Di Francesco, V., Gurgone, D., Palomba, R., Ferreira, M. F. M. M., Catelani, T., Cervadoro, A., Maffia, P. and Decuzzi, P. (2020) Modulating lipoprotein transcellular transport and atherosclerotic plaque formation in apoe-/- mice via nanoformulated lipid-methotrexate conjugates. ACS Applied Materials and Interfaces, 12(34), pp. 37943-37956. (doi: 10.1021/acsami.0c12202) (PMID:32805983) (PMCID:PMC7453397)
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Abstract
Macrophage inflammation and maturation into foam cells, following the engulfment of oxidized low-density lipoproteins (oxLDL), are major hallmarks in the onset and progression of atherosclerosis. Yet, chronic treatments with anti-inflammatory agents, such as methotrexate (MTX), failed to modulate disease progression, possibly for the limited drug bioavailability and plaque deposition. Here, MTX-lipid conjugates, based on 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), were integrated in the structure of spherical polymeric nanoparticles (MTX-SPN) or intercalated in the lipid bi-layer of liposomes (MTX-LIP). Although, both nanoparticles were colloidally stable with an average diameter of ∼ 200 nm, MTX-LIP exhibited a higher encapsulation efficiency (> 70%) and slower release rate (∼50% at 10h) compared to MTX-SPN. In primary bone marrow derived macrophages (BMDM), MTX-LIP modulated the transcellular transport of oxLDL more efficiently than free MTX mostly by inducing a 2-fold overexpression of ABCA1 (regulating oxLDL efflux); while the effect on CD36 and SRA-1 (regulating oxLDL influx) was minimal. Furthermore, in BMDM, MTX-LIP showed a stronger anti-inflammatory activity than free MTX reducing the expression of IL-1β by 3-fold, IL-6 by 2-fold and also moderately of TNF-α. In 28 days high-fat-diet fed apoE-/- mice, MTX-LIP reduced the mean plaque area by 2-fold and the hematic amounts of RANTES by half as compared to free MTX. These results would suggest that the nano-enhanced delivery to vascular plaques of the anti-inflammatory DSPE-MTX conjugate could effectively modulate the disease progression by halting monocytes’ maturation and recruitment already at the onset of atherosclerosis.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Maffia, Professor Pasquale and Gurgone, Dr Danila |
| Authors: | Di Francesco, V., Gurgone, D., Palomba, R., Ferreira, M. F. M. M., Catelani, T., Cervadoro, A., Maffia, P., and Decuzzi, P. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Research Centre: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology |
| Journal Name: | ACS Applied Materials and Interfaces |
| Publisher: | American Chemical Society |
| ISSN: | 1944-8244 |
| ISSN (Online): | 1944-8252 |
| Published Online: | 28 July 2020 |
| Copyright Holders: | Copyright © 2020 American Chemical Society |
| First Published: | First published in ACS Applied Materials and Interfaces 12(34):37943-37956 |
| Publisher Policy: | Reproduced in accordance with the publisher copyright policy |
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