靶向骨髓中E-选择素和亲环素A的siRNA脂质聚合物纳米粒子用于联合治疗多发性骨髓瘤。

IF 2.3 4区 医学 Q3 BIOPHYSICS Cellular and molecular bioengineering Pub Date : 2023-09-14 eCollection Date: 2023-08-01 DOI:10.1007/s12195-023-00774-y
Christian G Figueroa-Espada, Pedro P G Guimarães, Rachel S Riley, Lulu Xue, Karin Wang, Michael J Mitchell
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引用次数: 0

摘要

简介:多发性骨髓瘤(MM)是一种骨髓癌症,在很大程度上仍然无法治愈,部分原因是其与骨髓微环境的物理相互作用。这种相互作用增强MM细胞的归巢、增殖和耐药性。具体而言,骨髓内皮细胞分别表达的粘附受体和归巢因子E-选择素(ES)和亲环素A(CyPA)增强了MM的定植和扩散。因此,ES和CyPA的沉默提供了一种潜在的治疗策略来逃避MM的传播。然而,骨髓内皮细胞表达的ES和CyPA的小分子抑制仍然具有挑战性,阻断抗体诱导MM的进一步繁殖。因此,ES和CyPA是通过RNA干扰(RNAi)抑制的有希望的候选者。方法:在这里,我们使用了一种先前开发的脂质聚合物纳米颗粒进行RNAi治疗,该纳米颗粒将siRNA递送到骨髓血管周围小生境。我们利用我们的平台共同递送ES和CyPA siRNA,以防止MM在体内传播。结果:脂质聚合物纳米颗粒在体外有效下调ES的表达,降低MM细胞通过内皮单层的粘附和迁移。此外,共包封ES和CyPA siRNA的脂质聚合物纳米颗粒的体内递送延长了MM异种移植小鼠模型中的存活率,无论是单独递送还是与蛋白酶体抑制剂硼替佐米组合递送。结论:我们的siRNA脂质聚合物纳米颗粒联合治疗提供了一种血管微环境靶向策略,作为MM治疗的潜在范式转变,可以扩展到其他骨髓定植的癌症。补充信息:在线版本包含补充材料,请访问10.1007/s12195-023-00774-y。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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

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.

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来源期刊
CiteScore
5.60
自引率
3.60%
发文量
30
审稿时长
>12 weeks
期刊介绍: The field of cellular and molecular bioengineering seeks to understand, so that we may ultimately control, the mechanical, chemical, and electrical processes of the cell. A key challenge in improving human health is to understand how cellular behavior arises from molecular-level interactions. CMBE, an official journal of the Biomedical Engineering Society, publishes original research and review papers in the following seven general areas: Molecular: DNA-protein/RNA-protein interactions, protein folding and function, protein-protein and receptor-ligand interactions, lipids, polysaccharides, molecular motors, and the biophysics of macromolecules that function as therapeutics or engineered matrices, for example. Cellular: Studies of how cells sense physicochemical events surrounding and within cells, and how cells transduce these events into biological responses. Specific cell processes of interest include cell growth, differentiation, migration, signal transduction, protein secretion and transport, gene expression and regulation, and cell-matrix interactions. Mechanobiology: The mechanical properties of cells and biomolecules, cellular/molecular force generation and adhesion, the response of cells to their mechanical microenvironment, and mechanotransduction in response to various physical forces such as fluid shear stress. Nanomedicine: The engineering of nanoparticles for advanced drug delivery and molecular imaging applications, with particular focus on the interaction of such particles with living cells. Also, the application of nanostructured materials to control the behavior of cells and biomolecules.
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