Modulating lipoprotein transcellular transport and atherosclerotic plaque formation in apoe-/- mice via nanoformulated lipid-methotrexate conjugates

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, Dr Pasquale and Gurgone, Miss 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 > Institute of Infection Immunity and Inflammation
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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
308639Defining the individual and integrated roles of inflammatory chemokine receptors (iCCRs) in atherosclerosisPasquale MaffiaBritish Heart Foundation (BHF)PG/19/84/34771CAMS - Cardiovascular Science
190814BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177Institute of Cardiovascular & Medical Sciences
190739In Situ Nanoparticle Assemblies for Healthcare Diagnostics and Therapy. Reference: 130479Pasquale MaffiaEngineering and Physical Sciences Research Council (EPSRC)EP/L014165/1III - Immunology
171799NanoMATePasquale MaffiaEuropean Commission (EC)661369III - Immunology
173707Institutional Strategic Support Fund (2016)Anna DominiczakWellcome Trust (WELLCOTR)204820/Z/16/ZInstitute of Cardiovascular & Medical Sciences