S-EPMC7453397 - Modulating Lipoprotein Transcellular Transport and Atherosclerotic Plaque Formation in ApoE-/- Mice via Nanoformulated Lipid-Methotrexate Conjugates. - OmicsDI

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Modulating Lipoprotein Transcellular Transport and Atherosclerotic Plaque Formation in ApoE-/- Mice via Nanoformulated Lipid-Methotrexate Conjugates.

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-SPNs) or intercalated in the lipid bilayer 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 10 h) compared to MTX-SPN. In primary bone marrow derived macrophages (BMDMs), 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 BMDMs, MTX-LIP showed a stronger anti-inflammatory activity than free MTX, reducing the expression of IL-1? by 3-fold, IL-6 by 2-fold, and also moderately of TNF-?. 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 nanoenhanced 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.

SUBMITTER: Di Francesco V

PROVIDER: S-EPMC7453397 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Modulating Lipoprotein Transcellular Transport and Atherosclerotic Plaque Formation in ApoE<sup>-/-</sup> Mice via Nanoformulated Lipid-Methotrexate Conjugates.

Di Francesco Valentina V Gurgone Danila D Palomba Roberto R Ferreira Miguel Filipe Moreira Marques MFMM Catelani Tiziano T Cervadoro Antonio A Maffia Pasquale P Decuzzi Paolo P

ACS applied materials & interfaces 20200814 34

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-<i>sn</i>-glycero-3-phosphoethanolamine (DSPE), were integra ...[more]

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