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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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The origin and biosynthesis of the naphthalenoid moiety of juglone in black walnut

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Horticulture Research 2018年第1期5卷 159-169页

作者： rachel m.mcCoy Sagar m.Utturkar Joseph W.Crook Jyothi Thimmapuram Joshua R.Widhalm Department of Horticulture and Landscape Architecture Purdue University625 Agriculture Mall DriveWest LafayetteIN47907USA Purdue Center for Plant Biology Purdue UniversityWest LafayetteIN47907USA Bioinformatics Core Purdue University155 South Grant StreetWest LafayetteIN47907USA

Several members of the Juglandaceae family produce juglone,a specialized 1,4-naphthoquinone(1,4-NQ)natural product that is responsible for the notorious allelopathic effects of black walnut(Juglans nigra).Despite its documented ecological roles and potential for being developed as a novel natural product-based herbicide,none of the genes involved in synthesizing juglone have been *** on classical labeling studies,we hypothesized that biosynthesis of juglone’s naphthalenoid moiety is shared with biochemical steps of the phylloquinone ***,using comparative transcriptomics in combination with targeted metabolic profiling of 1,4-NQs in various black walnut organs,we provide evidence that phylloquinone pathway genes involved in 1,4-dihydroxynaphthoic acid(DHNA)formation are expressed in roots for synthesis of a compound other than *** experiments using axenic black walnut root cultures revealed that stable isotopically labeled L-glutamate incorporates into juglone resulting in the same mass shift as that expected for labeling of the quinone ring in *** together,these results indicate that in planta,an intermediate from the phylloquinone pathway provides the naphthalenoid moiety of ***,this work shows that juglone can be de novo synthesized in roots without the contribution of immediate precursors translocated from aerial *** present study illuminates all genes involved in synthesizing the juglone naphthoquinone ring and provides RNA-sequencing datasets that can be used with functional screening studies to elucidate the remaining juglone pathway *** of the generated knowledge is expected to inform future metabolic engineering strategies for harnessing juglone as a novel natural product-based herbicide.

关键词： moiety roots synthesizing

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B cells in pancreatic cancer stroma

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World Journal of Gastroenterology 2022年第11期28卷 1088-1101页

作者： Francesca Romana Delvecchio michelle R Goulart rachel Elizabeth Ann Fincham michele Bombadieri Hemant m Kocher William Harvey Research Institute Queen Mary University of LondonLondon EC1M 6BQUnited Kingdom Barts Cancer Institute Queen Mary University of LondonLondon EC1M 6BQUnited Kingdom Barts and the London HPB Centre Barts Health NHS TrustLondon E11BBUnited Kingdom

Pancreatic cancer is a disease with high unmet clinical *** cancer is also characterised by an intense fibrotic stroma,which harbours many immune *** in both human and animal models have demonstrated that the immune system plays a crucial role in modulating tumour onset and *** human pancreatic ductal adenocarcinoma,high B-cell infiltration correlates with better patient ***,B cells have received recent interest in pancreatic cancer as potential therapeutic ***,the data on the role of B cells in murine models is unclear as it is dependent on the pancreatic cancer model used to ***,it appears that B cells do organise along with other immune cells such as a network of follicular dendritic cells(DCs),surrounded by T cells and DCs to form tertiary lymphoid structures(TLS).TLS are increasingly recognised as sites for antigen presentation,T-cell activation,Bcell maturation and differentiation in plasma *** this review we dissect the role of B cells and provide directions for future studies to harness the role of B cells in treatment of human pancreatic cancer.

