Polyinosinic acid decreases sequestration and improves systemic therapy of measles virus

Abstract

Off target binding or vector sequestration can significantly limit the efficiency of systemic virotherapy. We report here that systemically administered oncolytic measles virus (MV) was rapidly sequestered by the mononuclear phagocytic system (MPS) of the liver and spleen in measles receptor CD46-positive and CD46-negative mice. Since scavenger receptors on Kupffer cells are responsible for the elimination of blood-borne pathogens, we investigated here if MV uptake was mediated by scavenger receptors on Kupffer cells. Pretreatment of cells with poly(I), a scavenger receptor ligand, reduced MV expression by 99% in murine (J774A.1) macrophages and by 50% in human (THP-1) macrophages. Pre-dosing of mice with poly(I) reduced MPS sequestration of MV and increased circulating levels of MV by 4 to 15-folds at 2 minutes post virus administration. Circulating virus was still detectable 30 mins post infusion in mice predosed with poly(I) while no detectable MV was found at 5–10 min post infusion if mice did not receive poly(I). MPS blockade by poly(I) enhanced virus delivery to human ovarian SKOV3ip.1 and myeloma KAS6/1 xenografts in mice. Higher gene expression and improved control of tumor growth was noted early post therapy. Based on these results, incorporation of MPS blockade into MV treatment regimens is warranted.

Surface Functionality of Nanoparticles Determines Cellular Uptake Mechanisms in Mammalian Cells

“…Scavenger receptors bind to a variety of ligands including low density lipoproteins and polysaccharides [33] and have been shown to be involved in gold NP uptake. [34] Poly I, a well-known inhibitor of scavenger receptors, [35] inhibited NP1 and NP3 uptake in both HeLa and MCF10A cells (Figure 3b), confirming the involvement of scavenger receptors for NP uptake in different mammalian cells. Significant uptake inhibition was observed for NP2 in MCF10A cells in the presence of poly I, however, this effect was not pronounced in HeLa cells.…”

Oncolytic measles virus strains as novel anticancer agents

“…Systemic oncolytic MV delivery is required for treatment of metastatic or hematologic cancers. However, therapeutic viruses inoculated into the bloodstream may be scavenged by the mononuclear phagocytic system in the liver and spleen [107] or be neutralized by antibodies and serum complement [108, 109]. In order to reduce MV sequestration by the mononuclear phagocytic system, macrophage scavenger receptors can be saturated by ligands such as polyinosinic acid [107].…”

Structure–Activity Relationship of PEGylated Polylysine Peptides as Scavenger Receptor Inhibitors for Non-Viral Gene Delivery

“…Inhibition of SR-A1 with Poly-I led to an increase in adenovirus transduction of hepatocytes 15,16 . Similarly, inhibition of Kupffer cell SR-A1 with Poly-I effective blocked liver uptake resulting in increased oncolytic measles virus transduction in solid tumor 17 .…”