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Life sciences · Journal article
Small · November 2, 2026
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ABSTRACT Small molecule nanodrugs (SMNs) offer unique advantages for cancer therapy, yet accurately tracking their in vivo fate without perturbing their native assembly remains challenging. Here, we report a spacer engineering strategy that enables efficient 1 8 F‐labeling while preserving SMNs self‐assembly. Erlotinib‐based amphiphilic derivatives containing oligoethylene glycol (OEG) spacers of tunable length were designed to simultaneously regulate steric hindrance for aliphatic S N 2 radiofluorination and the amphiphilic balance required for nanoparticle formation. Spacer elongation reduced steric hindrance at the labeling site and thereby improved radiochemical yields, while also enabling precise control over nanoparticle size. The optimized radiolabeled formulation, [ 18 F]E3F NPs, exhibited prolonged blood circulation and rapid tumor accumulation, enabling high‐contrast PET imaging of PANC‐1 xenografts as early as 15 min after injection. In addition, the corresponding nonradioactive formulation, E3F NPs, showed significantly improved antitumor efficacy compared with nonassembled E3F through reduced EGFR phosphorylation and increased tumor cell apoptosis. This work provides an initial evaluation that spacer engineering can coordinate radiolabeling and self‐assembly while enabling PET tracking of SMNs, supporting the development of image‐guided cancer theranostics.