关键词： B cells Pancreatic cancer Cancer immunology Tertiary lymphoid structures Anti-tumour immunoglobulins Plasma cells

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T cells in pancreatic cancer stroma

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World Journal of Gastroenterology 2021年第46期27卷 7956-7968页

作者： michelle R Goulart Konstantinos Stasinos rachel Elizabeth Ann Fincham Francesca R Delvecchio Hemant m Kocher Centre for Tumour Biology Barts Cancer Institute-A CRUK Centre of Excellence Queen Mary University of LondonLondon EC1M 6BQUnited Kingdom Barts and the London HPB Centre The Royal London HospitalBarts Health NHS TrustLondon E11BBUnited Kingdom Centre for Experimental medicine and Rheumatology William Harvey Research InstituteQueen Mary University of LondonLondon EC1M 6BQUnited Kingdom

Pancreatic ductal adenocarcinoma(PDAC)is a highly devastating disease with a dismal 5-year survival *** has a complex tumour microenvironment;characterised by a robust desmoplastic stroma,extensive infiltration of immunesuppressive cells such as immature myeloid cells,tumour-associated macrophages,neutrophils and regulatory T cells,and the presence of exhausted and senescent T *** cross-talk between cells in this fibrotic tumour establishes an immune-privileged microenvironment that supports tumour cell escape from immune-surveillance,disease progression and spread to distant *** tumours,considered to be non-immunogenic or cold,express low mutation burden,low infiltration of CD8+cytotoxic lymphocytes that are localised along the invasive margin of the tumour border in the surrounding fibrotic tissue,and often display an exhausted ***,we review the role of T cells in pancreatic cancer,examine the complex interactions of these crucial effector units within pancreatic cancer stroma and shed light on the increasingly attractive use of T cells as therapy.

关键词： Immunosuppression T cell exhaustion Tumour microenvironment Pancreatic ductal adenocarcinoma Pancreatic cancer stroma

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HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma

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Protein & Cell 2020年第7期11卷 472-482页

作者： Xiaoguang Wang Brittany C.Waschke rachel A Woolaver Samantha m.Y.Chen Zhangguo Chen Jing H.Wang Department of Immunology and microbiology University of Colorado Anschutz Medical CampusSchool of Medicine12800 E.19th AveMail Stop 8333AuroraCO 80045USA

Immunotherapy has been applied successully to treat B-cell lymphomas in preclinical models or clinical ***,immunotherapy resistance is a major challenge for B-cell lymphoma *** overcome this issue,combinatorlal therapeutic strategies have been pursued to achieve a better efficacy for treating B-cell *** of such strategies is to combine immunotherapy with histone deacetylase(HDAC)*** inhibitors can potentially increase tumor immunogenicity,promote antitumor immune respon-ses,or reverse immunosuppressive tumor ***,the combination of HDAC inhibitors and immunotherapy has drawn much attention in current cancer ***,not all HDAC inhibitors are created equal and their net effects are highly dependent on the specific inhibitors used and the HDACs they ***,we suggest that optimal treatment effh-cacy requires personalized design and rational combination based on prognostic biomarkers and unique profiles of HDAC ***,we discuss the possible mechanisms by which B-cell lymphomas acquire immunotherapy resistance and the effects of HDAC inhibitors on tumor cells and immune cells that could help overcome immunotherapy resistance.

关键词： cancer immunotherapy HDAC inhibitor B-cell lymphomas anti-PD1 resistance tumor immunogenicity

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Unusual case of drug-induced cholestasis due to glucosamine and chondroitin sulfate

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World Journal of Hepatology 2015年第24期7卷 2559-2562页

作者： Stephen Ip rachel Jeong David F Schaeffer Eric m Yoshida Division of Gastroenterology Vancouver General HospitalUniversity of British Columbia Faculty of medicine and Dentistry University of Alberta Department of Pathology and Laboratory medicine University of British Columbia

Glucosamine(GS) and chondroitin sulfate(CS) are common over-the-counter(OTC) supplements used in the treatment of osteoarthritis. These medications are seemingly safe, but there are increasing reports of hepatotoxicity with these supplements. We reported a unique case of drug-induced cholestasis caused by GS and CS in a combination tablet. The etiology of the jaundice was overlooked despite extensive investigations over a three-month period. Unlike drug-induced hepatocellular injury, drug-induced cholestatic jaundice with GS and CS has only been reported twice before. This case emphasizes the importance of a complete medication history, especially OTC supplements, in the assessment of cholestasis.

