Vitamin B12 In Drug Delivery: Breaking Through The Barriers To A B12 Bioconjugate Pharmaceutical

In press in Expert Opinion On Drug Delivery (DOI:10.1517/17425247.2011.539200). The theory section (the only part I can properly speak to) builds on the discussion section of the full theory paper in Molecular Biosystems from earlier this year, providing an outlet for some of the more speculative design possibilities for trinary B12 bioconjugate design. Given that (1) there are mechanisms for cleavage at both of the proposed positions and (2) the molecular dynamics work indicates that, at least, TCII (transcobalamin II) can easily accommodate a bi-functionalized cobalamin, the A-B12-C design possibility is probably the most interesting long-term idea to come out of the computational side of the B12-insulin bioconjugate study (or so I argue).

Having "B12" and "cobalamin" in a blog post guarantees a bunch of useless moderation-necessary comments from vita-spam sites.

Susan M. Clardy, Damian G. Allis, Timothy J. Fairchild & Robert P. Doyle

Syracuse University, Syracuse, Department of Chemistry, NY 13244-4100, USA

Importance of the field: Vitamin B12 (B12) is a rare and vital micronutrient for which mammals have developed a complex and highly efficient dietary uptake system. This uptake pathway consists of a series of proteins and receptors, and has been utilized to deliver several bioactive and/or imaging molecules from 99mTc to insulin.

Areas covered in this review: The current field of B12-based drug delivery is reviewed, including recent highlights surrounding the very pathway itself.

What the reader will gain: Despite over 30 years of work, no B12-based drug delivery conjugate has reached the market-place, hampered by issues such as limited uptake capacity, gastrointestinal degradation of the conjugate or high background uptake by healthy tissues. Variability in dose response among individuals, especially across ageing populations and slow oral uptake (several hours), has also slowed development and interest.

Take home message: This review is intended to stress again the great potential, as yet not fully realized, for B12-based therapeutics, tumor imaging and oral drug delivery. This review discusses recent reports that demonstrate that the issues noted above can be overcome and need not be seen as negating the great potential of B12 in the drug delivery field.

B12-Insulin Bioconjugate/Transcobalamin(II)/Insulin Receptor Cover Image For The April Issue Of Clinical Chemistry

A brief post about some free research press (and the new addition to the Cover Gallery). Having already been featured on the cover of the ChemMedChem March 2009 issue (see the New B12-Insulin-TCII-Insulin Receptor Cover Image For This Month's ChemMedChem (March 2009) post) , the side-on view of the B12-Insulin/TCII/Insulin Receptor structure was chosen for this month's cover of Clinical Chemistry. While the originating article itself is not included in the issue (I should have recommended citing the ChemMedChem article in the image caption), several diabetes-related articles are featured in this month's issue.

ON THE COVER: Scientists are investigating ways to develop effective oral insulin therapies. One such model is a vitamin B12-insulin conjugate bound to transcobalamin II and is shown here docked in the insulin receptor. The discovery of easier ways to deliver insulin into the blood stream would improve the lives of the millions of individuals living with diabetes. This month's issue of Clinical Chemistry contains 4 articles related to diabetes. The first 2 articles provide readers with a point/counterpoint discussion of the value of reporting estimated glucose along with Hb A1c. Next is an article on the association of apolipoprotein B with incident type 2 diabetes. Lastly, the development of the first radioimmunoassay for insulin led to a Nobel Prize and is chronicled in this month's Citation Classic feature. (See pages 545, 547, 666, and 671.) Image reproduced with permission from Damian G. Allis and Robert P. Doyle, Department of Chemistry, Syracuse University.

As a brief explanation of the image, this "scene" is meant to show (without proper molecular dynamics simulations to show how well it would work) that the Transcobalamin(II) transport/protection protein for cobalamin/cyanocobalamin (vitamin B12) and the B12-insulin bioconjugate discussed in the ChemMedChem article is small enough to fit within the Insulin Receptor protein such that insulin may still be able to bind to its receptor. This is the final piece of the puzzle in the proposed mechanism (and experimentally demonstrated event) by which the B12-insulin bioconjugate retains all of the benefits of free B12 (transport from the digestive system to the bloodstream) and insulin (proper receptor binding and the subsequent induction of cellular glucose uptake).

The figure caption and April 2010 Table of Contents can be found in PDF format at the Clinical Chemistry website (with a local copy of the PDF also available HERE.