Publications

@article{hudson_comparing_2025,

title = {Comparing the Altis RepliGut Organoid System to MDCK Monolayers in Predicting the Oral Absorption of Lenalidomide},

author = {Cole S. Hudson and Jonathan Cheong and Jesse Yu and Eugene C. Chen and Laurent Salphati and Matthew R. Durk and Benjamin Lai and Karen Samy},

url = {https://www.mdpi.com/1999-4923/17/9/1140},

doi = {10.3390/pharmaceutics17091140},

issn = {1999-4923},

year  = {2025},

date = {2025-08-30},

journal = {Pharmaceutics},

volume = {17},

number = {9},

pages = {1140},

abstract = {Background: Predicting oral drug absorption in humans is critical during early drug development. Current in vitro systems to predict absorption (e.g., PAMPA and MDCK cells) are lacking for certain classes of drugs. Intestinal organoids are emerging as a promising alternative that offers several potential advantages. In this study, we utilized human intestinal organoid-derived monolayers to predict oral absorption of lenalidomide. Methods: Human jejunal organoids (RepliGut®) were cultured as monolayers on transwell plates and differentiated into intestinal epithelial cells. Lenalidomide permeability in the organoid system was compared with the permeability in the conventional Madin-Darby Canine Kidney cell (MDCK) monolayer system, as well as P-gp knockout, human P-gp overexpressing, and human BCRP overexpressing MDCK cells across a concentration range of 1 to 500 µM. Male Sprague Dawley rats were administered lenalidomide orally/intravenously, and concentrations in the serum, urine, and feces were measured and modeled in Phoenix WinNonlin. Results: Orally administered lenalidomide was well absorbed by rats at all doses (bioavailability = 68–120%). In the human jejunal organoid model, lenalidomide apparent permeability (Papp) was approximately 0.6 × 10−6 cm/s independent of the concentration used (1–500 µM). In contrast, lenalidomide Papp was significantly lower in gMDCK cell monolayers, approximately 0.2 × 10−6 cm/s. Additionally, lenalidomide was identified as a P-gp/BCRP substrate in intestinal organoids and gMDCK P-gp and BCRP overexpressing cells. Conclusions: Lenalidomide Papp was significantly lower in gMDCK monolayers than expected based on its high bioavailability. Our results suggest that organoid systems can better capture transporter and paracellularly mediated effects on drug permeability, which may allow for more accurate predictions of in vivo absorption.},

note = {Publisher: Multidisciplinary Digital Publishing Institute},

keywords = {{MDCK} cells, drug permeability, intestinal organoids, lenalidomide, oral bioavailability},

pubstate = {published},

tppubtype = {article}

}

@article{sarma_design_2023,

title = {Design of 8-mer Peptides that Block Clostridioides difficile Toxin A in Intestinal Cells},

author = {Sudeep Sarma and Carly M. Catella and Ellyce T. San Pedro and Xingqing Xiao and Deniz Durmusoglu and Stefano Menegatti and Nathan Crook and Scott T. Magness and Carol K. Hall},

doi = {10.1101/2023.01.10.523493},

year  = {2023},

date = {2023-01-12},

urldate = {2023-01-12},

pages = {2023.01.10.523493},

abstract = {Clostridioides difficile ( C. diff .) is a bacterium that causes severe diarrhea and inflammation of the colon. The pathogenicity of C. diff . infection is derived from two major toxins, toxins A (TcdA) and B (TcdB). Peptide inhibitors that can be delivered to the gut to inactivate these toxins are an attractive therapeutic strategy. In this work, we present a new approach that combines a pep tide b inding d esign algorithm (PepBD), molecular-level simulations, rapid screening of candidate peptides for toxin binding, a primary human cell-based assay, and surface plasmon resonance (SPR) measurements to develop peptide inhibitors that block the glucosyltransferase activity of TcdA by targeting its glucosyltransferase domain (GTD). Using PepBD and explicit-solvent molecular dynamics simulations, we identified seven candidate peptides, SA1-SA7. These peptides were selected for specific TcdA GTD binding through a custom solid-phase peptide screening system, which eliminated the weaker inhibitors SA5-SA7. The efficacies of SA1-SA4 were then tested using a trans-epithelial electrical resistance (TEER) assay on monolayers of the human gut epithelial culture model. One peptide, SA1, was found to block TcdA toxicity in primary-derived human jejunum (small intestinal) and colon (large intestinal) epithelial cells. SA1 bound TcdA with a K D of 56.1 ± 29.8 nM as measured by surface plasmon resonance (SPR). 

SIGNIFICANCE STATEMENT: Infections by Clostridioides difficile , a bacterium that targets the large intestine (colon), impact a significant number of people worldwide. Bacterial colonization is mediated by two exotoxins: toxins A and B. Short peptides that can inhibit the biocatalytic activity of these toxins represent a promising strategy to prevent and treat C. diff . infection. We describe an approach that combines a Peptide B inding D esign (PepBD) algorithm, molecular-level simulations, a rapid screening assay to evaluate peptide:toxin binding, a primary human cell-based assay, and surface plasmon resonance (SPR) measurements to develop peptide inhibitors that block Toxin A in small intestinal and colon epithelial cells. Importantly, our designed peptide, SA1, bound toxin A with nanomolar affinity and blocked toxicity in colon cells.},

keywords = {Adverse events, epithelial barrier, In vitro model, inflammatory bowel disease, intestinal organoids, intestinal stem cells, microbiome},

pubstate = {published},

tppubtype = {article}

}