No abstract

Sialoadhesin (Sn, Siglec-1, CD169) is a member of the sialic acid binding Ig-like lectin (siglec) family expressed on macrophages. Its macrophage specific expression makes it an attractive target for delivering antigens to tissue macrophages via Sn-mediated endocytosis. Here we describe a novel approach for delivering antigens to macrophages using liposomal nanoparticles displaying high affinity glycan ligands of Sn. The Sn-targeted liposomes selectively bind to and are internalized by Sn-expressing cells, and accumulate intracellularly over time. Our results show that ligand decorated liposomes are specific for Sn, since they are taken up by bone marrow derived macrophages that are derived from wild type but not Sn−/− mice. Importantly, the Sn-targeted liposomes dramatically enhance the delivery of antigens to macrophages for presentation to and proliferation of antigen-specific T cells. Together, these data provide insights into the potential of cell-specific targeting and delivery of antigens to intracellular organelles of macrophages using Sn-ligand decorated liposomal nanoparticles.

Body image: Self‐activating Huisgen 1,3‐dipolar cycloaddition and 6π azaelectrocyclization of lysine‐based dendrimers (see picture) enable the in vivo dynamics and organ‐specific accumulation of N‐glycans to be visualized. The sugar structure and glycosyl bond linkages of N‐glycans control the whole‐body trafficking of the clusters in nude mice and a cancer model.

CD22 is a member of the siglec (Sialic acid-binding immunoglobulin-like lectin) family expressed on B cells that recognizes glycans of glycoproteins as ligands. Because siglecs exhibit restricted expression on one or a few leukocyte cell types, they have gained attention as attractive targets for cell-directed therapies. Several antibody-based therapies targeting CD22 (Siglec-2) are currently in clinical trials for treatment of hairy cell leukemia and other B cell lymphomas. As an alternative to antibodies we have developed liposomal nanoparticles decorated with glycan ligands of CD22 that selectively target B cells. Because CD22 is an endocytic receptor, ligand-decorated liposomes are bound by CD22 and rapidly internalized by the cell. When loaded with a toxic cargo, such as doxorubicin, they are efficacious in prolonging life in a Daudi B cell lymphoma model. These B cell targeted nanoparticles have been demonstrated to bind and kill malignant B cells from patients with hairy cell leukemia, marginal zone lymphoma, and chronic lymphocytic leukemia. The results demonstrate the potential of using CD22-ligand-targeted liposomal nanoparticles as an alternative approach for treatment of B cell malignancies.

Ganzkörperaufnahme: Eine selbstaktivierende 1,3‐dipolare Huisgen‐Cycloaddition und eine 6π‐Azaelektrocyclisierung von Lysin‐haltigen Dendrimeren (siehe Bild) ermöglichen die Visualisierung der In‐vivo‐Dynamik und organspezifischen Anreicherung von N‐Glycanen. Über Strukturvarianten der N‐Glycane lässt sich der Ganzkörpertransport des Clusters in Nacktmaus‐ und Krebsmodellen steuern.