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DTSTART;TZID=America/New_York:20240613T090000
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UID:4975-1718269200-1718276400@che.northeastern.edu
SUMMARY:ChE PhD Dissertation Defense: Ian Smith
DESCRIPTION:PhD Dissertation Defense: A Primary Intestinal Model to Assay Lymphatic Drug Transport \nIan Smith \nLocation: Dodge Hall 070 & Zoom \nAbstract: Lipophilic drugs (logP > 5) often fail to develop as commercial oral medications due to poor absorption\, distribution\, metabolism\, excretion and/or toxicity (ADMET) properties. Beyond-rule-of-5 (bro5) candidate attrition in the clinic may be relieved by targeted delivery to chylomicrons (CMs) as chaperones into the mesenteric lymphatics. Lymph-cannulated animal models that estimate lymphatic bioavailability (F%) are surgically challenging\, costly and highly variable between species. In vitro models of the human intestinal epithelium can preserve enterocyte-like CM assembly and thereby recapitulate on the benchtop drug intercalation with CM components during transcytosis (i.e. the “lymphatic permeability” mechanism). This thesis proposes primary small intestinal epithelia as alternative platforms to the Caco-2 Transwell® culture for assaying lymphatic drug transport. \nPrimary monolayers cultured from small intestinal enteroids were investigated for CM synthesis\, secretion\, and transport of lymphotropic small molecules. The specific aims were to: 1) establish a mixed bile micelle formulation compatibile with primary cultures\, 2) develop a first-principle mathematical description of poorly water-soluble drug (PWSD) partitioning and uptake from lipid-containing micelles\, 3) characterize apolipoprotein B (apoB)-containing lipoprotein secretion from primary cultures along an oleic acid (OA)/2-monoloein (2-MO) stimulation axis\, and 4) compare CM-transported drug in culture to lymph-cannulated F% estimations. Exposure of mixed bile micelles containing 4:1 taurocholate (TC) and phosphatidylcholine (PC) to the brush border membrane of human duodenum (hDuo) and Caco-2/HT29-MTX co-cultures (Co-C) compromised tight junctional resistance and paracellular permeability in Co-C above 5 mM TC whereas hDuo were unaffected. Permeability measurements in the Co-C monolayer showed PWSD transport from TC/PC micelles to be reasonably predicted by changes in the apical (i.e. lumen-side) free or total drug concentration (CD\,free or CD\,total)\, but extent of fatty acid (FA)-induced supersaturation was limited by lipo-toxicity. Over a time course aligned to the window of lymph triglyceride (TG) turnover in vivo (i.e. 6 hours)\, controlled 2-monooloein (2-MO) stimulation of hDuo and murine ileum (mIle) monolayers induced significant increases in TG mass (~3.5-fold) and particle diameter (Dh) (~2-fold) of  < 1.006 g/mL lipoproteins. Primary enterocytes upregulated mgat2 transcription in the presence of 2-MO substrate to indicate that TG output in these FBS-differentiated cultures engaged the sn-1\,2-monoglyceride (2-MG) re-esterification pathway. Organoid cultures also favored basal-polarized apoB-48 release distinct from the bidirectional apoB-100 output of Caco-2. Finally\, apparent permeability of halofantrine (Hf; logP 7.34; BCS Class II) and navitoclax (Nx; logP 7.93; BCS Class IV) in CMs secreted from mIle but not Caco-2 were increased from TC/PC control conditions by inclusion of +OA/2-MO in micelles. For Hf\, the fraction of dose absorbed by CMs (faCM = 6.8 ± 0.9%) was similar to the fraction of dose transported into the lymph of cannulated rats (falymph = 5.5 ± 0.8%). \nDevelopment of an in vitro-in vivo correlation between lymph-cannulated animals and the primary transport assay developed herein might assist preclinical programs in translating lipid-based oral modalities to humans. Expansion of the organoid donor set (by species and small intestinal region)\, combinatorial probing of more lipid stimulation axes (by substrate chain length and saturation)\, and scaling of monolayer culture could refine the lymphatic assay into a high-throughput screen. Beyond a drug delivery context\, de novo CM assembly in enterocytes that retain a native small intestinal phenotype enables closed-system study of outstanding questions regarding intestinal lipoprotein formation and dyslipidemia disease intervention.
URL:https://che.northeastern.edu/event/che-phd-dissertation-defense-ian-smith/
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