Poly(amino acid) Copolymers as a Potential Soluble Drug Delivery System. 2. Body Distribution and Preliminary Biocompatibility Testing In Vitro and In Vivo

Poly(amino acid) copolymers of M _w 25,000-50,000 daltons con taining GluNa,Tyr (either 1:1 or 4:1) or GluNa,Ala,Tyr (either 1:1:1 or 6:3:1) were radioiodinated and their body distribution measured in rats following in travenous administration. In all cases the blood clearance was rapid (more than 80% over 15 min), but organ distribution was markedly dependent on the poly(amino acid) copolymer composition. Copolymers with high tyrosine con tent were recovered in the lungs (80% at 15 min), poly(GluNa,Tyr) (4:1) was located in liver and kidney and poly(GluNa,Ala,Tyr) (6:3:1) located almost ex clusively in the kidney. Kidney-associated radioactivity probably represented material destined for excretion in urine. These structure-dependent organ- specific distributions are important for the design of poly(amino acid) copoly mers as targetable drug-carriers. All the copolymers examined were much less toxic than poly-L-lysine to P388D ₁ and Hep G ₂ cells cultured in vitro. When ad ministered intravenously to T _o mice, poly(GluNa,Tyr) (1:1) showed immediate respiratory toxicity at a dose of 100 mg/kg and later onset respiratory toxicity when given at 10 mg/kg. Poly(GluNa,Tyr) (4:1) and poly(GluNa,Ala,Tyr) (6:3:1) at 100 mg/kg and poly(GluNa,Ala,Tyr) (1:1:1) at 10 mg/kg showed no overt signs of toxicity when administered intravenously, and did not alter blood levels of alanine transaminase, aspartate transaminase or alkaline phospha tase, therefore showing no signs of impaired liver function.