Stable and pH-responsive polyamidoamine based unimolecular micelles capped with a zwitterionic polymer shell for anticancer drug delivery

To improve the circulation stability of polyamidoamine (PAMAM) based drug delivery systems in complex biological microenvironments, a series of generation-3.0 PAMAM-graft-poly[3-dimethyl(methacryloyloxyethyl)-ammonium propanesulfonate] (PAMAM3.0-g-PDMAPS) copolymers are synthesized via atom transfer radical polymerization. The zwitterionic PDMAPS segments serve as a shell to stabilize the unimolecular micelles, whereas the PAMAM3.0 dendrimers constitute a hydrophobic core. The sizes of the PAMAM3.0-g-PDMAPS unimolecular micelles range from 6.5 to 8.5 nm. Furthermore, PAMAM3.0-g-PDMAPS can keep the micelle-like structure when it is diluted by large volumes of fluids. More importantly, the PDMAPS shell layer can suppress non-specific protein adsorption on the surface of the micelles. The excellent stability to dilution and anti-biofouling are beneficial for prolonged circulation time in a complex biological microenvironment. In addition, anticancer doxorubicin (DOX) can be encapsulated both in the PAMAM3.0 core via hydrophobic interactions and the PDMAPS shell layer via hydrogen bonds. Drug release studies confirm the pH-responsive nature of PMAMA3.0-g-PDMAPS micelles by achieving 65.23% DOX release at pH 5.1 as compared to 16.38% at pH 7.4. Based on these results, the cytotoxicity and anticancer effects against human hepatocellular carcinoma cells (HepG2) of the PAMAM3.0-g-PDMAPS system loaded with DOX are investigated. The results suggest that the PDMAPS shell layer can significantly decrease the cytotoxicity via decreasing/shielding of the positive charges on the PAMAM dendrimers. After internalization by HepG2 cells, DOX is released from the micelles to the nucleus and further inhibits the proliferation of HepG2. Therefore, these PAMAM3.0-g-PDMAPS unimolecular micelles are a potential platform for anticancer drug delivery.