Melittin (M) has attracted increasing attention for its significant antitumor effects and various immunomodulatory effects. However, various obstacles such as the short plasma half-life and adverse reactions restrict its application. This study aimed to systematically investigate the self-assembly mechanism, components of the protein corona, targeting behavior, and anti-4 T1 tumor effect of vitamin E-succinic acid-(glutamate)n /melittin nanoparticles with varying amounts of glutamic acid. Here, we present a new vitamin E-succinic acid-(glutamate)5 (E5), vitamin E-succinic acid-(glutamate)10 (E10) or vitamin E-succinic acid-(glutamate)15 (E15), and their co-assembly system with positively charged melittin in water. The molecular dynamics simulations demonstrated that the electrostatic energy and van der Waals force in the system decreased significantly with the increase in the amount of glutamic acid. The melittin and E15 system exhibited the optimal stability for nanoparticle self-assembly. When nanoparticles derived from different self-assembly systems were co-incubated with plasma from patients with breast cancer, the protein corona showed heterogeneity. In vivo imaging demonstrated that an increase in the number of glutamic acid residues enhanced circulation duration and tumor-targeting effects. Both in vitro and in vivo antitumor evaluation indicated a significant increase in the antitumor effect with the addition of glutamic acid. According to our research findings, the number of glutamic acid residues plays a crucial role in the targeted delivery of melittin for immunomodulation and inhibition of 4 T1 breast cancer. Due to the self-assembly capabilities of vitamin E-succinic acid-(glutamate)n in water, these nanoparticles carry significant potential for delivering cationic peptides such as melittin.
Keywords: Breast cancer therapy; Circulation duration; Glutamic acid residues; Peptide assembly; Protein corona.
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