A special class of self-assembling peptides has been found to be capable of stabilizing the hydrophobic anticancer agent ellipticine in aqueous solution. Here we study the effect of peptide sequence on the complex formation and its anticancer activity in vitro. Three peptides, EAK16-II, EAK16-IV and EFK16-II, were selected to have either a different charge distribution (EAK16-II vs. EAK16-IV) or a varying hydrophobicity (EAK16-II vs. EFK16-II). Results on their complexation with ellipticine revealed that EAK16-II and EAK16-IV were able to stabilize protonated ellipticine or ellipticine microcrystals depending on the peptide concentration; EFK16-II could stabilize neutral ellipticine molecules and ellipticine microcrystals. These different molecular states of ellipticine were expected to affect ellipticine delivery. The anticancer activity of these complexes was tested against two cancer cell lines: A549 and MCF-7, and related to the cell viability. The viability results showed that the complexes with protonated ellipticine were effective in eradicating both cancer cells (viability <0.05), but their dilutions in water were not stable, leading to a fast decrease in their toxicity. In contrast, the complexes formulated with EFK16-II were relatively stable upon dilution, but their original toxicity was relatively low compared to that with protonated ellipticine. Overall, the charge distribution of the peptides seemed not to affect the complex formation and its therapeutic efficacy in vitro; however, the increase in hydrophobicity of the peptides significantly altered the state of stabilized ellipticine and increased the stability of the complexes. This work provides essential information for peptide sequence design in the development of self-assembling peptide-based delivery of hydrophobic anticancer drugs.
Protein adsorption on a surface plays an important role in biomaterial science and medicine. It is strongly related to the interaction between the protein residues and the surface. Here we report all-atom molecular dynamics simulations of the adsorption of an ionic complementary peptide, EAK16-II, to the hydrophobic highly ordered pyrolytic graphite surface. We find that, the hydrophobic interaction is the main force to govern the adsorption, and the peptide interchain electrostatic interaction affects the adsorption rate. Under neutral pH condition, the interchain electrostatic attraction facilitates the adsorption, whereas under acidic and basic conditions, because of the protonation and deprotonation of glutamic acid and lysine residues, respectively, the resulting electrostatic repulsion slows down the adsorption. We also found that under basic condition, during the adsorption peptide Chain II will be up against a choice to adsorb to the surface through the hydrophobic interaction or to form a temporary hydrophobic core with the deposited peptide Chain I. These results provide a basis for understanding some of the fundamental interactions governing peptide adsorption on the surface, which can shed new light on novel applications, such as the design of implant devices and drug delivery materials.
The interaction between a peptide-based drug delivery system and two serum proteins, bovine serum albumin (BSA) and immunoglobulin G (IgG), is investigated using fluorescence quenching and calorimetric techniques. An ionic-complementary self/co-assembling peptide, EAR8-II, is employed to encapsulate the hydrophobic anticancer drug pirarubicin (THP) and stabilize it in protein environments. Self/co-assembling properties of the peptide-drug complex (EAR8-II-THP) are shown to be different while interacting with serum proteins compared with the properties of the isolated complex. The results from thermodynamic studies suggest that the drug delivery system has a strong binding affinity (K(SV) 1689 M(-1)), exothermic and enthalpy-driven interaction, with BSA and a relatively weak affinity with IgG (K(SV) 295.2 M(-1)). In the presence of salt ions, the enthalpy and binding affinity remain unchanged, implying other interactions such as hydrogen bonding and Van der Waals interactions are present that are not affected by reduced polarity. This work forms the basis for further studies of EAR8-II-THP complexes in the presence of important proteins and for further evaluation of the complexes' immune response and anticancer activity.
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