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In vitro and in vivo study of an albumin-binding prodrug of doxorubicin that is cleaved by cathepsin B

Item Type:Article
Title:In vitro and in vivo study of an albumin-binding prodrug of doxorubicin that is cleaved by cathepsin B
Creators Name:Abu Ajaj, K. and Graeser, R. and Fichtner, I. and Kratz, F.
Abstract:PURPOSE: This study was designed to evaluate the in vitro and in vivo antitumor activity of an albumin-binding prodrug of doxorubicin 1 which incorporates a maleimide moiety and a para-aminobenzyloxycarbonyl (PABC) spacer coupled to the dipeptide Phe-Lys that is cleaved by cathepsin B. METHODS: Cleavage of the albumin conjugate was studied with cathepsin B and in homogenates of MDA-MB 435 tumors. For in vivo studies, nude mice were injected with (a) glucose buffer, (b) doxorubicin (2 x 8 mg/kg, i.v, on days 10 and 17), or (c) compound 1 (3 x 24 mg/kg doxorubicin equivalent, on days 10, 17 and 24). RESULTS: Prodrug 1 once bound to albumin was effectively cleaved by cathepsin B and in tumor homogenates releasing doxorubicin. A cytotoxicity assay of the albumin conjugate of 1 in two human tumor cell lines showed that doxorubicin was ~6 times more active than the conjugate. In contrast, in an in vivo study, the prodrug exhibited superior antitumor activity (T/C 15%) compared to doxorubicin (T/C 49%) in an equitoxic comparison. CONCLUSIONS: The cathepsin B cleavable spacer Phe-Lys-PABC incorporated in an albumin-binding prodrug is an effective way to increase the therapeutic index of doxorubicin.
Keywords:Albumin-Binding Prodrug, Albumin, Cathepsin B, 1,6-Self-Immolative Spacer, Doxorubicin, Animals, Mice
Source:Cancer Chemotherapy and Pharmacology
ISSN:0344-5704
Publisher:Springer (Germany)
Volume:64
Number:2
Page Range:413-418
Date:July 2009
Official Publication:https://doi.org/10.1007/s00280-009-0942-8
PubMed:View item in PubMed

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