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siRNA Lipid-Polymer Nanoparticles Targeting E-Selectin and Cyclophilin A in Bone Marrow for Combination Multiple
Christian G Figueroa-Espada1, Pedro P G Guimarães2, Rachel S Riley3
1Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, 240 Skirkanich Hall, 210 South 33rd Street, Philadelphia, PA 19104 USA.
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.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s12195-023-00774-y.
Insights
This study developed a novel lipid-polymer nanoparticle therapy to deliver RNA interference (RNAi) targeting E-selectin and cyclophilin A, effectively inhibiting multiple myeloma (MM) cell spread and improving survival in mice.
Area of Science:
- Oncology
- Nanomedicine
- Molecular Biology
Background:
- Multiple myeloma (MM) is an incurable bone marrow cancer.
- MM cell interactions with the bone marrow microenvironment promote disease progression.
- E-selectin (ES) and cyclophilin A (CyPA) are key factors in MM cell homing and survival.
Purpose of the Study:
- To develop a targeted RNA interference (RNAi) therapy for multiple myeloma.
- To investigate the efficacy of co-delivering ES and CyPA siRNAs using lipid-polymer nanoparticles.
- To evaluate the potential of this strategy in preventing MM dissemination and enhancing treatment outcomes.
Main Methods:
- Utilized a lipid-polymer nanoparticle platform for targeted siRNA delivery to the bone marrow perivascular niche.
- Co-delivered siRNAs targeting E-selectin (ES) and cyclophilin A (CyPA).
- Assessed the downregulation of ES expression and its effect on MM cell adhesion and migration in vitro.
- Evaluated the in vivo efficacy in a xenograft mouse model of MM, with and without bortezomib combination therapy.
Main Results:
- Lipid-polymer nanoparticles successfully downregulated ES expression in vitro.
- Reduced MM cell adhesion and migration through endothelial monolayers.
- In vivo administration of nanoparticles co-delivering ES and CyPA siRNA significantly extended survival in a mouse model of MM.
- Combination therapy with bortezomib further improved survival outcomes.
Conclusions:
- Lipid-polymer nanoparticle-mediated co-delivery of ES and CyPA siRNA is a promising therapeutic strategy for multiple myeloma.
- This approach targets the vascular microenvironment, offering a potential paradigm shift in MM treatment.
- The strategy may be applicable to other bone marrow-colonizing cancers.
