Lipid nanoparticle-mediated siRNA delivery for safe targeting of human CML in vivo
Lipid nanoparticle-mediated siRNA delivery for safe targeting of human CML in vivo
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DOI：
10.1007/s00277-019-03713-y
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发表时间：
2019-08-01
影响因子：
3.5
通讯作者：
Heuser, Michael
中科院分区：
文献类型：
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作者：
Jyotsana, Nidhi;Sharma, Amit;Heuser, Michael
体内 siRNA 的高效、安全递送是基于 RNA 干扰 (RNAi) 的疗法临床转化的最大障碍。迄今为止，脂质纳米颗粒 (LNP) 已显示出可有效地将 siRNA 递送至肝脏；然而，输送到其他器官，特别是造血组织仍然是一个挑战。我们开发了基于 DLin-MC3-DMA 脂质的 LNP-siRNA 制剂，用于针对驱动癌基因的全身递送，以靶向人体内慢性粒细胞白血病 (CML) 细胞。使用微流体混合技术获得可重复的可电离阳离子 LNP，该 LNP 负载有针对 CML 中发现的 BCR-ABL 融合癌基因的 siRNA 分子。我们在体外和体内展示了 siRNA 的高效、无毒递送，在白血病模型的骨髓中几乎 100% 吸收了 LNP-siRNA 制剂。通过靶向 BCR-ABL 融合癌基因，我们在髓性白血病小鼠模型中显示出白血病负担的减少，并证明与 LNP-CTRL siRNA 相比，用 LNP-BCR-ABL siRNA 治疗的小鼠的疾病负担减少。我们的研究提供了原理证明，即融合癌基因特异性 RNAi 疗法可用于对抗白血病细胞，并为白血病患者提供新的治疗选择。
Efficient and safe delivery of siRNA in vivo is the biggest roadblock to clinical translation of RNA interference (RNAi)-based therapeutics. To date, lipid nanoparticles (LNPs) have shown efficient delivery of siRNA to the liver; however, delivery to other organs, especially hematopoietic tissues still remains a challenge. We developed DLin-MC3-DMA lipid-based LNP-siRNA formulations for systemic delivery against a driver oncogene to target human chronic myeloid leukemia (CML) cells in vivo. A microfluidic mixing technology was used to obtain reproducible ionizable cationic LNPs loaded with siRNA molecules targeting the BCR-ABL fusion oncogene found in CML. We show a highly efficient and non-toxic delivery of siRNA in vitro and in vivo with nearly 100% uptake of LNP-siRNA formulations in bone marrow of a leukemic model. By targeting the BCR-ABL fusion oncogene, we show a reduction of leukemic burden in our myeloid leukemia mouse model and demonstrate reduced disease burden in mice treated with LNP-BCR-ABL siRNA as compared with LNP-CTRL siRNA. Our study provides proof-of-principle that fusion oncogene specific RNAi therapeutics can be exploited against leukemic cells and promise novel treatment options for leukemia patients.