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. 2008 Jun 5;357(1-2):272-9.
doi: 10.1016/j.ijpharm.2008.01.041. Epub 2008 Feb 2.

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

Tamer A Elbayoumi  1 , Vladimir P Torchilin
Affiliations

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

Tamer A Elbayoumi et al. Int J Pharm. .

Abstract

A mucocutaneous reaction in mice associated with Doxil treatment was identified as auricular erythema (AE). Given that the immuno-targeting of Doxil to tumors was found to influence also its systemic biodistribution pattern, the attempt was made to exploit a specific targeting of Doxil to reduce the manifestation of this adverse reaction. This problem is of general significance, since cutaneous reactions often lead to alterations of Doxil 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 (the clinically used anti-cancer formulation) coupled with the anti-cancer monoclonal 2C5 antibody (mAb 2C5) as well as AE caused by Doxil application. The modification of Doxil with mAb 2C5 resulted in a significant decrease in the normal skin accumulation of doxorubicin compared to original Doxil 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 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 therapy.

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Figures

Figure 1
Figure 1
Figure 1A. In vitro doxorubicin release from various Doxil® preparations in cell culture media containing 10% BSA Figure 1B. Biodistribution data of 111In-labeled Doxil®-mimicking liposomal preparations in skin (auricular) tissue of the ears, in healthy BALB/C mice (left panel); and 4T1-tumor-bearing mice (right panel). (◆) Doxil®-mimicking liposomes; and (Δ) mAb 2C5-modified Doxil®-mimicking liposomes. (n = 4, results indicated ± SD) Figure 1C. Hybrid representation of the different Doxil®-mimicking liposome accumulation and doxorubicin release profiles; 1-original Doxil®; 2- mAb 2C5- Doxil®, determined for 24 hrs and extrapolated up to 4 days.
Figure 1
Figure 1
Figure 1A. In vitro doxorubicin release from various Doxil® preparations in cell culture media containing 10% BSA Figure 1B. Biodistribution data of 111In-labeled Doxil®-mimicking liposomal preparations in skin (auricular) tissue of the ears, in healthy BALB/C mice (left panel); and 4T1-tumor-bearing mice (right panel). (◆) Doxil®-mimicking liposomes; and (Δ) mAb 2C5-modified Doxil®-mimicking liposomes. (n = 4, results indicated ± SD) Figure 1C. Hybrid representation of the different Doxil®-mimicking liposome accumulation and doxorubicin release profiles; 1-original Doxil®; 2- mAb 2C5- Doxil®, determined for 24 hrs and extrapolated up to 4 days.
Figure 1
Figure 1
Figure 1A. In vitro doxorubicin release from various Doxil® preparations in cell culture media containing 10% BSA Figure 1B. Biodistribution data of 111In-labeled Doxil®-mimicking liposomal preparations in skin (auricular) tissue of the ears, in healthy BALB/C mice (left panel); and 4T1-tumor-bearing mice (right panel). (◆) Doxil®-mimicking liposomes; and (Δ) mAb 2C5-modified Doxil®-mimicking liposomes. (n = 4, results indicated ± SD) Figure 1C. Hybrid representation of the different Doxil®-mimicking liposome accumulation and doxorubicin release profiles; 1-original Doxil®; 2- mAb 2C5- Doxil®, determined for 24 hrs and extrapolated up to 4 days.
Figure 2
Figure 2
Auricular Erythema manifestation in C57/BL mice implanted with LLC tumors (I); and BALB/C mice implanted with C26 tumors (II), as a result of drug administration, showing untreated mouse (A); compared to Doxil®-treated mice (B1–4), exhibiting the progression of AE manifestation during chemotherapy; and to mAb 2C5-Doxil®-treated mice (C, showing AE manifestation developed only after the last administered dose).
Figure 2
Figure 2
Auricular Erythema manifestation in C57/BL mice implanted with LLC tumors (I); and BALB/C mice implanted with C26 tumors (II), as a result of drug administration, showing untreated mouse (A); compared to Doxil®-treated mice (B1–4), exhibiting the progression of AE manifestation during chemotherapy; and to mAb 2C5-Doxil®-treated mice (C, showing AE manifestation developed only after the last administered dose).
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