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

초록

Photodynamic therapy shows promise for glioma treatment with powerful efficacy and low resistance, however, its effectiveness is significantly lowered by inadequate light delivery through the skull. Herein, a needle-type implantable microLED device and cathepsin B-responsive prodrug nanoparticles (PNPs) are newly exploited for glioma's chemo-photodynamic combination therapy. The microLED containing four small LEDs on the tip of its guide needle can be implanted into the center of glioma tissues without large area opening of skull, uniformly irradiating light to deep glioma tissues. PNPs are formulated via self-assembly of heterobifunctional prodrug composed of doxorubicin, verteporfin, and cathepsin B-cleavable peptide linker, wherein they stably maintain inactive nanoparticle structures in normal physiological conditions and specifically deliver therapeutic age to cathepsin B-overexpressed glioma tissues. In vitro 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 via the nanoparticle-driven enhanced permeation and retention (EPR) effect and they also exhibited remarkable therapeutic efficacy against glioma under microLED-mediated light irradiation via 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. A new approach of implantable needle-type microscale LED-guided chemo-photodynamic combination therapy cooperatively using the implantable microLED and chemodrug-photosensitizer dual prodrug nanoparticles (PNPs) that is mainly responsive to brain cancer cell-overexpressed cathepsin B is suggested for glioma treatment. image

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