Acid-sensitive dissociation between poly(lysine) and histamine-modified poly(glutamate) as a model for drug-releasing from carriers in endosomes.
Histamine was coupled to poly(L-glutamate) (PLG) to give a copolymer, poly(glutamylhistamineglutamate) (PHG), with approx. 40% of carboxyl groups in PLG being modified. Unlike either poly(L-histidine) (PLH) or PLG, PHG precipitated only in buffers with pH between 4 and 5. A complex was formed between PHG and poly(L-lysine) (PLL) at pH 7, but it was rapidly dissociated at pH 5 or lower. When PHG-linked transferrin (Tf-PHG) was used to deliver a PLL-conjugated [3H]methotrexate ([3H]MTX-PLL) in K562 leukemia cell cultures, an intracellular accumulation of the radioactivity was observed. These results suggest that a copolymer with both imidazole and carboxyl groups can be useful in the design of acid-sensitive, carrier-mediated drug delivery systems.
Drug Targeting Research, School of Pharmacy, University of Southern California, Los Angeles 90033.
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D002478:Cells, Cultured; D004337:Drug Carriers; D006632:Histamine / Q000008:administration & dosage*; D006863:Hydrogen-Ion Concentration; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics; D010455:Peptides / Q000008:administration & dosage*; D011099:Polyglutamic Acid / Q000008:administration & dosage*; D011107:Polylysine / Q000008:administration & dosage*; D014168:Transferrin / Q000008:administration & dosage
D004337:Drug Carriers; D010455:Peptides; D014168:Transferrin; D011107:Polylysine; D011099:Polyglutamic Acid; D006632:Histamine; D008727:Methotrexate