L-Type Amino Acid Transporter 1 Enables the Efficient Brain Delivery of Small-Sized Prodrug across the Blood–Brain Barrier and into Human and Mouse Brain Parenchymal Cells

Abstract

Membrane transporters have long been utilized to improve the oral, hepatic, and renal (re)absorption. In the brain, however, the transporter-mediated drug delivery has not yet been fully achieved due to the complexity of the blood−brain barrier (BBB). Because L-type amino acid transporter 1 (LAT1) is a good candidate to improve the brain delivery, we developed here four novel LAT1-utilizing prodrugs of four nonsteroidal anti-inflammatory drugs. As a result, all the prodrugs were able to cross the BBB and localize into the brain cells. The brain uptake of salicylic acid (SA) was improved five times, not only across the mouse BBB but also into the cultured mouse and human brain cells. The naproxen prodrug was also transported efficiently into the mouse brain achieving less peripheral exposure, but the brain release of naproxen from the prodrug was not improved. Contrarily, the high plasma protein binding of the flurbiprofen prodrug and the premature bioconversion of the ibuprofen prodrug in the mouse blood hindered the efficient brain delivery. Thus, the structure of the parent drug affects the successful brain delivery of the LAT1-utilizing prodrugs, and the small-sized LAT1-utilizing prodrug of SA constituted a successful model to specifically deliver its parent drug across the mouse BBB and into the cultured mouse and human brain cells.

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“…The peptides were eluted following a constant flow rate of 0.3 mL/min and a gradient of 2–7% B for 2 min, followed by 7–30% B for 48 min, 30–45% B for 3 min, and 45–80% B for 2.5 min before re-equilibrating the column again for 4.5 min. The proteins were quantified based on the ratio between the light and heavy standard peptides, as described previously ( Table 3 ) [ 37 ]. Data were acquired using Agilent MassHunter Workstation Acquisition (Agilent Technologies, Data Acquisition for Triple Quadrupole, version B.03.01) and processed by using Skyline software, MacCossLab, University of Washington, Seattle, WA, USA (version 20.1).…”

Targeting Systems to the Brain Obtained by Merging Prodrugs, Nanoparticles, and Nasal Administration

“…The prodrugs, different from the parent drugs, appeared efficiently transported by LAT1 in the cells. The amide conjugation of the drugs with phenylalanine was chosen to obtain peripheral stability in vivo of the conjugates, avoiding a premature bioconversion that was previously observed for the parent ester conjugates [ 64 ]. Following in vivo administration, three prodrugs showed concentration ratios (brain/plasma) higher than their parent drugs (FLB, SA, NAP), whereas the IBU prodrug evidenced the same values of the parent drug.…”

“…SA and NAP were released into the mouse brain by the prodrugs, in contrast to FLB and IBU, which were not released. The problems related to the FLB and IBU prodrugs were attributed to nonspecific protein binding in plasma, and unexpected peripheral instability, respectively [ 64 ].…”

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“…Different transporters are used for prodrug delivery the most common is LAT-1 (Large amino acid transporter 1) (Gynther et al, 2008) (Peura et al, 2011).To LAT-1 meta substituted phenylalanine prodrug (Valproic acid) had greater affinity as compared to the para-substituted derivative (Gynther et al, 2008). LAT-1 antagonist can minimize the binding of LAT-1 to prodrug (Peura et al, 2011) (Montaser et al, 2020). The main strategy of the prodrug is that they bind to FAAH (fatty acid amide hydrolase) and this enzyme clears the prodrug in the brain and the drug produces their pharmacological effect.…”