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.