Implantable MicroLED-Mediated Chemo-Photodynamic Combination Therapy for Glioma Treatment

Photodynamic therapy can be a potential modality for the combination therapy of glioma with powerful efficacy and low resistance, however, its therapeutic outcome is significantly lowered due to the inadequate light delivery throughout glioma tissues under the skull. Herein, a needle-type implantable microLED device and cathepsin B-responsive prodrug nanoparticles (PNPs) are newly exploited for glioma's synergistic chemo-photodynamic combination therapy. The implantable microLED consists of four small LEDs aligned onto the tip of the guide needle and it can be implanted into the center of glioma tissues without opening skulls, uniformly irradiating light to deep glioma tissues. As therapeutic agents, PNPs are formulated <i>via</i> self-assembly of heterobifunctional prodrug composed of doxorubicin, verteporfin, and cathepsin B-cleavable peptide linker, wherein they stably maintain their inactive nanoparticle structures in normal physiological conditions and specifically deliver doxorubicin and verteporfin to cathepsin B-overexpressed glioma tissues. <i>In vitro </i>cellular assays, PNPs irradiated with showed the synergistic cytotoxicity of DOX and VFP only in cathepsin B-overexpressed cancer cells rather than normal cells. In tumor-bearing mice, PNPs showed high tumor accumulation <i>via</i> the nanoparticle-driven enhanced permeation and retention (EPR) effect and they also exhibited remarkable therapeutic efficacy against glioma under microLED-mediated light irradiation <i>via</i> chemo-photodynamic combination therapy. Accordingly, applying microLED with PNPs is an outstanding strategy to defeat glioma with cooperative chemo-photodynamic effects, minimal invasiveness, and desirable systemic/local safety.