A Bioinspired Nanoprobe with Multilevel Responsive T1‐Weighted MR Signal‐Amplification Illuminates Ultrasmall Metastases

Metastasis remains the major cause of death in cancer patients. Thus, there is a need to sensitively detect tumor metastasis, especially ultrasmall metastasis, for early diagnosis and precise treatment of cancer. Herein, an ultrasensitive T1 -weighted magnetic resonance imaging (MRI) contrast agent, UMFNP-CREKA is reported. By conjugating the ultrasmall manganese ferrite nanoparticles (UMFNPs) with a tumor-targeting penta-peptide CREKA (Cys-Arg-Glu-Lys-Ala), ultrasmall breast cancer metastases are accurately detected. With a behavior similar to neutrophils' immunosurveillance process for eliminating foreign pathogens, UMFNP-CREKA exhibits a chemotactic "targeting-activation" capacity. UMFNP-CREKA is recruited to the margin of tumor metastases by the binding of CREKA with fibrin-fibronectin complexes, which are abundant around tumors, and then release of manganese ions (Mn2+ ) to the metastasis in response to pathological parameters (mild acidity and elevated H2 O2 ). The localized release of Mn2+ and its interaction with proteins affects a marked amplification of T1 -weighted magnetic resonance (MR) signals. In vivo T1 -weighted MRI experiments reveal that UMFNP-CREKA can detect metastases at an unprecedented minimum detection limit of 0.39 mm, which has significantly extended the detection limit of previously reported MRI probe.

[1]  K. Raymond,et al.  High-relaxivity MRI contrast agents: where coordination chemistry meets medical imaging. , 2008, Angewandte Chemie.

[2]  Jie Zheng,et al.  Clearance Pathways and Tumor Targeting of Imaging Nanoparticles. , 2015, ACS nano.

[3]  Baorui Liu,et al.  Successively activatable ultrasensitive probe for imaging tumour acidity and hypoxia , 2017, Nature Biomedical Engineering.

[4]  Juan Li,et al.  Simultaneous Fenton-like Ion Delivery and Glutathione Depletion by MnO2 -Based Nanoagent to Enhance Chemodynamic Therapy. , 2018, Angewandte Chemie.

[5]  Xun Sun,et al.  Enhanced antitumor and anti‐metastasis efficacy against aggressive breast cancer with a fibronectin‐targeting liposomal doxorubicin , 2018, Journal of controlled release : official journal of the Controlled Release Society.

[6]  Anna Huttenlocher,et al.  Neutrophil migration in infection and wound repair: going forward in reverse , 2016, Nature Reviews Immunology.

[7]  Jing Xu,et al.  Renal clearable noble metal nanoparticles: photoluminescence, elimination, and biomedical applications. , 2017, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[8]  Xiaoyuan Chen,et al.  Structure–Relaxivity Relationships of Magnetic Nanoparticles for Magnetic Resonance Imaging , 2019, Advanced materials.

[9]  Mingwu Shen,et al.  RGD-functionalized ultrasmall iron oxide nanoparticles for targeted T₁-weighted MR imaging of gliomas. , 2015, Nanoscale.

[10]  Yu Cheng,et al.  Fibrin-binding, peptide amphiphile micelles for targeting glioblastoma☆ , 2013, Biomaterials.

[11]  Wei Shi,et al.  Fibrin-targeting peptide CREKA-conjugated multi-walled carbon nanotubes for self-amplified photothermal therapy of tumor. , 2016, Biomaterials.

[12]  I. Aoki,et al.  A pH-activatable nanoparticle with signal-amplification capabilities for non-invasive imaging of tumour malignancy. , 2016, Nature nanotechnology.

[13]  P. Francis,et al.  Strategies for the discovery and development of therapies for metastatic breast cancer , 2012, Nature Reviews Drug Discovery.

[14]  N. Karssemeijer,et al.  Multireader Study on the Diagnostic Accuracy of Ultrafast Breast Magnetic Resonance Imaging for Breast Cancer Screening , 2018, Investigative radiology.

