Anti‐tumor activity of daunorubicin linked to poly‐L‐aspartic acid

Abstract

Daunorubicin was bound to poly-L-aspartic acid via the methylketone side chain of the drug to avoid reaction of the sugar amino group believed to be essential for optimal drug activity. Attachment of the drug to the polyamino acid by an ester linkage was achieved by nucleophylic substitution reaction of 14-bromo-daunorubicin. Compared with free daunorubicin, the polymeric derivative was less cytotoxic to HeLa cells in vitro, but more effective against all tumor models tested (P388 leukemia, Gross leukemia, MS-2 sarcoma). The binding to the polypeptide markedly reduced drug toxicity but only slightly decreased drug potency. The daunorubicin-poly-L-aspartic acid conjugate demonstrated antitumor activity comparable to that of doxorubicin in leukemia models, but superior to that of doxorubicin in a solid tumor model (MS-2 sarcoma).

Poly-L-aspartic acid as a carrier for doxorubicin: A comparative in vivo study of free and polymer-bound drug

“…The vesicant action of (Zunino et al, 1982(Zunino et al, , 1984 and, as already observed for other antitumour drugs, optimal treatment was at the maximum tolerated doses, in antitumour activity experiments the dose levels were usually selected in the range of the highest non-toxic doses (.LD1O). The relative effectiveness of doxorubicin, in the survival time than did doxorubicin.…”

“…Reduction of local toxicity is also consistent with the observation that high doses of the conjugate were well tolerated after i.p. administration (Zunino, 1982). Again, this might have clinical relevance because of the therapeutic potential of doxorubicin in the intraperitoneal chemotherapy of abdominal neoplastic diseases (Myers & Collins, 1983).…”

“…Further studies aimed at other tumour models and different schedules would therefore be appropriate. Thus, although the covalent linkage of the drug to polymer also resulted in a reduction in drug potency, the therapeutic advantage, reflected by a greater margin of safety, was generally observed in a variety of experimental models (Zunino et al, 1982(Zunino et al, , 1984.…”

“…wt 20,000) was obtained from Sigma Chemical Co. (St Louis, Mo., USA). Doxorubicin-PAA conjugate (poly-L-aspartic acid doxorubicinyl ester; previously referred to as daunorubicin-PAA conjugate since a daunorubicin derivative was used in the conjugation procedure) was prepared essentially according to the previously described procedure (Zunino et al, 1982(Zunino et al, , 1984 (Bertazzoli et al, 1979). Myocardial lesions were graded according to: (severity degree) x (extension degree).…”

“…Recently, we have reported that daunorubicin covalently linked to poly-L-aspartic acid (PAA) reduce the toxicity of the anthracycline, whereas it maintained or improved the antitumour efficacy (Zunino et al, 1982(Zunino et al, , 1984. Doxorubicin may be released in vivo through hydrolysis of the ester linkage formed between the carboxyl group of the polymer and drug side chain.…”