Ecdysteroid-Containing Squalenoylated Self-Assembling Nanoparticles Exert Tumor-Selective Sensitization to Reactive Oxygen Species (ROS)-Induced Oxidative Damage While Protecting Normal Cells: Implications for Selective Radiotherapy

Central nervous system (CNS) tumors are exceptionally
difficult
to treat, and oxidative stress-inducing radiotherapy is an important
treatment modality. In this study, we examined self-assembling pro-drug
nanoconjugates of naturally derived antitumor ecdysteroids, which
were designed to interfere with oxidative stress in brain tumor cells.
Eight ecdysteroid-squalene conjugates were semi-synthesized and formulated
into self-assembled aqueous nanosuspensions, which showed excellent
stability for up to 16 weeks. The nanoassemblies demonstrated a strong
dose-dependent sensitizing effect to tert-butyl hydroperoxide
(tBHP)-induced oxidative damage in SH-SY5Y cells, while exerting a
strong protective effect in MRC-5 fibroblast cells. In contrast, free
ecdysteroids protected both cell lines from tBHP-induced damage. This
suggests an important role for squalenoylation in the antitumor effect
and indicates that our conjugates have potential as highly selective
adjuvants in radiotherapy by sensitizing cancer cells and protecting
surrounding tissues. Furthermore, our findings suggest a potential
neuroprotective effect of nonconjugated ecdysteroids.