Terminal Linear Polyglycerol Modification Attenuates Anti-lactosome IgM Yet Fails to Preserve Repeated-Dose Biodistribution

Lactosome is a polymeric micelle composed of the amphiphilic block polymer polysarcosine₇₀ (PSar₇₀)-block-poly-l-lactic acid₃₀ (PLLA₃₀) and has been investigated as a tumor drug delivery system platform given its preferential accumulation in tumors via the enhanced permeability and retention effect. However, lactosome administration induces anti-lactosome immunoglobulin M (IgM) production 3-5 d after administration, causing accelerated blood clearance (ABC) and reduced tumor accumulation after repeated administration. We previously reported that 10% lin-PG₁₀-PLLA₃₀ lactosome reduces anti-lactosome IgM production but does not sufficiently suppress the ABC phenomenon. Hence, in this study, we prepared 10% lin-PG₁₀-PSar₇₀ lactosome using lin-PG₁₀-block-PSar₇₀-block-PLLA₃₀ to assess whether terminal presentation of lin-PG₁₀ on the PSar chain improves antigenicity and repeated-dose biodistribution. Anti-lactosome IgM production was markedly reduced in mice administered the 10% lin-PG₁₀-PSar₇₀ lactosome compared with those administered conventional lactosome. Nevertheless, after a second administration of ¹²⁵I-labeled 10% lin-PG₁₀-PSar₇₀ lactosome to Colon-26 tumor-bearing mice, blood retention markedly decreased, and tumor radioactivity retention was not maintained even after the first administration. These findings indicate that reducing anti-lactosome IgM production alone is insufficient to prevent the ABC phenomenon or to preserve tumor radioactivity retention after initial administration. Therefore, hydrophilic polymer modification of the lactosome should be optimized by considering antigenicity, systemic circulation, tumor retention, and non-target organ accumulation.