Modulating blood-brain barrier interactions of amino acid-based anticancer agents.
The large neutral amino acid (LNAA) transporter at the blood-brain barrier (BBB) mediates brain uptake of amino acid-based anticancer agents (e.g., melphalan and acivicin). In this study, we blocked the amino acid terminus of the anticancer agents using a bioreductive drug delivery system (TDDS). This molecular modification of the anticancer agents is expected to prevent LNAA carrier-mediated transport across the BBB. In this study, we demonstrate that the parent amino acid containing anticancer agents are substrates for the LNAA transporter at the BBB, whereas the TDDS is not recognized by the LNAA transporter. An in situ rat brain perfusion technique was used to determine competition for LNAA carrier-mediated transport at the BBB using [14C]L-leucine. The BBB capillary permeability-surface area (PA) product for the radiotracer [14C]L-leucine (control) was determined to be 5.18 +/- 0.32 x 10(-2) ml/s/g (100%). The control PA value for [14C]L-leucine was competitively inhibited (down to 7-18% of control) by excess L-phenylalanine as well as by excess concentration of the anticancer amino acids, melphalan and acivicin, showing competition for the LNAA transporter at the BBB. In contrast, brain perfusion of [14C]L-leucine in presence of excess TDDS resulted in no competition for brain uptake of [14C]L-leucine via the LNAA transporter. Thus, bioreversible derivatization of the parent anticancer amino acids resulted in blocking the amino acid functional group, thereby leading to loss of recognition for the cerebrovascular LNAA transporter at the BBB.
Killian
D M
DM
Department of Pharmaceutical Sciences, University of Maryland-School of Pharmacy, Baltimore 21201, USA.
Gharat
L
L
Chikhale
P J
PJ
D000465:Algorithms; D026905:Amino Acid Transport Systems; D000596:Amino Acids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D001667:Binding, Competitive; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002199:Capillary Permeability; D002352:Carrier Proteins / Q000378:metabolism*; D016503:Drug Delivery Systems; D007930:Leucine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D010296:Parietal Lobe / Q000378:metabolism; D010477:Perfusion; D010539:Permeability; D051381:Rats
D026905:Amino Acid Transport Systems; D000596:Amino Acids; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D007930:Leucine