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.

Antimicrobial peptides with selective antitumor mechanisms: prospect for anticancer applications

“…As shown by the Gumbleton group and others, pegylation of AMPs can result in lower host toxicity without affecting antimicrobial activity [177]. Pegylation enhances the pharmacological properties of a given drug in a number of ways [178–183]. Because it increases hydrophilicity, PEG serves as a shield that protects against protease digestion, prolongs circulation time, and reduces the glomerular filtration rate.…”

“…Because it increases hydrophilicity, PEG serves as a shield that protects against protease digestion, prolongs circulation time, and reduces the glomerular filtration rate. An interesting example of AMP pegylation is a recent design by Kelly et al ., 2016 as shown in Figure 4 [183]. A pro-peptide was designed using the AMP P18 covalently attached to a linker region that is sensitive to the cysteine protease cathepsin B, followed by a PEG region to confer thermodynamic stability to the peptide.…”

“…Combining AMPs with a chemotherapeutic agent may help decrease dosage, which would result in lower toxicity. While the current clinical trial of LTX-315 including combination with immunotherapeutics (Ipilimumab or Pembrolizumab) is a step in the right direction, combination therapy using AMPs and chemotherapeutic agents needs to be explored for possible synergy [183]. …”

Unraveling the bioactivity of anticancer peptides as deduced from machine learning

“…substitution with non-canonical amino acid, peptide-peptide hybridization, target or polymer modification, PEGylation etc.) of therapeutic peptides (Narayana et al, 2015[59]; Braunstein et al, 2004[6]; Papo and Shai, 2003[65]; Hu et al, 2016[27]; Spinks et al, 2017[84]; Kelly et al, 2016[33]; Li et al, 2016[41]). Another concern is the short half-life of peptides.…”

Evaluation the synergistic antitumor effect of methotrexate–camptothecin codelivery prodrug from self‐assembly process to acid‐catalyzed both drugs release: A comprehensive theoretical study

“…Chemotherapy is a type of cancer therapy that uses one or more anticancer drugs to destroy or control tumors. Although the numerous number of anticancer drugs have been used extensively in clinical trials, the single‐agent chemotherapy commonly suffers from low in vivo potency due to the physiological complexity of various cancer cells .…”