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Modulating Oral Delivery and Gastrointestinal Kinetics of Recombinant Proteins via Engineered Fungi

  • Research Article
  • Theme: Rising Stars in Drug Delivery and Novel Carriers
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Abstract

A new modality in microbe-mediated drug delivery has recently emerged wherein genetically engineered microbes are used to locally deliver recombinant therapeutic proteins to the gastrointestinal tract. These engineered microbes are often referred to as live biotherapeutic products (LBPs). Despite advanced genetic engineering and recombinant protein expression approaches, little is known on how to control the spatiotemporal dynamics of LBPs and their secreted therapeutics within the gastrointestinal tract. To date, the fundamental pharmacokinetic analyses for microbe-mediated drug delivery systems have not been described. Here, we explore the pharmacokinetics of an engineered, model protein-secreting Saccharomyces cerevisiae, which serves as an ideal organism for the oral delivery of complex, post-translationally modified proteins. We establish three methods to modulate the pharmacokinetics of an engineered, recombinant protein-secreting fungi system: (i) altering oral dose of engineered fungi, (ii) co-administering antibiotics, and (iii) altering recombinant protein secretion titer. Our findings establish the fundamental pharmacokinetics which will be essential in controlling downstream therapeutic response for this new delivery modality.

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Acknowledgements

We thank Dr. J. Heitman for kindly gifting the wild type fungal strain. We thank UNC Nanomedicines Characterization Core Facility for training and equipment utilization for western blot imaging. Illustrations created with BioRender.com.

Funding

Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R35GM137898.

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  1. Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 125 Mason Farm Road, North Carolina, 27599, Chapel Hill, USA

    Mairead K. Heavey & Aaron C. Anselmo

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Contributions

M.H. and A.A. conceived the ideas presented, designed the studies, organized experimental work, and wrote and revised the manuscript. M.H. performed all experiments and data analyses. A.A. supervised the project and data analyses. M.H. and A.A agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Aaron C. Anselmo.

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Heavey, M.K., Anselmo, A.C. Modulating Oral Delivery and Gastrointestinal Kinetics of Recombinant Proteins via Engineered Fungi. AAPS J 23, 76 (2021). https://doi.org/10.1208/s12248-021-00606-9

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