PEG Surface Design Modulates Repeated-Dose Pharmacokinetics of Single-Walled Carbon Nanotubes

Single-walled carbon nanotubes (SWCNTs) are promising nanomaterials for cancer imaging and drug delivery owing to their near-infrared optical properties and tumor accumulation via the enhanced permeability and retention effect. Polyethylene glycol-modified phospholipids (PL-PEG) are widely used to disperse SWCNTs for in vivo applications; however, whether this formulation represents the optimal PEGylation strategy, particularly under repeated administration, remains unclear. Here, we perform a systematic head-to-head comparison between conventional 5 kDa PL-PEG/SWCNTs and SWCNTs encapsulated within a PEG-based cross-linked polymer network synthesized via CNT micelle polymerization. Quantitative biodistribution analysis using Raman spectroscopy demonstrates that cross-linked PEG/EAA/SWCNTs exhibit blood circulation profiles and tumor accumulation comparable to those of PL-PEG/SWCNTs following initial intravenous injection in mice. Striking differences emerge upon repeated dosing. PL-PEG/SWCNTs display reduced systemic exposure consistent with accelerated blood clearance (ABC)-like pharmacokinetics, accompanied by a trend of increased hepatic accumulation. In contrast, PEG/EAA/SWCNTs maintain largely preserved pharmacokinetic profiles (ABC index ≈ 0.8-0.9) and induce significantly lower anti-PEG IgM responses. These results suggest that the observed differences are attributable to differences in PEG molecular weight and/or PEG presentation architecture. By expanding the design space beyond the widely used PL-PEG standard, this study identifies PEG/EAA/SWCNTs as a promising alternative formulation for repeated-dose biomedical applications and highlights the importance of systematically evaluating PEG molecular weight and surface presentation in future studies.