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.