Abstract
Gene therapy presents promising opportunities to target critical pathways in complex cancers like glioblastoma multiforme, though it necessitates the use of efficient delivery vectors. Polyphosphazenes (PPZs) are highly flexible materials that lead to biodegradable, high-performance materials in various applications, including gene delivery. In this work, we synthesized various PPZ derivatives, incorporating primary amines, secondary amines, hydrophilic, and hydrophobic groups, and evaluated their gene transfection capabilities in combination with an anionic polyphosphazene (6MHA-PPZ) that acts as a charge quencher and transfection enhancer. Combining 6MHA-PPZ with a hydrophobic polymer demonstrated the highest gene delivery efficiency and safety, significantly surpassing previous benchmarks. Using these optimized nanoparticles, we delivered a BMP4-expressing plasmid (pBMP4) in glioblastoma models. The pBMP4 nanoparticles, when combined with the chemotherapeutic agent temozolomide (Tz), resulted in significant reductions in tumor volume, improved survival rates in preclinical models, and normalized the expression of drug resistance markers, providing a synergistic antitumoral effect with Tz. This study highlights the potential of PPZ-based nanoparticles for gene delivery and suggests that the combination of pBMP4-NPs and Tz could offer a promising therapeutic strategy for treating glioblastoma.