The ability of nanocarriers to enter tumor cells can be enhanced by positive surface charge. Nonetheless, the relationship between the spatial distributions of cationic groups and the endocytosis and tumor penetration of nanocarriers remains largely elusive. Here, using quaternary ammonium salt (QAS) as a model cationic group, a series of hybrid micelles (HMs) bearing QAS with different spatial distributions were prepared from star-shaped polymers with well-defined molecular architectures. The structural characteristics of HM, such as spatial location of QAS and local poly(ethylene glycol) (PEG) density near QAS, were investigated by both experimental techniques and dissipative particle dynamics (DPD) simulation. We show that the drug carriers with QAS extending to the micellar outer space allows QAS to facilitate cell surface binding with minimized hindrance, resulting in greatly enhanced endocytosis compared with nanocarriers with QAS attached onto the micellar surface or shielded by a PEG corona. This study offers cues for future development of tumor-penetrating drug delivery systems.
Keywords: cationic groups; endocytosis; hybrid micelles; spatial regulation; tissue penetration.