Work

HER2-targeted star polymer conjugates for improved tumor distribution and efficacy

Year: 2025

Type: article

Abstract: Actively targeted nanoparticle systems have the potential to improve delivery to tumors over untargeted systems however the design rules to achieve this have not been fully elucidated. A HER2-targeted polymer drug delivery system composed of a 32-arm star polymer (SD) conjugated with the TOP1 inhibitor molecule SN-38, with a trastuzumab antigen binding fragment (HER2-Fab), has been used to target cancer cells overexpressing this receptor. The HER2-Fab was attached to the SD at two different densities (average of 1 or 3 Fabs per star polymer) and compared to the native star polymer without Fab. In vitro experimentation showed that both the targeted star polymers (HER2-SDs) had better binding and uptake in HER2-positive cell lines (SK-BR3 and HEK293) compared to the non-targeted SD. In vivo biodistribution studies showed enhanced accumulation of HER2-targeted SDs in tumors, but not normal tissues, particularly at the later (96 h post-dose) timepoint. The HER2-SDs demonstrated increased localization with tumor cells rather than in stromal regions, greater penetration into the tumor core and a more homogenous distribution in the tumor section than the untargeted SD. The targeted star polymer conjugated to SN-38 was tested for anti-tumor activity in a HER2-positive gastric cancer xenograft in mice and showed significantly greater efficacy compared to untargeted SDs. • Star polymer (SD)-SN-38 conjugate targeted to HER2 receptors via antibody fragment, HER2-SDs. • Variable ligand density to evaluate ligand/SD ratio impact on tumor uptake and distribution. • Selective binding and improved uptake for targeted polymer-conjugates HER2-SDs in HER2-positive cell lines. • Enhanced tumor uptake, distribution and retention for HER2-targeted versus non-targeted SDs. • Improved efficacy in HER2-positive NCI-N87 xenograft model for HER2-SDs.

Source: Journal of Controlled Release

DOI: 10.1016/j.jconrel.2025.113654