Encapsulation of a cationic antimicrobial peptide into self-assembled polyion complex nano-objects enhances its antitumor properties

Abstract

Antimicrobial peptides, a large class of molecules synthetized by various organisms as an innate defense against pathogens are more and more used for their anticancer properties as well. In order to overcome some of their limitations and to enhance their therapeutic efficiency, the use of delivery systems was taken into consideration. In this study we describe an original delivery system for antimicrobial peptides based on its physico-chemical properties, namely the selfassembled polyion complexes (PIC) based on electrostatic interactions of cationic antimicrobial peptide P6 with negatively charged double hydrophilic block copolymers, the poly(ethylene oxide)-poly(acrylic acid) (PEO-PAA) in our study. The drug delivery system was tested on 3D human tumor HCT-116 spheroids. The spheroid evolution and cell viability were monitored at 24 and 48 h after the treatment was applied. Our study demonstrates for the first time the feasibility of forming a polyion complex PIC with an antimicrobial peptide and that this self-assembled organisation provides added value in terms of anti-tumour therapeutic efficacy compared to the free form of the antimicrobial peptide.

Cancer Wars: Revenge of the AMPs (Antimicrobial Peptides), a New Strategy against Colorectal Cancer

“…The tumor spheroid model can be used in testing new chemotherapeutic agents; however, to our knowledge, there are only a limited number of studies reporting on antitumor peptides [ 17 , 45 , 46 , 47 ]. A recent study by Hadianamrei and collaborators has reported on the anticancer activity of short cationic a-helical peptides against both HCT-116 cells grown in a monolayer or spheroids [ 45 ].…”

“…Four of the peptides had reduced toxicity against human dermal fibroblasts, which indicated that the use of lysine residues instead of arginine ones would reduce the cytotoxic effect on normal cells [ 45 ]. We also reported previously the antitumor activity of one known AMP, Gramicidin A [ 17 ], and a new synthetized peptide, P6 [ 46 ], with improved activity against HT-29 and HCT-116 spheroids, respectively.…”

Crafting Stable Antibiotic Nanoparticles via Complex Coacervation of Colistin with Block Copolymers

“…Most often, the neutral block that provides colloidal stability through steric repulsion is poly­(ethylene oxide) (PEO), ,,, but sometimes other polymer blocks are used, such as poly­(vinyl alcohol) (PVA) or poly­(acrylamide) (PAAm), to name a few. Previously, other proteins, drugs, and peptides, e.g., (helical) polypeptides, , doxorubicin, lysozyme, , myoglobin, bovine serum albumin (BSA), and many others have been successfully complexed into C3Ms. ,,,, In contrast, complex coacervation involving AMPs is limited to a few studies. ,,− The AMPs polymyxin B, colistin, temporin-L, KSL-W, P6, and MSI-78 have successfully been complexed into coacervates, with only the latter two into C3Ms, which are generally recognized for their enhanced stability compared to typical coacervates . Răileanu et al complexed P6 with PEO- b -poly­(acrylic acid) (PAA), while Wang et al prepared C3Ms from the complexation of MSI-78 with methoxyPEO- b -poly­(α-glutamic acid) (PGlu) .…”

“…Previously, other proteins, drugs, and peptides, e.g., (helical) polypeptides, , doxorubicin, lysozyme, , myoglobin, bovine serum albumin (BSA), and many others have been successfully complexed into C3Ms. ,,,, In contrast, complex coacervation involving AMPs is limited to a few studies. ,,− The AMPs polymyxin B, colistin, temporin-L, KSL-W, P6, and MSI-78 have successfully been complexed into coacervates, with only the latter two into C3Ms, which are generally recognized for their enhanced stability compared to typical coacervates . Răileanu et al complexed P6 with PEO- b -poly­(acrylic acid) (PAA), while Wang et al prepared C3Ms from the complexation of MSI-78 with methoxyPEO- b -poly­(α-glutamic acid) (PGlu) . As shown by these examples, in combination with the limited research on the detailed structural investigation of the AMP complexes, the complexation of AMPs is still widely unexplored, even though this structural analysis is potentially highly relevant in the development of new antibiotic formulations.…”

“… 23 , 24 , 27 , 45 , 46 In contrast, complex coacervation involving AMPs is limited to a few studies. 21 , 25 , 47 − 51 The AMPs polymyxin B, 48 colistin, 21 temporin-L, 47 KSL-W, 51 P6, 49 and MSI-78 50 have successfully been complexed into coacervates, with only the latter two into C3Ms, which are generally recognized for their enhanced stability compared to typical coacervates. 27 Răileanu et al complexed P6 with PEO- b -poly(acrylic acid) (PAA), 49 while Wang et al prepared C3Ms from the complexation of MSI-78 with methoxyPEO- b -poly(α-glutamic acid) (PGlu).…”