Biomimetic, Hypoxia-Responsive Nanoparticles Overcome Residual Chemoresistant Leukemic Cells with Co-Targeting of Therapy-Induced Bone Marrow Niches

被引：46

作者：

Dong, Xiao ^{[1
,2
]}

Mu, Li-Li ^{[3
]}

Liu, Xue-Liang ^{[1
,2
]}

Zhu, Hua ^{[4
]}

Yang, Si-Cong ^{[1
,2
]}

Lai, Xing ^{[1
,2
]}

Liu, Hai-Jun ^{[1
,2
]}

Feng, Hai-Yi ^{[1
,2
]}

Lu, Qin ^{[1
,2
]}

Zhou, Bin-Bing S. ^{[1
,2
]}

Chen, Hong-Zhuan ^{[5
]}

Chen, Guo-Qiang ^{[6
]}

Lovell, Jonathan F. ^{[7
]}

Hong, Deng-Li ^{[3
]}

Fang, Chao ^{[1
,2
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Med, Hongqiao Int Inst Med, Tongren Hosp, Shanghai 200025, Peoples R China

[2] Shanghai Jiao Tong Univ, Sch Med, Dept Pharmacol & Chem Biol, Inst Med Sci, Shanghai 200025, Peoples R China

[3] SJTU SM, Key Lab Cell Differentiat & Apoptosis, Shanghai Key Lab Reprod Med, Minist Educ,Shanghai Inst Hematol,Ruijin Hosp,Dep, Shanghai 200025, Peoples R China

[4] SJTU SM, Key Lab Pediat Hematol & Oncol, Dept Hematol Oncol, Minist Hlth,Shanghai Childrens Med Ctr, Shanghai 200025, Peoples R China

[5] Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Biomed Res, Shanghai 201210, Peoples R China

[6] SJTU SM, Key Lab Cell Differentiat & Apoptosis, Minist Educ, Dept Pathophysiol, Shanghai 200025, Peoples R China

[7] Univ Buffalo State Univ New York, Dept Biomed Engn, Buffalo, NY 14260 USA

来源：

ADVANCED FUNCTIONAL MATERIALS | 2020年 / 30卷 / 12期

基金：

中国国家自然科学基金;

关键词：

bone marrow; hypoxia responsive; leukemia; nanoparticles; niche; DRUG-DELIVERY; STEM-CELLS; FACTOR-I; CXCR4;

D O I：

10.1002/adfm.202000309

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页数：13

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