Particle Design via Lactosome-Based Polycarboxybetaine Modification and Initial Evaluation of the Accelerated Blood Clearance Phenomenon.

Lactosome is a biocompatible micelle particle composed of the amphiphilic polymers poly(l-lactic acid)30 (PLLA30) and poly(sarcosine)70 (PSar70) (PLLA30-block-PSar70). Lactosome has tumor accumulation properties via its enhanced permeability and retention effect, making it promising for probe imaging and drug delivery systems in tumor tissues. However, anti-lactosome immunoglobulin M (IgM) is produced after lactosome dosing, causing a marked reduction in the blood circulation and tumor accumulation of lactosome after multiple dosing. This phenomenon is called accelerated blood clearance (ABC). In this study, we aimed to modify lactosome with poly(carboxybetaine)20 (PCB20) to reduce anti-lactosome IgM production and the ABC phenomenon. We designed 10%PCB20-PLLA30-lactosome based on PLLA30-block-PCB20 and 10%PCB20-PSar70-lactosome or 100%PCB20-PSar70-lactosome based on PLLA30-block-PSar70-block-PCB20. Plasma anti-lactosome IgM levels were evaluated using an enzyme-linked immunosorbent assay 7 d after dosing in mice via the tail vein. Compared with lactosome, 10%PCB20-PSar70-lactosome significantly reduced anti-lactosome IgM production, and early blood clearance improved at the second dose. In contrast, 6 h post-dosing, blood clearance accelerated, and tumor accumulation decreased compared with the events under the first dose. The PCB20 modification of PLLA30-block-PSar70 more effectively reduced anti-lactosome IgM production than did the PCB20 modification of PLLA30; the early blood clearance associated with the ABC phenomenon also showed greater improvement in the former. Nevertheless, the promotion of blood clearance and reduction in tumor retention in the later phase could not be suppressed. These findings suggest that evading the ABC phenomenon requires particle design that comprehensively considers factors beyond enhancing the suppression of IgM production.