Sialyl Lewis X-Carboxymethylpullulan Conjugate: A Novel Homing Device to Spleen and Lymph Nodes

Abstract

We have previously found that carboxymethylpullulan (CMPul) conjugated with sialyl Lewis X (Neu5Aca a2-3Galb b1-4(Fuca a1-3)GlcNAc-, 2-3SLe x ) preferentially accumulates in the lymph nodes and spleen. In the present study, we investigated the structural requirements of the 2-3SLex moiety for this accumulation using rats. Radiolabeled CMPul conjugates with various degrees of substitution (d.s.) of the 2-3SLex moiety were intravenously administered to rats, and their tissue distributions were monitored by radioactivity. When the d.s. was more than 0.5, preferential accumulation in the lymph nodes as well as the spleen was observed. However, when the d.s. was 0.025, little effect of the 2-3SLex moiety was noted. Changes in the carbohydrate structure of 2-3SLe x , i.e., a change to a a2-6-linked sialic acid (Neu5Aca a2-6Galb b1-4(Fuca a1-3)GlcNAc-, 2-6SLe x ) or an elimination of the fucose (Neu5Aca a2-3Galb b1-4GlcNAc-, sialyl N-acethyllactosamine (SLN)), also made the 2-3SLex moiety ineffective. Furthermore, Microautoradiography analyses revealed that 2-3SLe x -CMPul was incorporated by particular subsets of macrophages in these tissues, and that CMPul and SLN-CMPul were also located in the same cells to a lesser extent. 2-3SLe x -CMPul may be able to serve as a novel drug delivery carrier to target drugs to the peripheral lymphoid tissues.

Cell surface glycan engineering of neural stem cells augments neurotropism and improves recovery in a murine model of multiple sclerosis

“…These findings are consistent with results of a study reporting that systemically administered NSCs tend to accumulate in the brains of mice with EAE, and also in the spleen and the liver (Politi et al 2007). E-selectin expression in the spleen has been described in humans, non-human primates and rodents (Redl et al 1991;Drake et al 1993;Schweitzer et al 1996;Alam et al 2000), and is upregulated by pro-inflammatory cytokines that are characteristically expressed in CNS inflammatory conditions (Weishaupt et al 2000;Emamgholipour et al 2013); indeed, conjugation of sLe x to polymers has been shown to markedly enhance the accumulation of such polymers within the spleen (Horie et al 2000(Horie et al , 2004, providing direct evidence that sLe x expression promotes splenic delivery. It has been reported that infiltration of the spleen by NSCs dampens production of inflammatory cytokines by resident spleen cells (e.g., macrophages) resulting in anti-inflammatory effects (Lee et al 2008).…”