The Delicate Disulfide-Acryloyl Modification of Prodrug Facilitates Precise Albumin Targeting, Enhanced Tumor Accumulation, and Reduced Toxicity

Doxorubicin (DOX), a widely used chemotherapy, suffers
from severe
cardiotoxicity. Doxil, the first FDA-approved antitumor nanoformulation,
mitigates the cardiotoxicity of DOX, but fails to enhance therapeutic
efficacy probably due to limited cellular uptake and restricted drug
release. To overcome these challenges, this study developed a novel
disulfide-acryloyl-modified DOX prodrug (DSSA) for albumin-targeted
drug delivery. DSSA could self-assemble into stable nanoassemblies
(DSSA NPs) with a high drug-loading capacity (65.46%). DSSA NPs could
covalently bind to endogenous albumin, significantly enhancing pharmacokinetics
with a nearly 40-fold increase in the area under the curve (AUC) compared
to DOX solution (DOX sol) and achieving over twice the tumor accumulation
of DOX sol and Doxil. Additionally, the reduction-responsive disulfide
bonds enabled selective drug release in tumor microenvironments, minimizing
off-target toxicity. These results demonstrate the potential of disulfide-acryloyl
modification as a promising prodrug strategy to enhance tumor targeting
and safety in chemotherapeutic delivery.