Dendrimer-Based Biocompatible Zwitterionic Micelles for Efficient Cellular Internalization and Enhanced Antitumor Effects

Zwitterionic materials have been employed to achieve excellent biocompatibility and the well-suppressed nonspecific protein adsorption of nanoparticles. However, a thick and compact zwitterionic layer may prevent the modified nanoparticles from entering tumor cells, resulting in low cellular internalization efficiency. To address this problem, new biocompatible micelles (PPIMYC) with a thin zwitterionic layer were designed and prepared. Zwitterionic generation 2 polypropyleneimine dendrimers (G2 PPI) serve as the hydrophilic external shell, and N-(2-mercaptoethyl)oleamide serves as the hydrophobic internal core. Drug-loaded dendritic micelles (PPIMYC-DOX-Ce6) were also prepared by self-assembly of PPIMYC with doxorubicin (DOX) and chlorin e6 (Ce6) to demonstrate chemo-photodynamic dual therapy. As potential drug delivery systems for antitumor therapy, PPIMYC-DOX-Ce6 exhibited sustained drug release under acidic conditions and high stability in fibrinogen solution. In addition, cytotoxicity studies showed an enhanced efficiency of PPIMYC-DOX-Ce6 in killing HeLa cells as compared to free DOX with or without irradiation (660 nm laser). More importantly, both flow cytometry and fluorescence microscopy results indicated that the cellular uptake efficiency of DOX was significantly enhanced in PPIMYC-DOX-Ce6-treated cells relative to free DOX treated cells. The intracellular internalization of PPIMYC-DOX-Ce6 was more efficient under acidic pH, representing the tumor environment, as compared to normal pH. This results from the pH sensitivity of the zwitterionic layer. Temperature was the only environmental factor affecting the cellular internalization process. It is believed that the enhanced intracellular internalization efficiency is due to the thin zwitterionic layer of PPIMYC-DOX-Ce6. The preparation scheme of zwitterionic micelles would offer a new strategy to design novel antitumor drug delivery systems with enhanced cellular internalization efficiency and high stability in a complex medium.