Biomedical applications of anionic-terminal phenylalanine-modified dendrimers with unique stimuli-responsive behaviors

Abstract Dendrimers are synthetic polymers with well-defined structures and drug-loading capacity and are useful as nanocarriers for drug delivery systems. Polyamidoamine (PAMAM) dendrimers modified with phenylalanine (Phe) showed pH- and temperature-sensitive properties, the sensitivities of which were controlled by the terminal groups. Anionic-terminal Phe-modified dendrimers showed upper critical solution temperature (UCST)-type thermosensitive properties at acidic pH. Some of them showed both lower critical solution temperature (LCST)- and UCST-type thermosensitive behaviors, which were switched by pH. Anionic-terminal dendrimers, including Phe-modified dendrimers, accumulated in the lymph nodes after intradermal injection at the foot pads. Carboxy-terminal hydrophobic dendrimers modified with cyclohexanedicarboxylic acid (CHex) and Phe, such as PAMAM-CHex-Phe, were associated with lymph node-resident immune cells, including T cells. Because of the stimuli sensitivity, the association of PAMAM-CHex-Phe with T cells was enhanced at pH 6.5. These dendrimers were applied to the delivery of model drugs and nucleic acids into T cells. Because T cells in lymph nodes are important for cancer immunotherapy, anionic-terminal Phe-modified dendrimers with the ability to deliver bioactive molecules into T cells are useful for applications in cancer immunotherapy.