Copolymers of poly(ethylene glycol) and L-lysine: New functionalized drug carriers

Unique properties of polyethylene glycol (PEG) such as a wide range of solubilities, lack of toxicity, absence of antigenicity and immunogenicity, noninterference with enzymatic activities and conformations of polypeptides and ease of excretion from the body, all suggest that this polymer may be an ideal drug carrier. However, PEG has only two reactive end groups (the terminal hydroxyl groups) that can be used for attachment of drug molecules. This limits both the drug "loading" capacity and the design options for making more complex PEG-based drug carrier systems.; In order to overcome this limitation new water soluble poly(ether urethanes) were synthesized, in which PEG chains of variable length were linked to the {dollar}alpha{dollar} and {dollar}varepsilon{dollar}-amino groups of the natural amino acid L-lysine through stable urethane linkages. Using the new bissuccinimidyl carbonate derivative (BSC-PEG) as starting material, the polymerization reaction with either L-lysine or L-lysine alkyl esters proceeded under mild conditions in aqueous or interfacial reaction systems and yielded polymers of high molecular weight. The resulting strictly alternating copolymers retained the desirable properties of PEG, and at the same time provided multiple pendent groups at regular intervals along the polymer backbone.; The pendent carboxyl groups of lysine could be converted to a variety of other reactive functional groups such as amine, alcohol, active ester and aldehyde in high yield. This facilitated the attachment of two antimicrobial agents penicillin V and cephradine and the anticancer drug doxorubucin to poly(PEG-Lys). Coupling to the carrier was achieved in good yields and the chemical versatility of the system was demonstrated by the attachment of drugs via biostable or degradable linkages, either directly or through a spacer.; Biodistribution studies in mice using radiolabelled poly(PEG-Lys) showed no preferential uptake by liver, spleen or kidney. No signs of acute toxicity were evident in mice or rats at doses up to 10 g/kg. These results suggest that poly(PEG-Lys) could be very promising as a precursor for the preparation of soluble drug conjugates.