关键词： Glucosamine Chondroitin Hepatotoxicity Cholestasis

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The role of systemic therapy in borderline resectable and locally advanced pancreatic ductal adenocarcinoma

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Journal of Cancer metastasis and Treatment 2022年第1期8卷 281-292页

作者： Victor C.K.Lo rachel A.Goodwin michael m.Vickers Department of medicine Division of Medical OncologyThe Ottawa Hospital Cancer CentreOttawaON K1H 8L6Canada

Pancreatic ductal adenocarcinoma(PDAC)remains a deadly disease,even in patients whose cancer is localized and *** resection provides the only option for cure,but long-term survival rates remain *** patients with borderline resectable(BR)disease who undergo upfront resection,many patients are either too unwell for subsequent adjuvant systemic therapy,develop recurrence soon after,or are found to have unresectable disease *** is increasing evidence for a neoadjuvant approach,using more conventional multi-agent chemotherapy regimens,which have demonstrated higher activity in the metastatic setting compared to single *** patients with locally advanced(LA)disease,which is unresectable by current definitions,there is mounting evidence that effective neoadjuvant systemic therapy is able to convert some patients’disease to a resectable state,offering the potential for long-term survival and *** we present a review of key trials focusing on prospective,randomized studies to provide high-level evidence supporting a neoadjuvant approach to both BR and LA ***,many knowledge gaps exist,such as the optimal neoadjuvant multi-agent chemotherapy regimen,the role of radiotherapy,and the safety and efficacy of adding immunotherapy to chemo/radiation *** challenges in determining the optimal approach to patients with BR or LA PDAC include not only overcoming the inherent difficulties in conducting complex,multidisciplinary,multicentre randomized trials in patients with a high-morbidity and mortality disease,but also trying to standardize disease definitions,treatment regimens,and outcome measures.

关键词： Borderline resectable locally advanced pancreatic ductal adenocarcinoma neoadjuvant chemotherapy

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Critical analysis of feeding jejunostomy following resection of upper gastrointestinal malignancies

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World Journal of Gastrointestinal Surgery 2017年第2期9卷 53-60页

作者： Andrew m Blakely Saad Ajmal rachel E Sargent Thomas T Ng Thomas J miner Department of Surgery Rhode Island HospitalProvidence Warren Alpert medical School of Brown University Providence

AIm To assess nutritional recovery,particularly regarding feeding jejunostomy tube(FJT)utilization,following upper gastrointestinal resection for malignancy. mETHODS A retrospective review was performed of a prospectively-maintained database of adult patients who underwent esophagectomy or gastrectomy(subtotal or total)for cancer with curative intent,from January 2001 to June 2014. Patient demographics,the approach to esophagectomy,the extent of gastrectomy,FJT placement and utilization at discharge,administration of parenteral nutrition(PN),and complications were evaluated. All patients were followed for at least ninety days or until *** The 287 patients underwent upper GI resection,comprised of 182 esophagectomy(n=107 transhiatal,58.7%; n=56 Ivor-Lewis,30.7%)and 105 gastrectomy [n=63 subtotal(SG),60.0%; n=42 total(TG),40.0%]. 181 of 182 esophagectomy patients underwent FJT,compared with 47 of 105 gastrectomy patients(99.5% vs 44.8%,P m most had undergone TG(n=39,92.9% vs n=8 SG,12.9%,P median length of stay was similar between esophagectomy and gastrectomy groups(14.7 d vs 17.1 d,P=0.076). Upon discharge,87 esophagectomy patients(48.1%)were taking enteral feeds,with 53(29.3%)fully and 34(18.8%)partially dependent. meanwhile,20 of 39 TG patients(51.3%)were either fully(n=3,7.7%)or partially(n=17,43.6%)dependent on tube feeds,compared with 5 of 8 SG patients(10.6%),all of whom were partially dependent. Gastrectomy patients were significantly less likely to be fully dependent on tube feeds at discharge compared to esophagectomy patients(6.4% vs 29.3%,P=0.0006). PN was administered despite FJT placement more often following gastrectomy than esophagectomy(n=11,23.4% vs n=7,3.9%,P=0.0001). FJT-specific complications requiring reoperation within 30 d of resection occurred more commonly in the gastrectomy group(n=6),all after TG,compared to 1 esophagectomy patient(12.8% vs 0.6%,P=0.0003). Six of 7 patients(85.7%)who experienced tube-re

