Biomimetic, Hypoxia-Responsive Nanoparticles Overcome Residual Chemoresistant Leukemic Cells with Co-Targeting of Therapy-Induced Bone Marrow Niches
Biomimetic, Hypoxia-Responsive Nanoparticles Overcome Residual Chemoresistant Leukemic Cells with Co-Targeting of Therapy-Induced Bone Marrow Niches
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仿生缺氧响应纳米颗粒通过共同靶向治疗诱导的骨髓龛来克服残留的化疗耐药白血病细胞
DOI：
10.1002/adfm.202000309
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发表时间：
2020-02-03
影响因子：
19
通讯作者：
Fang, Chao
中科院分区：
文献类型：
--
作者：
Dong, Xiao;Mu, Li-Li;Fang, Chao
白血病增殖细胞(LPCS)在治疗诱导的小生境(TI-NICE)中产生的化疗耐药是白血病治疗的主要障碍之一。规避生态位保护和消除常驻LPCS的有效方法仍有待开发。在这里，开发了一个利基靶向的纳米系统，使用白血病细胞膜包裹的介孔二氧化硅纳米颗粒(DA(Azo)@CMSN)共同传递柔红霉素用于白血病细胞化疗，并使用转化生长因子βRII中和抗体(aTGFβRII)来阻断利基信号。DA(Azo)@CMSN有效地瞄准了TI-利基市场。通过基于偶氮苯的缺氧反应连接体，两个活性分子的顺序递送克服了利基介导的化疗耐药，减轻了全身负担，并延长了白血病小鼠模型的生存时间。这项工作证明了一种用于克服白血病治疗诱导的化疗耐药的仿生和微环境激活的多重纳米颗粒药物传递策略的原理证明。
Chemoresistance conferred by leukemia propagating cells (LPCs) in a therapy-induced niche (TI-niche) within the bone marrow is one of the main obstacles in leukemia treatment. Effective approaches to circumvent the TI-niche protection and to eliminate the resident LPCs remain to be exploited. Here, developed is a niche-targeted nanosystem using leukemic cell membrane-coated mesoporous silica nanoparticles (DA(azo)@CMSN) for co-delivering daunorubicin for leukemia cell chemotherapy and a TGF beta RII neutralizing antibody (aTGF beta RII) to block niche signaling. DA(azo)@CMSN effectively targets the TI-niche. Through an azobenzene-based hypoxia-responsive linker, sequential delivery of the two active molecules overcomes niche-mediated chemoresistance, attenuates systemic burden, and prolongs survival in a mouse model of leukemia. This work demonstrates a proof-of-principle for biomimetic and microenvironment-activated multiplexed nanoparticulate drug delivery strategies for overcoming therapy-induced chemoresistance in leukemia.