Characterization of PGua₄, a Guanidinium-Rich Peptoid that Delivers IgGs to the Cytosol via Macropinocytosis.

ABSTRACT: To investigate the structure-cellular penetration relationship of guanidinium-rich transporters (GRTs), we previously designed PGua₄, a five-amino acid peptoid containing a conformationally restricted pattern of eight guanidines, which showed high cell-penetrating abilities and low cell toxicity. Herein, we characterized the cellular uptake selectivity, internalization pathway, and intracellular distribution of PGua₄, as well as its capacity to deliver cargo. PGua₄ exhibits higher penetration efficiency in HeLa cells than in six other cell lines (A549, Caco-2, fibroblast, HEK293, Mia-PaCa2, and MCF7) and is mainly internalized by clathrin-mediated endocytosis and macropinocytosis. Confocal microscopy showed that it remained trapped in endosomes at low concentrations but induced pH-dependent endosomal membrane destabilization at concentrations ≥10 μM, allowing its diffusion into the cytoplasm. Importantly, PGua₄ significantly enhanced macropinocytosis and the cellular uptake and cytosolic delivery of large IgGs following noncovalent complexation. Therefore, in addition to its peptoid nature conferring high resistance to proteolysis, PGua₄ presents characteristics of a promising tool for IgG delivery and therapeutic applications.

SUBMITTER: Laniel A 

PROVIDER: S-EPMC9997486 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature