Improving drug delivery to the brain: the prodrug approach

ABSTRACT

Introduction

The prodrug approach has been thought to be a simple solution to improve brain drug delivery for decades. Nevertheless, it still comes as a surprise that there is relatively little success in the field. The best example anti-parkinsonian drug levodopa has been serendipitously discovered to be a transporter-utilizing brain-delivered prodrug rather than a rationally developed one.

Areas Covered

The lack of success can mainly be explained by the insufficient understanding of the role of membrane proteins that can facilitate drug delivery at dynamic barriers, such as the blood-brain barrier (BBB), but also by the sparse knowledge of prodrug bioconverting enzymes in the brain. This review summarizes the current status of the prodrug attempts that have been developed in the past to improve brain drug delivery.

Expert Opinion

With the expandingly improved analytical and computational technologies, it is anticipated that enhanced brain drug delivery will be eventually achieved for most of the central nervous system (CNS) acting drugs. However, this requires that carrier-mediated (pro)drug delivery methods are implemented in the very early phases of the drug development processes and not as a last step to survive a problematic investigational drug candidate.

KEYWORDS:

• Bioconversion
• drug delivery
• membrane protein
• prodrug
• receptor
• transporter

Article highlights

• The central Nervous System (CNS) is protected by dynamic barriers, such as the blood-brain barrier (BBB), and the dynamicity arises from the wide variety of integral membrane proteins expressed in these barriers

• These membrane proteins, namely transporters and receptors, that carry essential nutrients for the brain cells directly or via endocytosis/transcytosis, respectively, can also be utilized to improve brain drug delivery across the dynamic barriers

• With the prodrug approach, drugs can be temporarily changed to mimic the substrate of the selected transporter or receptor without affecting the structure-activity relationships of the compounds toward their original pharmacological target

• However, a successful brain-targeted prodrug requires a detailed understanding of the interactions of the prodrug not only with the primary transporter and bioconverting enzyme but also with other possible transport and biorelease mechanisms, the expression and life cycle profiles of these proteins and their species differences

Acknowledgments

Dr. Ahmed B. Montaser and Dr. Johanna Huttunen are greatly acknowledged for the extensive literature research of their Ph.D. theses that were used as the basis of this review. Dr. Santosh K. Adla is acknowledged for the assistance with the figures. In memoriam, the greatest supporter Toni P. Korhonen, thank you for teaching how important it is to have an opinion and being able to justify it.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.