a UV-cleavable nitrobenzyl photolinker (PhL) covalently linked to TMZ and show that this UCNP@PAA-PhL-TMZ system releases TMZ under low laser power (1 W/cm²) NIR, with 100% release after 30 min irradiation. When a 5 min NIR pulse was used to trigger TMZ release after NP internalization into U87MG GBM cells, we observed significant cell death after 24 h, even at concentrations an order of magnitude lower than current TMZ tumor concentrations, with multiple pulses inducing a larger effect. This work highlights the importance of drug release after cellular internalization and is a key step toward enhancing TMZ effectiveness as well as developing a tool to administer time-sensitive treatments personalized to individual GBM patients.