Tumor-specific antibody-mediated targeted delivery of Doxil® reduces the manifestation of auricular erythema side effect in mice

A mucocutaneous reaction in mice associated with Doxil (R) treatment was identified as auricular erythema (AE). Given that the immuno-targeting of Doxil (R) to tumors was found to influence also its systemic biodistribution pattern, the attempt was made to exploit a specific targeting of Doxil (R) to reduce the manifestation of this adverse reaction. This problem is of general significance, since cutaneous reactions often lead to alterations of Doxil (R) dosing regimen in patients and might subsequently compromise the therapeutic outcome of cancer treatment. Tumor-bearing mice were used to study the biodistribution and skin-tissue accumulation effects of the tumor-targeted Doxil (R) (the clinically used anti-cancer formulation) coupled with the anti-cancer monoclonal 2C5 antibody (mAb 2C5) as well as AE caused by Doxil (R) application. The modification of Doxil (R) with mAb 2C5 resulted in a significant decrease in the normal skin accumulation of doxorubicin compared to original Doxil (R) and substantially reduced AE. The frequency of AE was decreased by three to fourfold with the mAb 2C5-modified doxorubicin-loaded long-circulating liposomes. Thus, targeting of Doxil (R) with the anti-cancer mAb 2C5 not only can increase the tumor-specific accumulation of the drug, but also diminishes the cutaneous side effect of the original Doxil (R) therapy. (c) 2008 Elsevier B.V. All rights reserved.