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Ultrasound-Boosted Liposomal Prodrug Overcomes Age-Associated Biodistribution Disparity in Pediatric Solid Tumor
Danfei Chen1, Junjun Xu2, Jian Chen1
1Department of Pediatrics, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Zhejiang Chinese Medical University, Hangzhou, China.
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.
Insights
Age-related differences in nanocarrier distribution hinder pediatric cancer nanodrugs. An ultrasound-activated liposomal prodrug (CSCPTL) overcomes these disparities, showing potent efficacy and biocompatibility in juvenile models.
Area of Science:
- Nanomedicine
- Pediatric Oncology
- Drug Delivery Systems
Background:
- Clinical nanodrug use for pediatric cancer faces challenges due to age-related distribution disparities.
- Mechanisms limiting nanotherapeutics in childhood solid tumors remain unclear, impacting treatment efficacy.
- Juvenile tumor-bearing mice exhibit worse off-target nanocarrier distribution than adults due to physiological differences.
Purpose of the Study:
- To develop an ultrasound-activated nanodrug delivery system to overcome age-related disparities in nanocarrier off-target distribution.
- To investigate the efficacy and biocompatibility of the novel nanodrug in pediatric cancer models.
- To address the limitations of current nanotherapeutics in treating childhood solid tumors.
Main Methods:
- Design of an ultrasound-activated liposomal prodrug (CSCPTL) comprising a camptothecin-lipid prodrug conjugate (SCPT) with a reactive oxygen species (ROS)-cleavable thioketal linker and a sonosensitizer (chlorin e6, Ce6).
- Evaluation of CSCPTL's in vivo biodistribution and off-target effects in juvenile and adult tumor-bearing mice.
- Assessment of CSCPTL's antitumor efficacy, biocompatibility, and side effects in juvenile hepatoblastoma models via ultrasound activation.
Main Results:
- CSCPTL demonstrated targeted drug release and activation upon ultrasound irradiation at the tumor site, generating ROS to cleave the linker and release active camptothecin.
- The novel nanodrug showed potent antitumor efficacy in juvenile hepatoblastoma models.
- CSCPTL exhibited superior biocompatibility and no observable side effects compared to clinically approved nanodrugs (Abraxane, Doxil, Onivyde).
Conclusions:
- CSCPTL effectively overcomes age-related off-target distribution issues in nanocarrier delivery for pediatric cancer.
- Ultrasound-activated nanomedicine offers a promising and safe strategy for treating childhood solid tumors.
- This approach highlights the importance of addressing age-specific physiological factors in nanotherapeutic development for pediatric oncology.
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