Brain uptake of ketoprofen–lysine prodrug in rats

Gynther, Mikko; Jalkanen, Aaro J.; Lehtonen, Marko; Forsberg, Markus; Laine, Krista; Ropponen, Jarmo; Leppänen, Jukka; Knuuti, Juhani; Rautio, Jarkko

doi:10.1016/j.ijpharm.2010.08.019

Cited by 67 publications

(68 citation statements)

References 30 publications

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“…Thus, LAT1 prodrug can also be used for the delivery of drugs such as phenylalanine derivative of dopamine [77], phenylalanine derivatives of valproic acid [78], L-tyrosine [76] and L-lysine analogues of ketoprofen [79] to the brain by overcoming BBB. In these studies, prodrugs showed a brain uptake potential, which was inhibited by a LAT1 inhibitor, suggesting that these amino acid prodrugs had entered the brain compartment through a mechanism of LAT1-mediated transport.…”

Section: Prodrug Development For Enhanced Deliverymentioning

confidence: 99%

Targeting L-type amino acid transporter 1 for anticancer therapy: clinical impact from diagnostics to therapeutics

Jin¹,

Jin²,

Hong³

2015

Expert Opinion on Therapeutic Targets

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Section: Prodrug Development For Enhanced Deliverymentioning

confidence: 99%

Targeting L-type amino acid transporter 1 for anticancer therapy: clinical impact from diagnostics to therapeutics

Jin¹,

Jin²,

Hong³

2015

Expert Opinion on Therapeutic Targets

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“…It can enable the loading of several bioactive molecules. 37 Here, we present a scalable fabrication of a photo-responsive nanocarrier platform by rapid ame-synthesis and one-step conjugation of ultra-ne TiO 2 agglomerates with lysine. 34 Reaction with an anti-inammatory drug such as ketoprofen to form a lysine-ketoprofen prodrug is particularly attractive.…”

Section: Introductionmentioning

confidence: 99%

Low-cost photo-responsive nanocarriers by one-step functionalization of flame-made titania agglomerates withl-Lysine

Gilroy

Stricker

et al. 2015

J. Mater. Chem. B

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A novel versatile photo-responsive nanocarrier that is able to load and release several functional molecules is obtained by one-step conjugation of scalable flame-made titania agglomerates. Highly crystalline anatase nano-crystals are synthesized by scalable flame spray pyrolysis of organometallic precursor solutions.Nanocarriers are self-assembled by adsorption of lysine molecules on the photocatalytic nanoparticles' surface leading to a minimal flocculation and highly reactive amine terminations. Time-controlled photo-release of the ligand and end-loaded molecules is achieved by short exposure to UV light. The application of these flexible nanoplatforms to intracellular delivery is demonstrated by dye loading and two-photon microscopic in vitro imaging of their penetration in living neurons of Wistar rat brain tissue.These scalable photo-responsive nanocarriers are a flexible platform with potential for in vivo controlled release of amine-reactive dyes and amino-acid modified pro-drugs, as demonstrated by the successful loading and release of fluorescein isothiocyanate dye (FITC) and ketoprofen.

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“…LAT-1 is also an important drug target because it transports several prescription drugs, such as the antiparkinsonian drug L-dopa and the anticonvulsant gabapentin, across the BBB, thereby enabling their pharmacologic effects (3,4). This function at the BBB has made LAT-1 a target for drug delivery by modifying CNS-impermeable drugs such that they become LAT-1 substrates and have enhanced BBB penetration (5,6).…”

mentioning

confidence: 99%

Structure-based ligand discovery for the Large-neutral Amino Acid Transporter 1, LAT-1

Geier¹,

Schlessinger

Fan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

162

219

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The Large-neutral Amino Acid Transporter 1 (LAT-1)-a sodiumindependent exchanger of amino acids, thyroid hormones, and prescription drugs-is highly expressed in the blood-brain barrier and various types of cancer. LAT-1 plays an important role in cancer development as well as in mediating drug and nutrient delivery across the blood-brain barrier, making it a key drug target. Here, we identify four LAT-1 ligands, including one chemically novel substrate, by comparative modeling, virtual screening, and experimental validation. These results may rationalize the enhanced brain permeability of two drugs, including the anticancer agent acivicin. Finally, two of our hits inhibited proliferation of a cancer cell line by distinct mechanisms, providing useful chemical tools to characterize the role of LAT-1 in cancer metabolism.arge-neutral Amino Acid Transporter 1 (LAT-1) is a sodiumindependent exchanger found in the brain, testis, and placenta, where it mediates transport of large-neutral amino acids (e.g., tyrosine) and thyroid hormones (e.g., triiodothyronine) across the cell membrane (1). More specifically, LAT-1 is highly expressed in the blood-and brain-facing membranes of the blood-brain barrier (BBB) to supply the central nervous system (CNS) with essential nutrients and to help maintain the neural microenvironment (2). LAT-1 is also an important drug target because it transports several prescription drugs, such as the antiparkinsonian drug L-dopa and the anticonvulsant gabapentin, across the BBB, thereby enabling their pharmacologic effects (3,4). This function at the BBB has made LAT-1 a target for drug delivery by modifying CNS-impermeable drugs such that they become LAT-1 substrates and have enhanced BBB penetration (5, 6).In addition, LAT-1 expression levels are increased in many types of cancer, including non-small-cell lung cancer and glioblastoma multiforme (GBM) (7,8). LAT-1 expression increases as cancers progress, leading to higher expression levels in highgrade tumors and metastases (9). In particular, LAT-1 plays a key role in cancer-associated reprogrammed metabolic networks by supplying growing tumor cells with essential amino acids that are used as nutrients to build biomass and signaling molecules to enhance proliferation by activating progrowth pathways such as the mammalian target of rapamycin (mTOR) pathway (10). Furthermore, inhibiting LAT-1 function reduces tumor cell proliferation, indicating that it may be a viable target for novel anticancer therapies (11-13). A cancer drug targeting LAT-1 can therefore be a LAT-1 inhibitor that deprives the cancer cells of nutrients or a cytotoxic LAT-1 substrate with an intracellular target (e.g., a metabolic enzyme).LAT-1 is a large protein with 12 putative membrane-spanning helices (14). To transport solutes across the membrane, LAT-1 binds SLC3A2, a glycoprotein with a single membrane-spanning helix that serves as a chaperone for LAT-1 (14). The atomic structure of human LAT-1 is not known, but LAT-1 exhibits significant sequence similarity to prokar...

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Brain uptake of ketoprofen–lysine prodrug in rats

Cited by 67 publications

References 30 publications

Targeting L-type amino acid transporter 1 for anticancer therapy: clinical impact from diagnostics to therapeutics

Targeting L-type amino acid transporter 1 for anticancer therapy: clinical impact from diagnostics to therapeutics

Low-cost photo-responsive nanocarriers by one-step functionalization of flame-made titania agglomerates withl-Lysine

Structure-based ligand discovery for the Large-neutral Amino Acid Transporter 1, LAT-1

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