Cancer cell-targeted drug delivery utilizing oligopeptide transport activity.
To study the drug delivery to tumor by utilization of an oligopeptide transport activity, we examined the accumulation of dipeptides and the peptide-mimetic anti-cancer drug, bestatin, a substrate of oligopeptide transporter PepT1. Firstly, we established HeLa cells stably expressing human peptide transporter (hPepT1) (HeLa-hPepT1). Secondly, we constructed an experimental model by inoculation of HeLa-hPepT1 cells subcutaneously into Balb/c nu/nu mice to demonstrate the contribution of PepT1 to the tissue-selective drug delivery. The accumulations of a hydrolysis-resistant dipeptide [(3)H]carnosine and bestatin in solid tumors formed by HeLa-hPepT1 or HeLa-pcDNA3, which are transfected with vector DNA (pcDNA3) were measured. After I.V. administration, tissue-to-plasma concentration ratios (K(p)) of both compounds, in HeLa-hPepT1 tumor was significantly greater than that of [(14)C]inulin, a marker for extracellular fluid space, those of dipeptides in muscle, or those in HeLa-pcDNA3 tumor. Furthermore, bestatin exhibited growth inhibition of HeLa-hPepT1 in vitro. In vivo, repeated oral administration of bestatin for 28 days suppressed the growth of HeLa-hPepT1 tumor specifically. When HT-1080 cells, which may naturally express oligopeptide transport activity, were transplanted, K(p) of [(3)H]carnosine was significantly increased in comparison with that in muscle. In addition, oligopeptide transport activities among various human cell lines were examined. These results provide the first demonstration for the selective delivery of oligopeptides to tumors by specific oligopeptide transport activity.
Nakanishi
T
T
Department of Pharmacobio-dynamics, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan.
Tamai
I
I
Takaki
A
A
Tsuji
A
A
D000818:Animals; D001692:Biological Transport; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D002336:Carnosine / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000378:metabolism*; D004151:Dipeptides / Q000493:pharmacokinetics; D004337:Drug Carriers; D006367:HeLa Cells; D006801:Humans; D007328:Insulin / Q000493:pharmacokinetics; D020014:K562 Cells; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000378:metabolism*; D000074011:Peptide Transporter 1; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027981:Symporters; D014018:Tissue Distribution; D014162:Transfection / Q000379:methods; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D004151:Dipeptides; D004337:Drug Carriers; D007328:Insulin; D009842:Oligopeptides; D000074011:Peptide Transporter 1; C082186:SLC15A1 protein, human; C489941:Slc15a1 protein, mouse; D027981:Symporters; C004194:glycylsarcosine; D002336:Carnosine