Ultrasound‐Boosted Liposomal Prodrug Overcomes Age‐Associated Biodistribution Disparity in Pediatric Solid Tumor Therapy

ABSTRACT Clinical adoption of nanodrugs for pediatric cancer is hindered by age‐associated disparities, with unclear mechanisms limiting nanotherapeutics for childhood solid tumors. Here, we originally find that the in vivo biodistribution of nanocarriers shows marked age differences: juvenile tumor‐bearing mice have worse off‐target distribution than adults, due to vigorous neovascular proliferation in normal tissues and heightened macrophage phagocytosis in liver and spleen. To address this challenge, an ultrasound‐activated liposomal prodrug (CSCPTL) is designed to overcome age‐related disparities in off‐target distribution. CSCPTL is composed of a camptothecin‐lipid prodrug conjugate (SCPT) containing the reactive oxygen species (ROS)‐cleavable thioketal linker, a sonosensitizer (chlorin e6, Ce6)‐modified lipid, and other commercially available lipids. Upon intravenous injection, the inactive SCPT exerts minimal pharmacological effects on healthy cells. Conversely, once CSCPTL reaches the tumor site and is internalized by cancer cells, ultrasound irradiation activates Ce6 rapidly to generate massive ROS, which cleaves the thioketal linker to release active camptothecin to induce cell apoptosis. CSCPTL showed potent antitumor efficacy in juvenile hepatoblastoma models, showing superior biocompatibility and no side effects, compared with clinically approved nanodrugs such as Abraxane, Doxil, and Onivyde. This study highlights age‐related off‐target issues and offers a promising ultrasound‐controlled strategy for childhood solid tumors.