POLY(ETHYLENE GLYCOL)-DOXORUBICIN CONJUGATES CONTAINING BETA-LACTAMASE-SENSITIVE LINKERS

7-Aminocephalosporin doxorubicin (AC-Dox) was condensed with monometho xypoly(ethylene glycol)propionic acid N-hydroxysuccinimide ester (5 kD a) or with a branched form of poly(ethylene glycol)-propionic acid N-h ydroxysuccinimide ester (10 kDa), forming M-PEG-AC-Dox and B-PEG-AC-Do x, respectively. These polymer drug derivatives were designed such tha t doxorubicin would be released upon Enterobacter cloacae beta-lactama se (bL)-catalyzed hydrolysis. Both M-PEG-AC-Dox (IC50 = 80 mu M) and B -PEG-AC-Dox (IC50 = 8 mu M) were less toxic to H2981 human lung adenoc arcinoma cells than doxorubicin (IC50 = 0.1-0.2 mu M) and could be act ivated in an immunologically specific manner by L6-bL, a monoclonal an tibody-bL conjugate that bound to H2981 cell surface antigens. In addi tion, the polymers were relatively stable in mouse plasma (<26% hydrol ysis after 24 h at 37 degrees C) and were less toxic to mice (maximum tolerated dose > 52 mu mol/kg) than doxorubicin (maximum tolerated dos e = 13.8 mu mol/kg). Pharmacokinetic studies were performed in mice be aring subcutaneous 3677 melanoma tumors. B-PEG-AC-Dox cleared from the blood more slowly than M-PEG-AC-Dox and was retained to a 2.1-fold gr eater extent in human 3677 melanoma tumor xenografts over a 4 h period . The intratumoral concentrations of both polymers far exceeded that o f doxorubicin. Thus, the PEG-AC-Dox polymers offer the possibility of generating large intratumoral doxorubicin concentrations owing to thei r reduced toxicities, the amounts that accumulate in tumors, and the f act that doxorubicin is released upon beta-lactam ring hydrolysis.