Enhancing selective photosensitizer accumulation and oxygen supply for high-efficacy photodynamic therapy toward glioma by 5-aminolevulinic acid loaded nanoplatform

Abstract

The complex biology of glioma compromises therapeutic efficacy and results in poor prognosis. Photodynamic therapy (PDT) has emerged as a promising modality for localized tumor ablation with limited damage to healthy brain tissues. However, low photosensitizer concentration and hypoxic microenvironment in glioma tissue hamper the practical applications of PDT. To address the challenges, biocompatible periodic mesoporous organosilica coated Prussian blue nanoparticles (PB@PMOs) are constructed to load a biosafe prodrug 5-aminolevulinic acid (5-ALA), which is pronouncedly converted to protoporphyrin IX (PpIX) in malignant cells. PB@PMO-5-ALA induces a higher accumulation of PpIX in glioma cells compared to free 5-ALA. Meanwhile, the PB@PMOs, with a mean edge length of 81 nm and good biocompatibility, effectively decompose hydrogen peroxide to oxygen in a temperature-responsive manner. Oxygen supply further contributes to the promotion of 5-ALA-PDT. Thus, the photodynamic effect of PB@PMO-5-ALA is significantly improved, imposing augmented cytotoxicity to glioma U87MG cells. Furthermore, ex vivo fluorescence imaging elucidates the tumor PpIX increases by 75% in PB@PMO-5-ALA treated mice than that in 5-ALA treated ones post 12 h injection. Magnetic resonance imaging (MRI) and iron staining strongly demonstrate the accumulation of PB@PMO-5-ALA in glioma tissues with negative contrast enhancement and blue staining deposits, respectively. The nanoparticle accumulation and high PpIX level collaboratively enhance PDT efficacy through PB@PMO-5-ALA, which efficiently suppresses tumor growth, providing a promising option with safety for local glioma ablation.

Keywords: 5-aminolevulinic acid; glioma; oxygen supply; photodynamic therapy; protoporphyrin IX.