Development of a Rare Earth Nanoprobe Enables In Vivo Real-Time Detection of Sentinel Lymph Node Metastasis of Breast Cancer Using NIR-IIb Imaging

Abstract

Sentinel lymph node (SLN) biopsy plays a critical role in axillary staging of breast cancer. However, traditional SLN mapping does not accurately discern the presence or absence of metastatic disease. Detection of SLN metastasis largely hinges on examination of frozen sections or paraffin-embedded tissues post-SLN biopsy. To improve detection of SLN metastasis, we developed a second near-infrared (NIR-II) in vivo fluorescence imaging system, pairing erbium-based rare-earth nanoparticles (ErNPs) with bright down-conversion fluorescence at 1556 nm. To visualize SLNs bearing breast cancer, ErNPs were modified by balixafortide (ErNPs@POL6326), a peptide antagonist of the chemokine receptor CXCR4. The ErNPs@POL6326 probes readily drained into SLNs when delivered subcutaneously, entering metastatic breast tumor cells specifically via CXCR4-mediated endocytosis. NIR fluorescence signals increased significantly in tumor-positive versus tumor-negative SLNs, enabling accurate determination of SLN breast cancer metastasis. In a syngeneic mouse mammary tumor model and a human breast cancer xenograft model, sensitivity for SLN metastasis detection was 92.86% and 93.33%, respectively, and specificity was 96.15% and 96.08%, respectively. Of note, the probes accurately detected both macrometastases and micrometastases in SLNs. These results overall underscore the potential of ErNPs@POL6326 for real-time visualization of SLNs and in vivo screening for SLN metastasis.

Repurposing GnRH-A as a Near-Infrared Fluorescent Probe for Diagnosis and Surgical Navigation of Breast Cancer Tumors and Metastases

“…To address these issues, researchers have engineered targeted near-infrared fluorescent molecular probes, such as RGD-HBc/ICG, 15 albumin-ICG, 16 and ErNPs@POL6326. 17 These probes have demonstrated superior recognition abilities and precision at the preclinical level, surpassing traditional methods. However, their larger molecular size predisposes them to hepatic accumulation, resulting in slower in vivo clearance and raising biosafety concerns that may impede their translation to clinical practice.…”

“…Despite these advantages, ICG’s clinical utility is hampered by several drawbacks: it accumulates at tumor sites primarily through the nonspecific enhanced permeability and retention (EPR) effect without active lymphatic targeting, and it exhibits suboptimal physicochemical characteristics, such as instability, a propensity for self-quenching, and a low quantum yield. , ICG’s inherent lack of tumor-specificity and limited capacity in demarcating tumor margins underscore its limitations as a nontargeted dye. To address these issues, researchers have engineered targeted near-infrared fluorescent molecular probes, such as RGD-HBc/ICG, albumin-ICG, and ErNPs@POL6326 . These probes have demonstrated superior recognition abilities and precision at the preclinical level, surpassing traditional methods.…”

Machine Learning Enabled Photoacoustic Spectroscopy for Noninvasive Assessment of Breast Tumor ProgressionIn Vivo: A Preclinical Study

“…There are reports on real-time label-free multiphoton imaging of histological sections in diagnosing breast cancer, sentinel lymph node metastasis detection using fluorescence nanoparticles with good biocompatibility in vitro and in vivo . The potential of Near Infrared-II (NIR-II) imaging for intraoperative, early sentinel lymph node metastasis assessment has also been demonstrated. , However, the strong optical scattering within turbid biological tissues restricts fluorescence-based imaging techniques’ imaging depth to the optical ballistic depth (<1 mm). This shallow observation depth limits fluorescence imaging techniques to superficial layers in biological tissues.…”

“…The potential of Near Infrared-II (NIR-II) imaging for intraoperative, early sentinel lymph node metastasis assessment has also been demonstrated. 8 , 9 However, the strong optical scattering within turbid biological tissues restricts fluorescence-based imaging techniques’ imaging depth to the optical ballistic depth (<1 mm). This shallow observation depth limits fluorescence imaging techniques to superficial layers in biological tissues.…”