Photodynamic Therapy for Glioblastoma: Potential Application of TiO₂ and ZnO Nanoparticles as Photosensitizers

Despite aggressive current therapies against glioblastoma (GB), residual tumor cells may remain at the edge of the surgical cavity after resection. These cells can rapidly proliferate, giving rise to tumor recurrence in more aggressive and drug-resistant forms. As photodynamic therapy (PDT) has advanced, it has emerged as an option to treat this brain tumor. The oncological basis of PDT involves the selective accumulation of a photosensitizer (PS) in the tumor, followed by its activation with electromagnetic radiation to generate reactive oxygen species (ROS), which induce tumor cell death. Given that first- and second-generation PSs present significant limitations, including poor tumor selectivity, suboptimal biodistribution, limited absorption within the therapeutic window, and slow systemic clearance, research has progressed toward the development of third-generation PSs based on nanotechnology to optimize their therapeutic properties. This review addresses the types of tumor cell death induced by PDT, as well as the advancements of PS design, focusing on titanium dioxide (TiO₂) and zinc oxide (ZnO) nanoparticles. These nanomaterials can be designed as carriers, encapsulating or conjugating conventional PSs, or act as PSs themselves, due to their favorable biocompatibility and intrinsic photoreactivity. Additionally, they can be functionalized with targeting ligands to achieve tumor-specific delivery, enhancing therapeutic selectivity while minimizing toxicity to healthy tissue. Overall, these nanotechnology-based PSs represent a versatile and promising therapeutic paradigm that warrants further investigation through basic research, supporting the development and potential clinical translation of a more precise and effective PDT-based intervention for glioblastoma, initially aimed at eliminating intra-surgical post-resection residual tumor cells.