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. 2018 Jan 16:2018:9076723.
doi: 10.1155/2018/9076723. eCollection 2018.

Accelerated Blood Clearance (ABC) Phenomenon Favors the Accumulation of Tartar Emetic in Pegylated Liposomes in BALB/c Mice Liver

Tamara C M Lopes  1 , Débora F Silva  1 , Walyson C Costa  1 , Frédéric Frézard  2 , José M Barichello  1   3 , Neila M Silva-Barcellos  4 , Wanderson G de Lima  5 , Simone A Rezende  1
Affiliations

Accelerated Blood Clearance (ABC) Phenomenon Favors the Accumulation of Tartar Emetic in Pegylated Liposomes in BALB/c Mice Liver

Tamara C M Lopes et al. Patholog Res Int. .

Abstract

Tartar emetic (TE) was the first drug used to treat leishmaniasis. However, its use was discontinued due to high toxicity. Association of TE with liposomes is a strategy to reduce its side effects. Pegylated liposomes (Lpeg) present lower rates of uptake by macrophages and prolonged circulation compared to their nonpegylated counterparts. However, repeated administration of Lpeg can cause an Accelerated Blood Clearance (ABC) phenomenon, whereby recognition of liposomes by antibodies results in faster phagocytosis. This work evaluated the effect of TE administration on histopathological aspects and the effect of the ABC phenomenon on targeting and toxicity in mice. Our results show that treatment with free or liposomal TE had no effect on the erythrocyte count, on liver and spleen weight, and on hepatic, splenic, and cardiac histology in mice. Severe lesions were observed on the kidneys of animals treated with a single dose of free TE. Treatment with TE in Lpeg after induction of ABC phenomenon caused a significant increase in Sb level in the liver without toxicity. Furthermore, mice treated with TE in liposomes showed normal renal histopathology. These results suggest site-specific targeting of Sb to the liver after induction of ABC phenomenon with no toxicity to other organs.

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Figures

Figure 1
Figure 1
Hemolytic activity of the different formulations and free tartar emetic over a suspension of human O+ red blood cells (RBC), after 1 h incubation. Differences were considered statistically significant where p < 0.05 with respect to blank Lconv.
Figure 2
Figure 2
Hematological parameters in noninfected BALB/c mice after treatment. (a) represents erythrocytes [RBC] and (b) represents hemoglobin [HGB]. Results are represented as mean ± SD (n = 8). ABC: Accelerated Blood Clearance phenomenon.
Figure 3
Figure 3
Biometric data of BALB/c mice. (a) represents the total body mass. (b) represents the liver mass, and (c) represents the spleen mass. Results are presented as mean ± SDs (n = 6). ABC: Accelerated Blood Clearance phenomenon.
Figure 4
Figure 4
(a) Concentration of Sb in the liver of BALB/c mice. (b) Concentration of Sb in the spleen of BALB/c mice. The results are represented as median, minimum value, and maximum value (n = 4). Differences were considered statistically significant where p < 0.05 with respect to (A) free TE; (B) Lconv + TE; (C) Lpeg + TE; (D) Lconv + TE with ABC phenomenon. ABC: Accelerated Blood Clearance phenomenon.
Figure 5
Figure 5
Photomicrographs of BALB/c mice kidney. (a) Normal histological micrograph with normal glomerulus (white arrowhead). (b1), (b2): Main lesions in BALB/c mice kidneys treated with free tartar emetic, corresponding to hyperemia (black arrow), glomerular sclerosis (white arrow), and tubular degeneration (black arrowhead). Images obtained with hematoxylin-eosin staining at a 440x magnification (bar = 50 μm).
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