Anionic Amino Acid Dendrimer-Trastuzumab Conjugates for Specific Internalization in HER2-Positive Cancer Cells

Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor 2 (HER2), offers a promising strategy of anticancer drug targeting to HER2-expressing cancer cells. Conjugation of trastuzumab to dendrimers, repeatedly branched polymers with a highly functionalized surface, can enhance the drug loading capacity. However, typical dendrimers such as cationic polyamidoamine dendrimers have exhibited a nonspecific cytotoxicity. In the present study, we developed a novel biocompatible amino acid dendrimer with potentially less toxicity by surface modification of the sixth generation lysine dendrimer with glutamate (KG6E). The synthesized KG6E showed a well-controlled particle size around 5-6 nm with low polydispersibility and negative surface potentials for negligible cytotoxicity. Next, the targeting efficiency of the fluorescent-labeled KG6E-trastuzumab conjugate was evaluated in HER2-positive (SKBR3) and -negative (MCF7) human breast cancer cell lines compared to free trastuzumab and KG6E dendrimers. The KG6E-trastuzumab conjugate was specifically bound to SKBR3 cells in a dose-dependent manner with low binding affinity to MCF7 cells. Furthermore, the conjugate was significantly internalized in SKBR3 cells and then trafficked to lysosomes. These results indicate the potential of KG6E-trastuzumab conjugates as HER2-targeting carriers for therapeutic and diagnostic approaches to cancer therapy.