The Impact of Pamam Dendrimers on Her2-Positive Breast Cancer and the Early Stages of Embryogenesis

Abstract

Poly (amidoamine) (PAMAM) dendrimers are widely used in drug delivery systems and gene transfection as drug carriers. They also exert several biological effects including modulating gene expression and interfering with transactivation of epidermal growth factor receptors, EGFR and HER2. HER2 is a major oncogene driving the proliferation of HER2-positive breast cancer cells and represents an important drug target in the treatment of breast cancer. However, it is not known whether PAMAMs can inhibit the activation of HER2 in breast carcinogenesis and whether this effect depends on the physicochemical properties of these polymers. In this study, we explored the anti-cancer effects of different generations and surface chemistries of PAMAMs on HER2-positive breast cancer cell lines. Additionally, the outcome of PAMAM dendrimers was examined in the early stages of embryogenesis. The anti-cancer effects of PAMAMs including cell viability, colony formation, and apoptosis were studied in HER2-positive breast cancer cells; SK-BR3 and ZR-75. Additionally, the effects of PAMAMs on angiogenesis and embryogenesis were investigated using a chicken embryo model. The underlying mechanisms of action were explored by RT-PCR and Western blotting analysis. PAMAMs exhibited significant anti-cancer effects that were more pronounced with cationic (-NH2) dendrimers, compared to neutral (-OH) or anionic (-COOH) and were greater in cationic G6 compared to cationic G4. Cationic G6 PAMAMs significantly decreased the viability of HER2-positive breast cancer cell lines down to 5.1% in SK-BR3 and to 5.7% in ZR-75 cells (p<0.001), in a dose and time-dependent fashion. Cationic polymers also resulted in cell cycle deregulation as well as inhibiting colony formation in soft agar compared to controls and to other PAMAMs studied (p<0.05). Cationic PAMAMs inhibited the phosphorylation of ErbB2, EGFR, and ERK1/2 and upregulated JNK1/2/3, similar to lapatinib, a clinically used inhibitor of HER2 receptor phosphorylation. Cationic PAMAMs also inhibited the angiogenesis of the chorioallantoic membrane (CAM) of the chicken embryo model. However, they exhibited substantial toxicity to the embryos at the early stages of their normal development. The exhibited anti-HER2 breast cancer effects of PAMAMs were generation and surface chemistry-dependent, and might be investigated further for the potential treatment of this cancer in the clinic