Elucidation of the Cellular Uptake Mechanisms of Polycationic HYDRAmers

Dendrimers and dendrons appeared to potentially fulfill the requirements for being good and well-defined carriers in drug and gene delivery applications. We recently demonstrated that polycationic adamantane-based dendrons called <i>HYDRAmers</i> are easily internalized by both phagocytic and nonphagocytic cells in vitro. The aim of the present study was to investigate which of the different pathways of cellular internalization is involved in the cellular uptake of the first and second generation ammonium and guanidinium <i>HYDRAmers</i>. For this purpose, we have evaluated the internalization of fluorescently labeled <i>HYDRAmers</i> in both phagocytic murine macrophages and nonphagocytic human cervix epithelioid carcinoma cells in the presence of different well-known active uptake inhibitors. Our data revealed that the first and second generation <i>HYDRAmers</i> are internalized via different endocytic pathways based on the cellular type and on the type of functional groups present at the periphery of the dendrons. In particular, it was registered that the first generations were mainly internalized by clathrin-mediated endocytosis and macropinocytosis while the cellular internalization of the second generations was less affected by the inhibitory conditions of the endocytic pathways. These results suggest the possibility of addressing dendrimers toward specific subcellular compartments by tuning their structure properties and, in particular, the functional groups at their periphery

Polycationic Adamantane-Based Dendrons of Different Generations Display High Cellular Uptake without Triggering Cytotoxicity

Dendrons used as synthetic carriers are promising nanostructures for biomedical applications. Some polycationic dendritic systems, such as the commercially available polyethylenimine (PEI), have the ability to deliver genetic material into cells. Nevertheless, polycationic vectors are often associated with potential cellular toxicity, which prevents their use in clinical development. In this context, our research focused on the design and synthesis of a novel type of polycationic dendrons that are able to penetrate into cells without triggering cytotoxic effects. We synthesized first- and second-generation polycationic adamantane-based dendrons via a combined protection/deprotection strategy starting from different adamantane scaffolds. The linker between the adamantane cores is constituted of short ethylene glycol chains, and the periphery consists of ammonium and guanidinium groups. None of these dendritic structures, which we previously called <i>HYDRAmers</i>, displayed significant cytotoxicity effects on two different cell lines (RAW 264.7 and HeLa). Conjugation of the fluorescent probe cyanine 5 at their focal point via click chemistry permitted the evaluation of their cellular internalization. All of the dendrons penetrated through the membrane with efficient cellular uptake depending of the dendron generation and the nature of the peripheral groups. These results suggest that the polycationic <i>HYDRAmers</i> are potentially interesting as new vectors in biomedical applications, including gene and drug delivery

“Click” Assemblies and Redox Properties of Arene- and Gold-Nanoparticle-Cored Triazolylbiferrocene-Terminated Dendrimers

Large dendritic assemblies terminated by organometallic groups that possess a rich redox chemistry and stability in two or more oxidation states are highly desired as electron-reservoir systems, sensors, and redox catalysts. Here the synthesis and click (CuAAC) chemistry of ethynyl biferrocene including branching onto dendrons, arene-cored dendrimers, and gold nanoparticles are developed, and the role of the 1,2,3-triazole linkers and redox chemistry of these assemblies are discussed including the properties and stabilities of the redox states