Self‐Assembling Peptide as a Potential Carrier for Hydrophobic Anticancer Drug Ellipticine: Complexation, Release and In Vitro Delivery

Abstract

The self‐assembling peptide EAK16‐II is capable of stabilizing hydrophobic compounds to form microcrystal suspensions in aqueous solution. Here, the ability of this peptide to stabilize the hydrophobic anticancer agent ellipticine is investigated. The formation of peptide‐ellipticine suspensions is monitored with time until equilibrium is reached. The equilibration time is found to be dependent on the peptide concentration. When the peptide concentration is close to its critical aggregation concentration, the equilibration time is minimal at 5 h. With different combinations of EAK16‐II and ellipticine concentrations, two molecular states (protonated or cyrstalline) of ellipticine could be stabilized. These different states of ellipticine significantly affect the release kinetics of ellipticine from the peptide‐ellipticine complex into the egg phosphatidylcholine vesicles, which are used to mimic cell membranes. The transfer rate of protonated ellipticine from the complex to the vesicles is much faster than that of crystalline ellipticine. This observation may also be related to the size of the resulting complexes as revealed from the scanning electron micrographs. In addition, the complexes with protonated ellipticine are found to have a better anticancer activity against two cancer cell lines, A549 and MCF‐7. This work forms the basis for studies of the peptide‐ellipticine suspensions in vitro and in vivo leading to future development of self‐assembling peptide‐based delivery of hydrophobic anticancer drugs.

pH-Triggered Release of Hydrophobic Molecules from Self-Assembling Hybrid Nanoscaffolds

“…Several hydrophobic anticancer drugs (e.g., paclitaxel, 23 ellipticine, 24,25 curcumin, 26 etc.) have been attempted to be released by (RADA) 4 or other similar ioncomplementary self-assembling peptides (e.g., EAK16-IV, EAK16-II and EFK-II, 24,27−29 MAX8, 30,31 etc.).…”

Self-assembling peptide-based nanoparticles enhance anticancer effect of ellipticine in vitro and in vivo

“…emission fluorescence peaks at about 390-440 nm, 468 nm, and 520 nm, respectively. 27 In the current study, the focus is on EAK-EPT complexes, where ellipticine was in a protonated state and is considered as green fluorescence. Both the flow cytometry and fluorescence microscopy used here were capable of detecting green fluorescence emitted by ellipticine at 520 nm.…”

“…The higher pH may lead to deprotonation of ellipticine and accordingly a lower zeta potential. 27 To study the interaction between EAK-EPT and plasma proteins under physiological conditions, the EAK-EPT complexes were incubated in bovine albumin serum, which is the most abundant protein in plasma. Over time, the zeta potential of EAK-EPT preincubated with bovine albumin serum decreased to -0.51 ± 0.08 mV with a stable particle size of ,100 nm.…”

“…26 Previous studies have shown that EAK16-II, an amino acid pairing, ionic-complementary self-assembling peptide, stabilizes ellipticine in aqueous solution. 21,27,28 EAK16-II has shown great potential to deliver ellipticine in a protonated state and to induce cytotoxicity in different cancer cells.…”

The origin of the dual fluorescence of protonated ellipticine in water

“…To gain a deeper understanding of the factors controlling the excited state relaxation processes, the fluorescent behavior of E was examined in organic solvents of a wide range of polarities and hydrogen bonding capabilities [3]. Selfassembling peptides was found to stabilize this alkaloid in water [4,5]. The native fluorescence of E and its protonated form (EH + ) was exploited to monitor their uptake and intracellular distribution [6,7].…”