Poly(ethylene glycol)-doxorubicin conjugates containing beta-lactamase-sensitive linkers.
7-Aminocephalosporin doxorubicin (AC-Dox) was condensed with monomethoxypoly(ethylene glycol)-propionic acid N-hydroxysuccinimide ester (5 kDa) or with a branched form of poly(ethylene glycol)-propionic acid N-hydroxysuccinimide ester (10 kDa), forming M-PEG-AC-Dox and B-PEG-AC-Dox, respectively. These polymer drug derivatives were designed such that doxorubicin would be released upon Enterobacter cloacae beta-lactamase (bL)-catalyzed hydrolysis. Both M-PEG-AC-Dox (IC50 = 80 microM) and B-PEG-AC-Dox (IC50 = 8 microM) were less toxic to H2981 human lung adenocarcinoma cells than doxorubicin (IC50 = 0.1-0.2 microM) and could be activated in an immunologically specific manner by L6-bL, a monoclonal antibody-bL conjugate that bound to H2981 cell surface antigens. In addition, the polymers were relatively stable in mouse plasma (< 26% hydrolysis after 24 h at 37 degrees C) and were less toxic to mice (maximum tolerated dose > 52 mumol/kg) than doxorubicin (maximum tolerated dose = 13.8 mumol/kg). Pharmacokientic studies were performed in mice bearing 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 greater extent in human 3677 melanoma tumor xenografts over a 4 h period. The intratumoral concentrations of both polymers far exceeded that of doxorubicin. Thus, the PEG-AC-Dox polymers offer the possibility of generating large intratumoral doxorubicin concentrations owing to their reduced toxicities, the amounts that accumulate in tumors, and the fact that doxorubicin is released upon beta-lactam ring hydrolysis.
Senter
P D
PD
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA.
Svensson
H P
HP
Schreiber
G J
GJ
Rodriguez
J L
JL
Vrudhula
V M
VM
D000230:Adenocarcinoma; D000818:Animals; D000911:Antibodies, Monoclonal; D002470:Cell Survival / Q000187:drug effects; D002511:Cephalosporins / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000633:toxicity*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000633:toxicity; D016972:Enterobacter cloacae / Q000201:enzymology; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity*; D008175:Lung Neoplasms; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000633:toxicity*; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D001618:beta-Lactamases / Q000378:metabolism*
C096729:7-aminocephalosporin doxorubicin-monomethoxypoly(ethylene glycol)propionic acid N-hydroxysuccinimide ester; C096730:7-aminocephalosporin doxorubicin-poly(ethylene glycol)propionic acid N-hydroxysuccinimide ester; D000911:Antibodies, Monoclonal; D002511:Cephalosporins; D000922:Immunotoxins; D011092:Polyethylene Glycols; D004317:Doxorubicin; D001618:beta-Lactamases