title: Polymeric prodrug combination to exploit the therapeutic potential of antimicrobial peptides against cancer cells.
abstract: Antimicrobial Peptides (AMPs) have unique anticancer properties, but their clinical application is currently limited by an inadequate margin of safety. A prodrug strategy associated with a combination therapy approach could address this limitation by increasing their therapeutic index and their efficacy. Accordingly, the first targeted anticancer polymeric prodrug candidates of AMPs, intended for combination therapy with another polymeric prodrug of an approved antineoplastic agent (doxorubicin), were synthesized as either a PEG-based dual-release prodrug or two individual pegylated prodrugs. The latter are based on a cathepsin B-labile peptide linker and an acid-sensitive acyl hydrazone bond for the AMP and doxorubicin prodrugs, respectively. Anticancer activities and toxicity differentials achieved with the free peptide and its polymer conjugates against ovarian, cancer and non-malignant, cells, indicate that protease-dependent reversible pegylation could be implemented to increase the therapeutic indices of AMPs in cancer therapy. The results obtained also show that this approach can be developed if the releasable PEG linker can be optimised to conciliate the attributes and restrictions of pegylation against proteases. In addition, combination of the polymeric prodrugs of the AMP and of doxorubicin provides additive antitumor effects which could be exploited to enhance the efficacy of the AMP candidate.
authors.affiliation: Centre for Synthesis and Chemical Biology, Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland. mdevocelle@rcsi.ie.
authors.forename: G J
authors.identifier: http://orcid.org/0000-0001-5138-9325
authors.initials: GJ
authors.lastname: Kelly
authors.affiliation: Department of Science, Institute of Technology Tallaght, Dublin 24, Ireland.
authors.forename: A Foltyn-Arfa
authors.initials: AF
authors.lastname: Kia
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland.
authors.forename: F
authors.initials: F
authors.lastname: Hassan
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland.
authors.forename: S
authors.initials: S
authors.lastname: O'Grady
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland.
authors.forename: M P
authors.initials: MP
authors.lastname: Morgan
authors.affiliation: Department of Science, Institute of Technology Tallaght, Dublin 24, Ireland.
authors.forename: B S
authors.initials: BS
authors.lastname: Creaven
authors.affiliation: Centre of Microbial Host Interactions, Institute of Technology Tallaght, Dublin 24, Ireland.
authors.forename: S
authors.initials: S
authors.lastname: McClean
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland.
authors.forename: J H
authors.initials: JH
authors.lastname: Harmey
authors.affiliation: Centre for Synthesis and Chemical Biology, Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland. mdevocelle@rcsi.ie.
authors.forename: M
authors.identifier: http://orcid.org/0000-0001-7641-1306
authors.initials: M
authors.lastname: Devocelle
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000494:pharmacology*; D002401:Cathepsin B / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D023181:Antimicrobial Cationic Peptides; D011108:Polymers; D011355:Prodrugs; D011092:Polyethylene Glycols; D004317:Doxorubicin; D002401:Cathepsin B