Characterization of novel kidney-specific delivery system using an alkylglucoside vector.
The alkylglucoside vector has been demonstrated to be a kidney-specific drug delivery system via cell surface-specific binding sites. In the present study, we examined the targeting efficiency of this vector derivatized with several types of ligand to determine the efficacy and limitations of this system. The tissue uptake clearance in the kidney (CL(uptake, kidney)) of alkylglucoside-acylated poly-L-lysine conjugates (Glc-S-C8-APL) with a mol. wt. of 4,500, 17,000, or 41,000 was greater than that accounted for by glomerular filtration and was reduced by coadministration of n-octyl-thioglucoside, which has an affinity for alkylglycoside binding sites. The mol. wt. distribution, assessed by gel filtration high-performance liquid chromatography, of the radioactivity associated with the kidney after intravenous administration of Glc-S-C8-APL41000 was shifted to a lower mol. wt. range compared with the authentic compound. The CL(uptake, kidney) and specific binding of Glc-S-C8-APL, fractionated based on mol. wt., to kidney membrane fractions was reduced as the mol. wt. of the fractionated Glc-S-C8-APL increased. These results suggest that the target efficiency of this vector depends on the size of the ligand that it delivers. Both the CL(uptake, kidney) and specific binding to kidney membranes of an alkylglucoside-tyrosine conjugate (Glc-S-C8-Tyr) with an acidic charge was much lower than that of Glc-S-C8-Tyr with cationic and neutral charges, suggesting that the anionic moiety could reduce the renal targeting efficiency. Thus, the targeting efficacy of the alkylglucoside vector seems to depend on, at least, the size and charge of the ligand that it delivers.
Shirota
K
K
Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
Kato
Y
Y
Suzuki
K
K
Sugiyama
Y
Y
D000818:Animals; D001345:Autoradiography; D001798:Blood Proteins / Q000378:metabolism; D002850:Chromatography, Gel; D016503:Drug Delivery Systems; D005079:Excipients; D005960:Glucosides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D008024:Ligands; D008297:Male; D008871:Microvilli / Q000378:metabolism; D008970:Molecular Weight; D011107:Polylysine; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014443:Tyrosine / Q000008:administration & dosage / Q000737:chemistry
D001798:Blood Proteins; D005079:Excipients; D005960:Glucosides; D007457:Iodine Radioisotopes; D008024:Ligands; D011107:Polylysine; D014443:Tyrosine