Breast cancer is the leading cause of cancer associated death among women. Techniques for non-invasive breast cancer detection and imaging are urgently needed. Multimodality breast cancer imaging is attractive since it can integrate the advantages from several modalities enabling more accurate cancer detection. In order to accomplish this, Indocyanine Green (ICG) conjugated superparamagnetic Iron Oxide Nanoworm (NW-ICG) has been synthesized as contrast agents. When evaluated in a spontaneous mouse breast cancer model, the NW-ICG gave high tumor to normal tissue contrasts in multiple imaging modalities including magnetic particle imaging (MPI), near-infrared fluorescence imaging (NIR-FI), and photoacoustic imaging (PAI), providing more comprehensive detection and imaging of breast cancer. Thus, NW-ICGs are an attractive platform for non-invasive breast cancer diagnosis.A major contributing cause to breast cancer related death is metastasis. Moreover, breast cancer metastasis often shows few symptoms until a large area of the organs has been occupied by metastatic cancer cells. Breast cancer multimodal imaging is attractive since it integrates advantages from several modalities, enabling more accurate cancer detection. Glycoprotein CD44 is overexpressed on most breast cancer cells, and is the primary cell surface receptor for hyaluronan (HA). To facilitate breast cancer diagnosis, we report an ICG and HA conjugated iron oxide nanoparticle (NP-ICG-HA), which enabled active targeting to breast cancer by HA-CD44 interaction and detected metastasis with MPI and NIR-FI. When evaluated in a transgenic breast cancer mouse model, NP-ICG-HA enabled the detection of multiple breast tumors in MPI and NIR-FI, providing more comprehensive images and diagnosis of breast cancer. Furthermore, NP-ICG-HAs were evaluated in a breast cancer lung metastasis model. Upon NP-ICG-HA administration, MPI showed clear signals in lungs, indicating the tumor sites. This is the first time that HA based NPs have enabled MPI of cancer. NP-ICG-HAs are an attractive platform for non-invasive detection of primary breast cancer and lung metastasis. Cancer stem cells (CSCs) are a critical subset of cancer cells that contribute to tumor heterogeneity and resistance due to their self-renewal and tumor-initiating abilities. Targeting these cells, which often express elevated levels of CD44 receptors, is promising for developing effective cancer treatments. To better target the breast CD44-expressing cancer cells, we developed a novel nanodrug, G2-Sal-ICG, comprising a HA-like compound (G2) conjugated with the anticancer drug salinomycin (Sal) and the imaging agent ICG. This nanodrug targets CD44 receptors and allows for NIR-FI to track drug delivery in real-time. Binding assays with CD44-expressing 4T1 breast cancer cells showed that G2-Sal-ICG had significantly higher binding affinity than the positive control of HA conjugated with Sal and ICG (HA-Sal-ICG). Fluorescence microscopy imaging of cells incubated with G2-Sal-ICG revealed that the nanodrug was primarily localized in lysosomes, indicating successful cellular uptake. In vitro studies demonstrated delayed but effective cancer cell killing, suggesting that lysosomal degradation and hydrolysis are necessary for drug release. In vivo experiments using orthotopic breast cancer models highlighted the superior tumor-targeting capability of G2-Sal-ICG, which showed three times higher fluorescence signals in tumors compared to HA-Sal-ICG. Tumor volume measurements indicated significantly better suppression of tumor growth by G2-Sal-ICG. Flow cytometry and histological analyses confirmed a greater reduction in CD44-expressing cancer cells. Our findings demonstrated G2-Sal-ICG as a promising theranostic nanodrug for CSC-targeted therapy, combining efficient drug delivery with real-time imaging capabilities, thus highlighting its potential for clinical applications in breast cancer treatment.
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