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Systematic development of ionizable lipid nanoparticles for placental mRNA delivery using a design of experiments approach

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Bioactive Materials 2024年第4期34卷 125-137页

作者： Rachel E.Young Katherine M.Nelson Samuel I.Hofbauer Tara Vijayakumar Mohamad-Gabriel Alameh Drew Weissman charalampos papachristou Jason P.Gleghorn Rachel S.Riley Department of Biomedical Engineering Henry M.Rowan College of EngineeringRowan University201 Mullica Hill RdGlassboroNJ 08028United States School of Translational Biomedical Engineering&Sciences Virtua College of Medicine&Life Sciences of Rowan University201 Mullica Hill RdGlassboroNJ 08028United States Department of Chemical and Biomolecular Engineering College of EngineeringUniversity of Delaware150 Academy StreetNewarkDE 19716United States Cooper Medical School of Rowan University Rowan University401 BroadwayCamdenNJ 08103United States Perelman School of Medicine University of Pennsylvania3400 Civic Center BlvdPhiladelphiaPA 19104United States Department of Mathematics College of Science&MathematicsRowan University201 Mullica Hill RdGlassboroNJ 08028United States Department of Biomedical Engineering College of EngineeringUniversity of Delaware590 Avenue 1743NewarkDE 19713United States

Ionizable lipid nanoparticles(LNPs)have gained attention as mRNA delivery platforms for vaccination against COVID-19 and for protein replacement *** enhance mRNA stability,circulation time,cellular uptake,and preferential delivery to specific tissues compared to mRNA with no carrier ***,LNPs are only in the beginning stages of development for safe and effective mRNA delivery to the placenta to treat placental ***,we develop LNPs that enable high levels of mRNA delivery to trophoblasts in vitro and to the placenta in vivo with no *** conducted a Design of Experiments to explore how LNP composition,including the type and molar ratio of each lipid component,drives trophoblast and placental *** data revealed that utilizing C12-200 as the ionizable lipid and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine(DOPE)as the phospholipid in the LNP design yields high transfection efficiency in *** of lipid molar composition as a design parameter in LNPs displayed a strong correlation between apparent pKa and poly(ethylene)glycol(PEG)content,as a reduction in PEG molar amount increases apparent ***,we present one LNP platform that exhibits the highest delivery of placental growth factor mRNA to the placenta in pregnant mice,resulting in synthesis and secretion of a potentially therapeutic ***,our high-performing LNPs have no toxicity to both the pregnant mice and *** results demonstrate the feasibility of LNPs as a platform for mRNA delivery to the placenta,and our top LNP formulations may provide a therapeutic platform to treat diseases that originate from placental dysfunction during pregnancy.

关键词： Lipid nanoparticles(LNPs) Drug delivery Nucleic acids Placental growth factor(PlGF) Placenta Pregnancy Preeclampsia

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Cardiovascular disease: Risk factors and applicability of a risk model in a Greek cohort of renal transplant recipients

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World Journal of Transplantation 2017年第1期7卷 49-56页

作者： Nikolaos-Andreas Anastasopoulos Evangelia Dounousi Evangelos papachristou charalampos Pappas Eleni Leontaridou Eirini Savvidaki Dimitrios Goumenos Michael Mitsis Department of Medicine School of Health Sciences University of Ioannina Renal Transplant Unit University Hospital of Ioannina School of Health Science University of Patras Department of Nephrology and Transplantation Patras University Hospital Department of Nephrology University Hospital of Ioannina

AIM To investigate the incidence and the determinants of cardiovascular morbidity in Greek renal transplant recipients(RTRs) expressed as major advance cardiac event(MACE) rate. METHODS Two hundred and forty-two adult patients with a functioning graft for at least three months and availabledata that were followed up on the August 31, 2015 at two transplant centers of Western Greece were included in this study. Baseline recipients' data elements included demographics, clinical characteristics, history of comorbid conditions and laboratory parameters. Follow-up data regarding MACE occurrence were collected retrospectively from the patients' records and MACE risk score was calculated for each patient. RESULTS The mean age was 53 years(63.6% males) and 47 patients(19.4%) had a pre-existing cardiovascular disease(CVD) before transplantation. The mean estimated glomerular filtration rate was 52 ± 17 mL /min per 1.73 m2. During follow-up 36 patients(14.9%) suffered a MACE with a median time to MACE 5 years(interquartile range: 2.2-10 years). Recipients with a MACE compared to recipients without a MACE had a significantly higher mean age(59 years vs 52 years, P < 0.001) and a higher prevalence of pre-existing CVD(44.4% vs 15%, P < 0.001). The 7-year predicted mean risk for MACE was 14.6% ± 12.5% overall. In RTRs who experienced a MACE, the predicted risk was 22.3% ± 17.1% and was significantly higher than in RTRs without an event 13.3% ± 11.1%(P = 0.003). The discrimination ability of the model in the Greek database of RTRs was good with an area under the receiver operating characteristics curve of 0.68(95%CI: 0.58-0.78).CONCLUSION In this Greek cohort of RTRs, MACE occurred in 14.9% of the patients, pre-existing CVD was the main risk factor, while MACE risk model was proved a dependable utility in predicting CVD post RT.

关键词： Cardiovascular disease Major advance cardiac event Risk factors Risk model Kidney Transplantation

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