Optimization of macromolecular prodrugs of the antitumor antibiotic adriamycin

C.J.T. Hoes, W. Potman, W.A.R. van Heeswijk, J. Mud, B.G. de Grooth, J. Greve, J. Feijen

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In our earlier work [10] on aminoribosyl-bound prodrugs of adriamycin (ADR) using poly(α-l-glutamic acid) (PGA) grafted in high yield (90–100 mol.%) with various peptide spacers as a plasma-soluble macromolecular carrier we observed rather low cytotoxic activities in L1210 leukemia and B16 melanoma in vitro assays. These results may be tentatively explained by a decreased susceptibility of the spacer-bound adriamycin moiety to hydrolysis by lysosomal enzymes due to the high spacer load. This hypothesis was tested by the study of two conjugates prepared by a different route. Peptide conjugates of adriamycin (Gly-Gly-Leu—ADR and Gly-Gly-Gly-Leu—ADR) were synthesized using the trityl N-protecting group and were coupled to PGA in 4.5 mol.% load according to the method described earlier [11]. However, these conjugates were almost totally devoid of cell growth-inhibiting activity in L1210 and B16 in vitro tests. The data suggest that either the uptake of the polymeric prodrugs into the cell by pinocytosis is highly dependent on spacer load or molecular weight, or that lysosomal digestion is too slow for efficient release of ADR. Possibly, enzymatic degradation of PGA which is known to occur only between pH 4 and 6 is rate-limiting for release of the drug. Current studies include the enzymatic degradation of PGA—peptide spacer—drug systems using p-nitroaniline as a model drug and papain as the enzyme. By variation of the length and load of spacer it can be estimated under which conditions the release of drug (using UV spectrometry) is faster than degradation of the polymer (as determined by viscometry). In addition, the uptake of PGA and derivatives with a fluorescent label into tumor cells is studied using laser flow cytometry and laser microscopy.
Original languageEnglish
Pages (from-to)205-213
JournalJournal of controlled release
Publication statusPublished - 1985
Event2nd International Symposium on Recent Advances in Drug Delivery Systems 1985 - Salt Lake City, United States
Duration: 27 Feb 19851 Mar 1985
Conference number: 2


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