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

• Published in: Cellular and molecular bioengineering 2023-08, Vol.16 (4), p.383-392
• Main Authors: Figueroa-Espada, Christian G., Guimarães, Pedro P. G., Riley, Rachel S., Xue, Lulu, Wang, Karin, Mitchell, Michael J.
• Format: Article
• Language: English
• Subjects: Adhesion; Antibodies; Biological and Medical Physics; Biomaterials; Biomedical Engineering and Bioengineering; Biomedical Engineering/Biotechnology; Biophysics; Blocking antibodies; Blood cancer; Bone cancer; Bone marrow; Bortezomib; Cancer; Cell adhesion; Cell Biology; Cell proliferation; Down-regulation; Drug resistance; E-selectin; Endothelial cells; Engineering; Gene expression; Homing; Homing behavior; Lipids; Microenvironments; Multiple myeloma; Nanoparticles; Polymers; Proteasome inhibitors; Proteasomes; RNA-mediated interference; SI: 2023 CMBE Young Innovators; siRNA; Therapy; Xenotransplantation
• ISSN: 1865-5025; 1865-5033
• DOI: 10.1007/s12195-023-00774-y

Introduction Multiple myeloma (MM) is a hematological blood cancer of the bone marrow that remains largely incurable, in part due to its physical 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 potential therapeutic 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 for inhibition via RNA interference (RNAi). Methods 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. Results Lipid-polymer nanoparticles effectively downregulated ES expression in vitro, which decreased MM cell adhesion and migration through endothelial monolayers. Additionally, in vivo delivery of lipid-polymer nanoparticles co-encapsulating ES and CyPA siRNA extended survival in a xenograft mouse model of MM, either alone or in combination with the proteasome inhibitor bortezomib. Conclusions Our combination siRNA lipid-polymer nanoparticle therapy presents a vascular microenvironment-targeting strategy as a potential paradigm shift for MM therapies, which could be extended to other cancers that colonize the bone marrow.