关键词： Feeding jejunostomy Esophagectomy Gastrectomy Nutritional recovery Outcomes

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Statin use and cognitive function in middle-aged adults with type 1 diabetes

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World Journal of Diabetes 2017年第6期8卷 286-296页

作者： Karen A Nunley Trevor J Orchard Christopher m Ryan rachel miller Tina Costacou Caterina Rosano Department of Epidemiology University of PittsburghPA 15213United States

AIm To test associations between statin use and cognitive impairment in adults with childhood-onset type 1 diabetes(T1D).mETHODS In 2010-13, n = 108 middle-aged participants from ongoing observational Pittsburgh Epidemiology of Diabetes Complications Study underwent neurocognitive assessment(mean age and T1 D duration of 49 and 41 years, respectively). All were diagnosed with childhoodonset(i.e., prior to age 18) T1 D between 1950 and 1980 and were seen within one year of diagnosis at Children's Hospital of Pittsburgh. Self-reported statin use(yes/no and if yes, name of statin) was collected biennially from parent study baseline(1986-1988) to time of neurocognitive testing. Logistic regression models tested associations between statin use groups and cognitive impairment(defined as having two or more cognitive test scores 1.5SD or worse than published norms) while linear regression models tested associations between statin use groups and cognitive domain z-scores(domains: Verbal IQ, memory, executive function, psychomotor speed, and visuo-construction). All models controlled for education and age. To address confounding by indication, models were repeated using a propensity score for statin *** Of the 108 participants, 51 reported never using statins. median duration of statin use among the 57 ever users was 6 years. These 57 ever statin users were split to create two groups(≤ or > median years of statin use): 1-6 years(n = 25), and 7-12 years(n = 32). Compared with never users, using statins 1-6 years tripled the odds of cognitive impairment(OR = 3.16; 95%CI: 0.93-10.72; P = 0.06) and using statins 7-12 years almost quintupled the odds of cognitive impairment(OR = 4.84; 95%CI: 1.63-14.44; P = 0.005). Compared with never users, using statins 1-6 or 7-12 years was related to worse performance in the memory domain(β =-0.52; P = 0.003, and-0.39; P = 0.014, respectively). Adjusting for coronary artery disease, low density lipoprotein cholesterol, and Apo E4 statu

关键词： Type 1 diabetes Cognitive impairment memory Statin use Cohort study

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Folate binding protein—Outlook for drug delivery applications

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Chinese Chemical Letters 2015年第4期26卷 426-430页

作者： rachel L.merzel Jun-Jie Chen E.Neil G.marsh mark m.Banaszak Holl Department of Chemistry University of Michigan

Serum proteins represent an important class of drug and imaging agent delivery vectors. In this mini- review, key advantages of using serum proteins are discussed, followed by the particular advantages and challenges associated with employing soluble folate binding protein. In particular, approaches employing drugs that target folate metabolism are reviewed. Additionally, the slow-onset, tight- binding interaction of folate with folate binding protein and the relationship to a natural oligomerization mechanism is discussed. These unique aspects of folate binding protein suggest interesting applications for the protein as a vector for further drug and imaging agent development.

关键词： Folate binding proteinSerum proteinDrug deliveryFolate conjugateFolic acid

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