Steric Hindrance-Engineered Redox-Responsive Disulfide-Bridged Homodimeric Prodrug Nanoassemblies for Spatiotemporally Balanced Cancer Chemotherapy

The rational design of tumor-responsive prodrug nanoassemblies
requires precise control over systemic stability and site-specific
activation. While α-position disulfide bonds are advantageous
for rapid response to redox conditions, they also risk premature drug
leakage during circulation. This study introduces a steric hindrance-guided
approach to engineer disulfide-bridged podophyllotoxin homodimeric
prodrugs for spatiotemporal controlled delivery. By monomethyl or
dimethyl substitution of the carbon atoms adjacent to the α-disulfide
bond, we can modulate steric hindrance. Excessive hindrance destabilizes
the nanoassemblies and slows effective drug release, while moderate
hindrance (monomethyl modification) enhances pharmacokinetic properties
and promotes selective tumor activation. In vivo studies indicate
that monomethyl-modified prodrug nanoassemblies exhibit superior antitumor
efficacy and reduced off-target toxicity compared to PPT solution.
This work underscores the importance of steric hindrance in optimizing
prodrug nanoassembly stability and tumor-specific activation, offering
a comprehensive strategy for redox-responsive nanomedicines.