Biotin conjugates in targeted drug delivery: is it mediated by a biotin transporter, a yet to be identified receptor, or (an)other unknown mechanism(s)?

Abstract

Conjugation of drugs with biotin is a widely studied strategy for targeted drug delivery. The structure–activity relationship (SAR) studies through H³-biotin competition experiments conclude with the presence of a free carboxylic acid being essential for its uptake via the sodium-dependent multivitamin transporter (SMVT, the major biotin transporter). However, biotin conjugation with a payload requires modification of the carboxylic acid to an amide or ester group. Then, there is the question as to how/whether the uptake of biotin conjugates goes through the SMVT. If not, then what is the mechanism? Herein, we present known uptake mechanisms of biotin and its applications reported in the literature. We also critically analyse possible uptake mechanism(s) of biotin conjugates to address the disconnect between the results from SMVT-based SAR and “biotin-facilitated” targeted drug delivery. We believe understanding the uptake mechanism of biotin conjugates is critical for their future applications and further development.

Graphical abstract

Keywords:

• Biotin
• targeted drug delivery
• SMVT
• biotin receptor
• SAR

Acknowledgements

We gratefully acknowledge the National Institutes of Health (R01DK119202 and R01DK128823) for partial financial support of our drug delivery work in general. We would also like to thank the Molecular Basis of Disease program for a graduate fellowship to R. Tripathi, internal resources at Georgia State University, the Georgia Research Alliance for an Eminent Scholar endowment, and the Dr. Frank Hannah endowment fund for providing financial support to our drug delivery and drug discovery programs in general. The graphical abstract and Figure 2 were created using BioRender.com.

Author contributions

The manuscript was prepared with contributions from all authors. RT and AG led the manuscript preparation work and contributed equally; RG assisted in the process. BW conceived the idea of the manuscript, guided the preparation process, revised the manuscript, and gave final approval of the manuscript. All authors have given approval to the submitted draft of the manuscript.

Disclosure statement

Binghe Wang is an associated editor of the Journal of Enzyme Inhibition and Medicinal Chemistry. There is no other potential conflict of interest to be declared by the authors.

Additional information

Funding

We gratefully acknowledge the National Institutes of Health (R01DK119202 and R01DK128823) for partial financial support of our drug delivery work in general.