SiRNA Lipid-Polymer Nanoparticles Targeting E-Selectin and Cyclophilin A in Bone Marrow for Combination Multiple Myeloma Therapy.

Abstract

Multiple myeloma (MM) is a hematological bloodcancerof the bone marrow that remains largely incurable, in partdue to itsphysical interactions with the bone marrow microenvironment. Such interactions enhance the homing, proliferation, and drug resistance of MM cells. Specifically, adhesion receptors and homing factors, E-selectin (ES) and cyclophilin A (CyPA), respectively, expressed by bone marrow endothelial cells enhance MM colonization and dissemination. Thus, silencing of ES and CyPA presents a potentialtherapeutic strategy to evade MM spreading. However,small molecule inhibition of ES and CyPA expressed by bone marrow endothelial cells remains challenging, and blocking antibodies induce further MM propagation. Therefore, ES and CyPA are promising candidates forinhibition via RNA interference (RNAi). Here, we utilized a previously developed lipid-polymer nanoparticle for RNAi therapy, that delivers siRNA to the bone marrow perivascular niche. We utilized our platform to co-deliver ES and CyPA siRNAs to prevent MM dissemination in vivo. Lipid-polymer nanoparticles effectively downregulated ESexpression in vitro, which decreased MM cell adhesion and migration through endothelial monolayers. Additionally, in vivo delivery oflipid-polymer nanoparticlesco-encapsulating ES and CyPA siRNA extended survival in a xenograft mouse modelof MM, either alone or in combination with the proteasome inhibitor bortezomib. Our combination siRNA lipid-polymer nanoparticle therapy presents a vascular microenvironment-targeting strategy as a potentialparadigm shift for MM therapies, which could be extended to other cancers that colonize the bone marrow. The online version contains supplementary material available at 10.1007/s12195-023-00774-y.