Nitric oxide nano-reactor DNMF/PLGA enables tumor vascular microenvironment and chemo-hyperthermia synergetic therapy

作者全名："Wang, Ruoyao; Cheng, Long; He, Lingyun; Du, Chier; Wang, Haiyang; Peng, Bohao; Yu, Xiaoqing; Liu, Weiwei; Luo, Wenpei; Ran, Haitao; Yang, Lu"

作者地址："[Wang, Ruoyao; Peng, Bohao; Yu, Xiaoqing; Yang, Lu] Chongqing Med Univ, Affiliated Hosp 2, Dept Breast & Thyroid Surg, Chongqing 400010, Peoples R China; [Cheng, Long; He, Lingyun; Du, Chier; Wang, Haiyang; Liu, Weiwei; Luo, Wenpei; Ran, Haitao] Chongqing Med Univ, Affiliated Hosp 2, Dept Ultrasound, Chongqing 400010, Peoples R China"

通信作者："Yang, L (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Breast & Thyroid Surg, Chongqing 400010, Peoples R China."

来源：JOURNAL OF NANOBIOTECHNOLOGY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001184965900002

JCR分区：Q1

影响因子：10.6

年份：2024

卷号：22

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Nitric oxide; Nanoparticle; Vessel normalization; Multi-modality image; Photo-thermal therapy

摘要："BackgroundBreast cancer ranks first among malignant tumors, of which triple-negative breast cancer (TNBC) is characterized by its highly invasive behavior and the worst prognosis. Timely diagnosis and precise treatment of TNBC are substantially challenging. Abnormal tumor vessels play a crucial role in TNBC progression and treatment. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis, while effective NO delivery can normalize the tumor vasculature. Accordingly, we have proposed here a tumor vascular microenvironment remodeling strategy based on NO-induced vessel normalization and extracellular matrix collagen degradation with multimodality imaging-guided nanoparticles against TNBC called DNMF/PLGA.ResultsNanoparticles were synthesized using a chemotherapeutic agent doxorubicin (DOX), a NO donor L-arginine (L-Arg), ultrasmall spinel ferrites (MnFe2O4), and a poly (lactic-co-glycolic acid) (PLGA) shell. Nanoparticle distribution in the tumor was accurately monitored in real-time through highly enhanced magnetic resonance imaging and photoacoustic imaging. Near-infrared irradiation of tumor cells revealed that MnFe2O4 catalyzes the production of a large amount of reactive oxygen species (ROS) from H2O2, resulting in a cascade catalysis of L-Arg to trigger NO production in the presence of ROS. In addition, DOX activates niacinamide adenine dinucleotide phosphate oxidase to generate and supply H2O2. The generated NO improves the vascular endothelial cell integrity and pericellular contractility to promote vessel normalization and induces the activation of endogenous matrix metalloproteinases (mainly MMP-1 and MMP-2) so as to promote extravascular collagen degradation, thereby providing an auxiliary mechanism for efficient nanoparticle delivery and DOX penetration. Moreover, the chemotherapeutic effect of DOX and the photothermal effect of MnFe2O4 served as a chemo-hyperthermia synergistic therapy against TNBC.ConclusionThe two therapeutic mechanisms, along with an auxiliary mechanism, were perfectly combined to enhance the therapeutic effects. Briefly, multimodality image-guided nanoparticles provide a reliable strategy for the potential application in the fight against TNBC."

基金机构："Senior Medical Talents Program of Chongqing for Young and Middle-aged; Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University; Science and Technology Bureau of Yuzhong District, Chongqing [20200145]"

基金资助正文："This study was supported by the Senior Medical Talents Program of Chongqing for Young and Middle-aged, the Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University, and the Science and Technology Bureau of Yuzhong District, Chongqing (Grant No. 20200145)."