Dendritic Star-shaped Zwitterionic Polymers Based On PAMAM For Anticancer Drug Release

Polyamidoamine(PAMAM) dendrimers have drawn much attention as drug release carriers owing to their unique structure and properties such as controlled nanometer size, monodisperse, numerous terminal functional groups and interior cavities, but the high cytotoxicity of PAMAM limits their clinical applications. With the aim to reduce the cytotoxicity and improve the drug loading concent(DLC) of PAMAM as well as realize the pH-sensitive drug release, a series of dendritic star-shaped zwitterionic polymers, polyamidoamine-graft-poly[3-dimethyl(methacryloyloxyethyl) ammonium propanesulfonate](PAMAM-g-PDMAPS) were designed and synthesized by ATRP of DMAPS on the surface of PAMAM dendrimers.In this paper, generation 3 of PAMAM dendrimers(G3 PAMAM) were first prepared by alternative Michael addition and amidation reaction of ethylenediamine(EDA) and methylacrylate(MA); and G3 PAMAM was then converted into the PAMAM-Br macroinitiator for ATRP through its reaction with 2-bromoisobutyryl bromide; finally ATRP of zwitterionic DMAPS on PAMAM-Br was carried out to obtain a series of dendritic star-shaped polymers PAMAM-g-PDMAPS with different PDMAPS chain length by adjusting the feeding mole ratio of DMAPS to effective PAMAM-Br. The polymers were characterized by fourier transform-infrared spectroscopy(FT-IR), proton nuclear magnetic resonance spectroscopy(1H-NMR) and gel permeation chromatography(GPC) techniques. Zetasizer and transmission electron microscopy(TEM) demonstrated that PAMAM-g-PDMAPS in aqueous solution exists as unimolecular micelles rather than polymeric aggregates. The particle size of PAMAM-g-PDMAPS increased with the increase of PDMAPS chain length and the size distributions were narrow(0.105 ? PDI?0.114). The unimolecular micelles exhibited excellent stability without aggregation in PBS and PBS with 1 mg/mL BSA, both of which were complex biologically relevant media.The drug loading and in vitro release studies of PAMAM-g-PDMAPS micelles were investigated in detail using adriamycin(ADR) as the hydrophobic anticancer model drug. The results indicated that the DLC of PAMAM-g-PDMAPS was significantly higher than that of G3 PAMAM. The in vitro drug release of ADR-P micelles was pH-sensitive. After 48 h, more than 59.74% ADR was released from ADR-P at pH 5.1, on the contrary, only less about 16.38% ADR was released at pH 7.4. MTT assay and AO/PI live/dead double staining test demonstrated the introduction of zwitterionic PDMAPS on the surface of PAMAM have successfully decreased the cytotoxicity of G3 PAMAM. Meanwhile, the results of cellular uptake and anticancer activity indicated that ADR-P micelles could effectively restrain the growth of HepG2 cells and even kill them by endocytosis. All these results demonstrated that PAMAM-g-PDMAPS unimolecular micelles are attractive candidates as anticancer drug delivery carriers.