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

Abstract

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 H2O2). 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.

Metabolic Conversion and Removal of Manganese Ferrite Nanoparticles in RAW264.7 Cells and Induced Alteration of Metal Transporter Gene Expression

“…Because of the impressive T 1 /T 2 relaxivity, Mn-IONPs have been widely studied and regarded as potential CAs to improve the sensitivity and specificity of molecular MRI. 36,39,40 In addition, benefiting from the nano scale, Mn-IONPs can be easily engineered and functionalized, making them capable and dispersible agents for drug delivery and hyperthermia therapy. 41,42 Even though Mn-IONPs have been studied in biomedicine for several years, there is a poor understanding of the nano-bio interaction of Mn-IONPs at the cellular levels.…”

Emerging Biomaterials‐Based Strategies for Inhibiting Vasculature Function in Cancer Therapy

“…[60] The iron oxide nanoparticles modified by CREKA were proven to achieve the inhibition of tumor growth through stopping tumor blood supply, and also to have tumor imaging capability. [61][62][63] For another case, nanoworm (nanoparticles with elongated wormlike shapes) were further engineered by combining two nanoparticles modified with tumor targeted peptides, CREKA and CRKDKC. Interestingly, optical and magnetic resonance imaging confirmed the tumor-specific targeting ability of the nanoworm.…”

Advances and Perspectives of Peptide and Polypeptide‐Based Materials for Biomedical Imaging

“…This composition was used for metastases detection by MRI. [ 65 ] CREKA peptides can specifically recognize fibrin–fibronectin complexes, which are overexpressed on tumor vessels and in tumor stroma. In addition, these nanoparticles utilize the mild acidity and elevated H 2 O 2 levels in the microenvironment of the tumor to trigger the release of Mn 2+ , enhancing the T1‐weighted MRI signals.…”