Poly(ethylene glycol)-Doxorubicin Conjugates Containing .beta.-Lactamase-Sensitive Linkers

Abstract

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.

Targeted Sialic Acid–Doxorubicin Prodrugs for Intracellular Delivery and Cancer Treatment

“…Recently, several PEG-peptide-DOX conjugates have been designed with 1:1:1 stoichiometry of PEG chain, amino acid spacer, and the drug. Such conjugates offer an opportunity to prepare an anticancer prodrug with a low polydispersity compared to pendent polymer conjugates (30). Continuing the efforts in this direction, we developed and reported in the present work a novel approach that has the flexibility of conjugating DOX and SA simultaneously to a bis PEG-CA conjugate.…”

“…C8) in DOX is expected to be more reactive than the other hydroxyl groups while conjugating with carboxyl groups of bis PEG-CA conjugate using EDC.HCl as a condensing agent. However, most of the prodrug conjugates show modifications at 3 ¶ amino of the hexopyranosyl ring in DOX by aminolysis (28)(29)(30). Other than aminolysis reactions, acetyl group at C8 in DOX.HCl was conjugated with cis-4,7,10,13,16,19-docosahexenoic acid to form a hydrazone bond (31).…”

Doxorubicin–polyphosphazene conjugate hydrogels for locally controlled delivery of cancer therapeutics

“…In order to overcome those problems above, antitumor agents have been conjugated to polymeric carriers such as dextran [14], polymeric amino acids [15], poly(ethylene glycol) (PEG) [16], synthetic polymer [17][18][19][20][21], and intrinsic albumin [22]. Some of these conjugates have progressed to phase I/II clinical and pharmacokinetic studies.…”

Polymeric pharmaceutical forms - the forms of the future

“…The use of such systems have led to the formation of new or the improvement of already existing therapies. A strategy to suppress the toxicity of drug substances involves their binding with polymers (4)(5)(6)(7)(8)(9)(10)(11). The idea of covalent binding of a low molecular weight drug to a hydrophilic polymer carrier in order to increase its therapeutic effect was suggested by Helmut Ringsdorf (4) in 1975 for the first time.…”