Size Effect of Zwitterionic Peptide-Based Nanoscale Micelles on Cancer Therapy

Negative-charge-biased zwitterionic nanodrugs showed “stealthy” in blood circulation and “sticky” to sialic acid abundant tumor cells in the tumor microenvironment (TME), thereby prolonging blood circulation, increasing tumor targeting, and reducing accumulation in healthy liver and kidney. However, the correlation between the particle size, one of the crucial parameters of these nanodrugs, and their interactions with biological systems is unclear. Here, KEKDCDEKE (EK9) small peptide was used to replace zwitterionic polypeptides to prepare doxorubicin (DOX)-conjugated nanodrugs with well-controlled size, which is, respectively, 30, 60, and 90 nm diameter, for investigating the size effect on cancer therapy. Results showed that the size increase of these zwitterionic nanodrugs improves their blood circulation and retention in tumor but reduces the internalization rate and tumor tissue penetration, although all nanodrugs were self-assembled by the same conjugates. There is an optimal particle size, 60 nm in this work, for the zwitterionic nanodrugs to balance these effects, thereby improving their ability to inhibit tumor growth. These findings suggest that the particle size of zwitterionic nanodrugs also plays a particularly important role in controlling the behaviors of zwitterionic peptide-based nanodrugs.