Copolymers of lysine and polyethylene glycol: a new family of functionalized drug carriers

• Published in: Bioconjugate chemistry 1993-01, Vol.4 (1), p.54-62
• Main Authors: Nathan, Aruna, Zalipsky, Samuel, Ertel, Sylvie I, Agathos, Spiro N, Yarmush, Martin L, Kohn, Joachim
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cephradine - administration & dosage; Cephradine - metabolism; Drug Carriers - chemistry; Drug Carriers - pharmacokinetics; General pharmacology; Kidney - metabolism; Liver - metabolism; Lysine - chemistry; Lysine - pharmacokinetics; Magnetic Resonance Spectroscopy; Male; Medical sciences; Mice; Molecular Structure; Penicillin V - administration & dosage; Penicillin V - metabolism; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polyethylene Glycols - chemistry; Polyethylene Glycols - pharmacokinetics; Polymers - chemistry; Polymers - pharmacokinetics; Spleen - metabolism; Tissue Distribution
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/bc00019a008

Poly(PEG-Lys), a new, water-soluble poly(ether urethane), derived from L-lysine and poly(ethylene glycol) was investigated as a precursor for the preparation of polymeric drug conjugates. To facilitate a wide variety of coupling chemistries, the pendent carboxyl groups of poly(PEG-Lys) were converted to other reactive functional groups (amino, hydroxyl, active ester, and aldehyde) in high yield. These reactive pendent chains were then used as anchors for the covalent attachment of penicillin V and cephradine, two clinically used antimicrobial agents. Coupling to the carrier was achieved in good yields and the chemical versatility of this system was demonstrated by the preparation of conjugates having antibiotic ligands linked via biostable or biodegradable linkages to the carrier, either directly or via a spacer. Conjugate 4, poly(PEG-Lys-penicillin V ester), was obtained by linking penicillin V to the polymer backbone via hydrolytically labile ester bonds. This conjugate exhibited activity similar to that of the parent drug against three clinically important strains of bacteria. Drug activity coincided with the release of the drug from the carrier. Hydrolytically stable cephradine-containing conjugates were prepared by three different coupling methods but showed no antibiotic activity. 14C-labeled poly(PEG-Lys) was injected into mice and its biodistribution was monitored for 48 h. The carrier showed no preferential uptake by liver, spleen, or kidney. No signs of acute toxicity were evident in mice or rats when poly(PEG-Lys) was administered iv and ip at doses up to 10 g/kg. These results indicate that poly(PEG-Lys) is a promising precursor for the preparation of soluble drug conjugates.