PMID- 32805983 OWN - NLM STAT- MEDLINE DCOM- 20210222 LR - 20240428 IS - 1944-8252 (Electronic) IS - 1944-8244 (Print) IS - 1944-8244 (Linking) VI - 12 IP - 34 DP - 2020 Aug 26 TI - Modulating Lipoprotein Transcellular Transport and Atherosclerotic Plaque Formation in ApoE(-/-) Mice via Nanoformulated Lipid-Methotrexate Conjugates. PG - 37943-37956 LID - 10.1021/acsami.0c12202 [doi] AB - 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 approximately 200 nm, MTX-LIP exhibited a higher encapsulation efficiency (>70%) and slower release rate ( approximately 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-1beta by 3-fold, IL-6 by 2-fold, and also moderately of TNF-alpha. 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. FAU - Di Francesco, Valentina AU - Di Francesco V AUID- ORCID: 0000-0003-4216-724X AD - Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy. AD - Department of Informatics, Bioengineering, Robotics and System Engineering, University of Genoa, Via Opera Pia, 13, 16145 Genoa, Italy. FAU - Gurgone, Danila AU - Gurgone D AUID- ORCID: 0000-0001-7736-1187 AD - Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom. AD - Department of Pharmacy, University of Naples Federico II, Naples 80131, Italy. FAU - Palomba, Roberto AU - Palomba R AUID- ORCID: 0000-0002-9715-3876 AD - Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy. FAU - Ferreira, Miguel Filipe Moreira Marques AU - Ferreira MFMM AUID- ORCID: 0000-0002-1560-3571 AD - Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy. FAU - Catelani, Tiziano AU - Catelani T AUID- ORCID: 0000-0002-3790-5749 AD - Electron Microscopy Facility, Istituto Italiano di Tecnologia, via Morego 30, Genova 16163, Italy. FAU - Cervadoro, Antonio AU - Cervadoro A AUID- ORCID: 0000-0003-3087-2363 AD - Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy. FAU - Maffia, Pasquale AU - Maffia P AUID- ORCID: 0000-0003-3926-4225 AD - Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom. AD - Department of Pharmacy, University of Naples Federico II, Naples 80131, Italy. AD - Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom. FAU - Decuzzi, Paolo AU - Decuzzi P AUID- ORCID: 0000-0001-6050-4188 AD - Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy. LA - eng GR - WT_/Wellcome Trust/United Kingdom GR - PG/19/84/34771/BHF_/British Heart Foundation/United Kingdom GR - RE/13/5/30177/BHF_/British Heart Foundation/United Kingdom PT - Journal Article DEP - 20200814 PL - United States TA - ACS Appl Mater Interfaces JT - ACS applied materials & interfaces JID - 101504991 RN - 0 (ATP Binding Cassette Transporter 1) RN - 0 (Anti-Inflammatory Agents) RN - 0 (Apolipoproteins E) RN - 0 (Interleukin-1beta) RN - 0 (Lipoproteins, LDL) RN - 0 (Liposomes) RN - 0 (Phosphatidylethanolamines) RN - 0 (oxidized low density lipoprotein) RN - 1G4B5265CQ (1,2-distearoylphosphatidylethanolamine) RN - YL5FZ2Y5U1 (Methotrexate) SB - IM MH - ATP Binding Cassette Transporter 1/genetics/metabolism MH - Animals MH - Anti-Inflammatory Agents/*chemistry/pharmacology/therapeutic use MH - Apolipoproteins E/deficiency/genetics MH - Atherosclerosis/drug therapy/pathology MH - Diet, High-Fat MH - Interleukin-1beta/metabolism MH - Lipoproteins, LDL/chemistry/metabolism MH - Liposomes/chemistry MH - Macrophages/cytology/drug effects/metabolism MH - Methotrexate/*chemistry MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Nanomedicine MH - Nanoparticles/chemistry MH - Particle Size MH - Phosphatidylethanolamines/*chemistry MH - RAW 264.7 Cells PMC - PMC7453397 OTO - NOTNLM OT - atherosclerosis OT - foam cells OT - inflammation OT - low-density lipoprotein transport OT - nanomedicine COIS- The authors declare no competing financial interest. EDAT- 2020/08/19 06:00 MHDA- 2021/02/23 06:00 PMCR- 2020/08/28 CRDT- 2020/08/19 06:00 PHST- 2020/08/19 06:00 [pubmed] PHST- 2021/02/23 06:00 [medline] PHST- 2020/08/19 06:00 [entrez] PHST- 2020/08/28 00:00 [pmc-release] AID - 10.1021/acsami.0c12202 [doi] PST - ppublish SO - ACS Appl Mater Interfaces. 2020 Aug 26;12(34):37943-37956. doi: 10.1021/acsami.0c12202. Epub 2020 Aug 14.