[15]  B. Bay,et al.  Ultrasmall Ferrite Nanoparticles Synthesized via Dynamic Simultaneous Thermal Decomposition for High-Performance and Multifunctional T1 Magnetic Resonance Imaging Contrast Agent. , 2017, ACS nano.

[16]  Rohan D A Alvares,et al.  A scale to measure MRI contrast agent sensitivity , 2017, Scientific Reports.

[17]  P. Kubes,et al.  Neutrophil recruitment and function in health and inflammation , 2013, Nature Reviews Immunology.

[18]  Robert A. Weinberg,et al.  Tumor Metastasis: Molecular Insights and Evolving Paradigms , 2011, Cell.

[19]  S. Bernardi,et al.  Type of breast cancer diagnosis, screening, and survival. , 2014, Clinical breast cancer.

[20]  Stuart A. Taylor,et al.  Imaging biomarker roadmap for cancer studies , 2016, Nature Reviews Clinical Oncology.

[21]  Hao Zhang,et al.  The Blood Clearance Kinetics and Pathway of Polymeric Micelles in Cancer Drug Delivery. , 2018, ACS nano.

[22]  H. Lei,et al.  Ultrasmall Manganese Ferrite Nanoparticles as Positive Contrast Agent for Magnetic Resonance Imaging , 2013, Advanced healthcare materials.

[23]  Robert J Gillies,et al.  Acidity generated by the tumor microenvironment drives local invasion. , 2013, Cancer research.

[24]  A. Yilmaz,et al.  Determination of Proton Relaxivities of Mn(II), Cu(II) and Cr(III) added to Solutions of Serum Proteins , 2009, Molecules.

[25]  Jinwoo Cheon,et al.  Artificially engineered magnetic nanoparticles for ultra-sensitive molecular imaging , 2007, Nature Medicine.

[26]  David L. Wilson,et al.  MRI detection of breast cancer micrometastases with a fibronectin-targeting contrast agent , 2015, Nature Communications.

[27]  S. Achilefu,et al.  Targeting CXCR4–CXCL12 Axis for Visualizing, Predicting, and Inhibiting Breast Cancer Metastasis with Theranostic AMD3100–Ag2S Quantum Dot Probe , 2018 .

[28]  M. Lustig,et al.  Improved pediatric MR imaging with compressed sensing. , 2010, Radiology.

[29]  J. Marco,et al.  Ultrasmall iron oxide nanoparticles for biomedical applications: improving the colloidal and magnetic properties. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[30]  Y. Sheng,et al.  New cofactors and inhibitors for a DNA-cleaving DNAzyme: superoxide anion and hydrogen peroxide mediated an oxidative cleavage process , 2017, Scientific Reports.

[31]  H. Lee,et al.  Presence of tertiary lymphoid structures determines the level of tumor-infiltrating lymphocytes in primary breast cancer and metastasis , 2018, Modern Pathology.

[32]  F. Arnold,et al.  Metal-substituted protein MRI contrast agents engineered for enhanced relaxivity and ligand sensitivity. , 2011, Journal of the American Chemical Society.

[33]  S. Khoury,et al.  Cumulative administrations of gadolinium-based contrast agents: risks of accumulation and toxicity of linear vs macrocyclic agents , 2019, Critical reviews in toxicology.

[34]  A. Puisieux,et al.  Metastasis: a question of life or death , 2006, Nature Reviews Cancer.

[35]  P. Zhang,et al.  PEGylated GdF3:Fe Nanoparticles as Multimodal T1/T2-Weighted MRI and X-ray CT Imaging Contrast Agents. , 2017, ACS applied materials & interfaces.

[36]  Yuliang Zhao,et al.  An Extendable Star-Like Nanoplatform for Functional and Anatomical Imaging-Guided Photothermal Oncotherapy. , 2019, ACS nano.

[37]  W. Bu,et al.  Chemodynamic Therapy: Tumour Microenvironment-Mediated Fenton and Fenton-like Reactions. , 2018, Angewandte Chemie.

[38]  D. Quail,et al.  Microenvironmental regulation of tumor progression and metastasis , 2014 .