Nitric oxide nano-reactor DNMF/PLGA enables tumor vascular microenvironment and chemo-hyperthermia synergetic therapy
Abstract Background Breast 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 cr...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | Journal of Nanobiotechnology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12951-024-02366-y |
| _version_ | 1827315760941236224 |
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| author | Ruoyao Wang Long Cheng Lingyun He Chier Du Haiyang Wang Bohao Peng Xiaoqing Yu Weiwei Liu Wenpei Luo Haitao Ran Lu Yang |
| author_facet | Ruoyao Wang Long Cheng Lingyun He Chier Du Haiyang Wang Bohao Peng Xiaoqing Yu Weiwei Liu Wenpei Luo Haitao Ran Lu Yang |
| author_sort | Ruoyao Wang |
| collection | DOAJ |
| description | Abstract Background Breast 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. Results Nanoparticles 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. Conclusion The 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. Graphical Abstract |
| first_indexed | 2024-04-24T23:02:45Z |
| format | Article |
| id | doaj.art-888a4e4468fe470691b5d498ccba8874 |
| institution | Directory Open Access Journal |
| issn | 1477-3155 |
| language | English |
| last_indexed | 2024-04-24T23:02:45Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj.art-888a4e4468fe470691b5d498ccba88742024-03-17T12:37:17ZengBMCJournal of Nanobiotechnology1477-31552024-03-0122112210.1186/s12951-024-02366-yNitric oxide nano-reactor DNMF/PLGA enables tumor vascular microenvironment and chemo-hyperthermia synergetic therapyRuoyao Wang0Long Cheng1Lingyun He2Chier Du3Haiyang Wang4Bohao Peng5Xiaoqing Yu6Weiwei Liu7Wenpei Luo8Haitao Ran9Lu Yang10Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Breast and Thyroid Surgery, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Breast and Thyroid Surgery, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Breast and Thyroid Surgery, The Second Affiliated Hospital of Chongqing Medical UniversityAbstract Background Breast 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. Results Nanoparticles 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. Conclusion The 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. Graphical Abstracthttps://doi.org/10.1186/s12951-024-02366-yNitric oxideNanoparticleVessel normalizationMulti-modality imagePhoto-thermal therapy |
| spellingShingle | Ruoyao Wang Long Cheng Lingyun He Chier Du Haiyang Wang Bohao Peng Xiaoqing Yu Weiwei Liu Wenpei Luo Haitao Ran Lu Yang Nitric oxide nano-reactor DNMF/PLGA enables tumor vascular microenvironment and chemo-hyperthermia synergetic therapy Journal of Nanobiotechnology Nitric oxide Nanoparticle Vessel normalization Multi-modality image Photo-thermal therapy |
| title | Nitric oxide nano-reactor DNMF/PLGA enables tumor vascular microenvironment and chemo-hyperthermia synergetic therapy |
| title_full | Nitric oxide nano-reactor DNMF/PLGA enables tumor vascular microenvironment and chemo-hyperthermia synergetic therapy |
| title_fullStr | Nitric oxide nano-reactor DNMF/PLGA enables tumor vascular microenvironment and chemo-hyperthermia synergetic therapy |
| title_full_unstemmed | Nitric oxide nano-reactor DNMF/PLGA enables tumor vascular microenvironment and chemo-hyperthermia synergetic therapy |
| title_short | Nitric oxide nano-reactor DNMF/PLGA enables tumor vascular microenvironment and chemo-hyperthermia synergetic therapy |
| title_sort | nitric oxide nano reactor dnmf plga enables tumor vascular microenvironment and chemo hyperthermia synergetic therapy |
| topic | Nitric oxide Nanoparticle Vessel normalization Multi-modality image Photo-thermal therapy |
| url | https://doi.org/10.1186/s12951-024-02366-y |
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