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Review
. 2022 May:184:114252.
doi: 10.1016/j.addr.2022.114252. Epub 2022 Mar 30.

Delivering macrolide antibiotics to heal a broken heart - And other inflammatory conditions

Vincent J Venditto  1 , David J Feola  2
Affiliations
Review

Delivering macrolide antibiotics to heal a broken heart - And other inflammatory conditions

Vincent J Venditto et al. Adv Drug Deliv Rev. 2022 May.

Abstract

Drug carriers to deliver macrolide antibiotics, such as azithromycin, show promise as antibacterial agents. Macrolide drug carriers have largely focused on improving the drug stability and pharmacokinetics, while reducing adverse reactions and improving antibacterial activity. Recently, macrolides have shown promise in treating inflammatory conditions by promoting a reparative effect and limiting detrimental pro-inflammatory responses, which shifts the immunologic setpoint from suppression to balance. While macrolide drug carriers have only recently been investigated for their ability to modulate immune responses, the previous strategies that deliver macrolides for antibacterial therapy provide a roadmap for repurposing the macrolide drug carriers for therapeutic interventions targeting inflammatory conditions. This review describes the antibacterial and immunomodulatory activity of macrolides, while assessing the past in vivo evaluation of drug carriers used to deliver macrolides with the intention of presenting a case for increased effort to translate macrolide drug carriers into the clinic.

Keywords: Antibiotic; Azithromycin; Drug delivery; Immune modulation; Macrolides.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Drs. Venditto and Feola are inventors on a pending patent related to liposomal azithromycin.

Figures

Figure 1.
Figure 1.
Structural comparison of macrolide derivative over three generations. Numbering of carbon atoms in the ring structure is shown for erythromycin and structural changes from erythromycin for each of the other derivatives are highlighted in red.
Figure 2.
Figure 2.
Macrolides promote macrophage polarization to a reparative M2-like phenotype. M1 macrophages treated with macrolides decrease expression of pro-inflammatory markers (HLA-II, CD11c, CD86, iNOS and inflammatory cytokines (IL1β, IL-12, IL-6, TNFα) and increase M2-like reparative phenotype markers including anti-inflammatory cytokines (IL10, TGFβ), Arginase (Arg1) and mannose receptor (CD206). Figure created with BioRender.com.
Figure 3.
Figure 3.
Examples of reagents used for lipid-based macrolide delivery. Ion pairs between the cation of the desosamine of azithromycin is shown with anions from cholesteryl hemisuccinate and octadecanesulfonate. Sorbitan monostearate used to prepare niosomes for skin delivery; rhamnolipid used for oral liposome delivery; polysorbate 80 used for systemic noisome delivery; PGP-Me for nanoarchaeosome pulmonary delivery.
Figure 4.
Figure 4.
Examples of polymer architectures utilized for delivery of macrolides for antibacterial and immunomodulatory activity. Non-covalent polymer formulations to encapsulate macrolides include polycarbophil, poloxamer and PLE-PEI-hyd-mPEG, while PAMAM dendrimers are used for covalent conjugation of azithromycin.
Figure 5.
Figure 5.
Lipase sensitive dual therapy liposomes prepared with erythromycin (denoted in blue) in the liposomal bilayer, and pullulan coating (denoted in grey) with hydrolysable pheophorbide (denoted in red) anchors in the bilayer. Figure prepared with Biorender.com.
See this image and copyright information in PMC

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