Transporter-utilizing prodrugs can enhance targeted brain delivery of drugs with intracellular targets

Public examination of a doctoral dissertation in the field of Pharmacy

Doctoral candidate: MSc Elena Puris

Date and venue: 23.8.2019 at 12 noon, Mediteknia MD100, Kuopio Campus

Drug delivery to brain can be improved with prodrugs utilizing transporter proteins expressed at the blood-brain barrier (BBB). In her doctoral thesis work, Elena Puris, Master of Science, evaluated the efficacy of transporter-mediated prodrug approach for targeted delivery of drugs into the brain parenchymal cells. The doctoral thesis also provides a stepwise methodology on the preclinical development of transporter-utilizing prodrugs for targeted brain delivery.

The central nervous system (CNS) diseases, such as neurodegenerative disorders and brain tumours are a growing problem globally. One of the reasons of limited number of drugs available for the treatment of CNS diseases is ineffective delivery of drugs across the BBB separating brain from blood. To overcome this issue, the development of prodrugs as substrates of the specific uptake transporters expressed at the BBB and brain parenchymal cell membrane such as L-type amino acid transporter 1 (LAT1) can be promising method.

In her doctoral thesis, Elena Puris evaluated the efficacy of targeted brain delivery of CNS agents in particular to intracellular compartment of the brain parenchyma using LAT1-mediated prodrug approach. The work presents systemic knowledge about preclinical pharmacokinetics of LAT1-utilizing prodrugs, their BBB transport and distribution within the brain.

The thesis demonstrated that promoiety structures of prodrugs designed to utilize LAT1 not only play an important role in binding to the transporter and its LAT1-mediated cellular uptake, but also affect systemic pharmacokinetics and brain delivery efficacy of parent drug in mice. Thus, the pharmacokinetic studies of ketoprofen prodrugs highlighted structural features such as meta- or para-conjugation of phenylalanine directly to parent drug, which provide targeted brain delivery and reduced systemic exposure to parent drug released from prodrug in mice. The findings  were confirmed by developed prodrugs of another CNS agent – ferulic acid.

Importantly, the investigation of intra-brain distribution of the LAT1-utilizing meta-substituted phenylalanine prodrug of ketoprofen revealed predominant distribution into the brain parenchymal cells, where the drug target and metabolizing enzymes are located. Moreover, the efficacy of delivery of ketoprofen to brain intracellular compartment via LAT1-utilizing prodrug was significantly higher than after ketoprofen dosing. In addition, in this thesis  it was shown that the distribution of the prodrug did not alter the physiological state of the transporter such as LAT1 protein expression and function at the brain cellular barrier.

Finally, the doctoral thesis provides stepwise methodology on the preclinical development of transporter-utilizing prodrugs exemplified by LAT1 to improve the brain delivery of drugs with targets located in the intracellular compartment of the brain parenchyma.

The doctoral dissertation of Elena Puris, Master of Science, entitled Pharmacokinetic concepts in drug delivery to the brain via transporter-mediated prodrug approach will be examined at the Faculty of Health Sciences. The Opponent in the public examination will be Professor Mikko Niemi of the University of Helsinki, and the Custos will be Docent Kristiina Huttunen of the University of Eastern Finland. The public examination will be held in English.