Sol-moiety: Discovery of a water-soluble prodrug technology for enhanced oral bioavailability of insoluble therapeutics

Arvin B. Karbasi, Jaden D. Barfuss, Theodore C. Morgan, Daniel Collins, Drew A. Costenbader, David G. Dennis, Andrew Hinman, KyuWeon Ko, Cynthia Messina, Khanh C. Nguyen, Rebecca C. Schugar, Karin A. Stein, Brianna B. Williams, Haixia Xu, Justin P. Annes and Mark Smith ()
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Arvin B. Karbasi: Stanford University
Jaden D. Barfuss: Stanford University
Theodore C. Morgan: Stanford University
Daniel Collins: Stanford University
Drew A. Costenbader: Stanford University
David G. Dennis: Stanford University
Andrew Hinman: Stanford University
KyuWeon Ko: Stanford University
Cynthia Messina: Stanford University
Khanh C. Nguyen: Stanford University School of Medicine
Rebecca C. Schugar: Stanford University School of Medicine
Karin A. Stein: Stanford University
Brianna B. Williams: Stanford University
Haixia Xu: Stanford University School of Medicine
Justin P. Annes: Stanford University School of Medicine
Mark Smith: Stanford University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Though conceptually attractive, the use of water-soluble prodrug technology to enhance oral bioavailability of highly insoluble small molecule therapeutics has not been widely adopted. In large part, this is due to the rapid enzymatic or chemical hydrolysis of prodrugs within the gastrointestinal tract, resulting in drug precipitation and no overall improvement in oral bioavailability relative to standard formulation strategies. We reasoned that an optimal water-soluble prodrug could be attained if the rate of prodrug hydrolysis were reduced to favor drug absorption rather than drug precipitation. In doing so, the rate of hydrolysis provides a pharmacokinetic control point for drug delivery. Herein, we report the discovery of a water-soluble promoiety (Sol-moiety) technology to optimize the oral bioavailability of highly insoluble small molecule therapeutics, possessing various functional groups, without the need for sophisticated, often toxic, lipid or organic solvent-based formulations. The power of the technology is demonstrated with marked pharmacokinetic improvement of the commercial drugs enzalutamide, vemurafenib, and paclitaxel. This led to a successful efficacy study of a water-soluble orally administered prodrug of paclitaxel in a mouse pancreatic tumor model.

Date: 2024
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DOI: 10.1038/s41467-024-52793-6

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