DESIGN OF SOLUBLE CONJUGATES OF BIODEGRADABLE POLYMERIC CARRIERS AND ADRIAMYCIN

To improve the therapeutic index of the cytostatic drug adriamycin (ADR), conjugates of ADR with poly(alpha-L-glutamic acid) (PGA), poly[N5-(2-hydroxyethyl)-L-glutamine] (PHEG) and conjugates of polymer-bound ADR and a human monoclonal antibody directed against colon tumour-associated antigens (IgM 16.88) have been prepared. Amide-bound conjugates of PGA and ADR were designed as macromolecular prodrugs for drug release mediated by the tumour cell-associated enzyme gamma-glutamyl transferase but were inactive in vitro. PGA-peptide spacer-ADR conjugates have been designed to effect drug release mediated by lysosomal enzymes after pinocytic entry of the conjugate in tumour cells. These conjugates were only weakly active in vitro against L1210 leukemia and B16 melanoma cells even with a lysosomally cleavable GlyGlyGlyLeu spacer. In contrast, the latter conjugate inhibited the growth of L1210 cells implanted intraperitoneally in mice to a significant extent. Polymeric ADR conjugates were studied with respect to their association behaviour in solution, their interaction with cells and their immunogenicity in mice. The biodistribution of conjugates of IgM 16.88 and PGA or PHEG in mice indicates that both polymers are useful as drug carrier in immunoconjugates. A multistep preparation of ADR bound to a conjugate of PHEG and IgM 16.88 has been developed with the aim of selective drug release in the acidic environment of the tumour. The immunoreactivity of IgM-PHEG-ADR with colon tumour antigen was retained to the extent of 70 % relative to IgM. PHEG-bound ADR shows an effective release of ADR at a pH of 6.0 as shown by incubation in buffer and by inhibition of the growth of HT-29 colon tumour cells in vitro. The data are consistent with the acid-labile nature of the drug-carrier bond.