Fabrication of tumor targeting rare-earth nanocrystals for real-time NIR-IIb fluorescence imaging-guided breast cancer precise surgery.

The near-infrared fluorescence imaging has been integrated into the operating room to guide tumor resection, potentially reducing the positive margin rates in breast-conserving surgery (BCS). Relative to the widely used first near-infrared fluorescence imaging, imaging in the second near-infrared (NIR-II) region possesses higher contrast and deeper tissue penetration, particularly in the NIR-IIb window, offering many new opportunities for imaging-guided BCS. Here, we fabricated the c(RGDfC) functionalized erbium-based rare-earth nanoparticles (ErNPs@cRGD) with superior optical property in NIR-IIb region. Owing to deeper tissue penetration and efficient tumor targeting, ErNPs@cRGD-based NIR-IIb fluorescence imaging achieved enhanced signal-to-background ratios in tumor visualization, which was able to guide more complete tumor resection, identify multiple microtumors and distinguish malignant lesions from normal tissues in various mice models. Based on these, this NIR-IIb imaging strategy for surgical navigation can significantly reduce positive margin rates and improve prognosis, laying a foundation for the clinical resection of breast cancer.

Development and Preclinical Evaluation of a Near-Infrared Fluorescence Probe Based on Tailored Hepatitis B Core Particles for Imaging-Guided Surgery in Breast Cancer.

Purpose: Tumor-free surgical margin is crucial but challenging in breast-conserving surgery (BCS). Fluorescence imaging is a promising strategy for surgical navigation that can reliably assist the surgeon with visualization Of the tumor in real-time. Notably, finding an optimized fluorescent probe has been a challenging research topic. Herein, we developed a novel near-infrared (NIR) fluorescent probe based on tailored Hepatitis B Core virus-like protein (HBc VLP) and presented the preclinical imaging-guided surgery. Methods: The RGD-HBc160 VLP was synthesized by genetic engineering followed encapsulation of ICG via disassembly-reassembly. The applicability of the probe was tested for cell and tissue binding capacities through cell-based plate assays, xenograft mice model, and MMTV-PyVT mammary tumor transgenic mice. Subsequently, the efficacy of RGD-HBc160/ICG-guided surgery was evaluated in an infiltrative tumor-bearing mouse model. The protein-induced body's immune response was further assessed. Results: The prepared RGD-HBc160/ICG showed outstanding integrin αvß3 targeting ability in vitro and in vivo. After intravenous administration of probe, the fluorescence guidance facilitated more complete tumor resection and improved overall survival Of the infiltrative tumor-bearing mice. The probe also showed the excellent capability to differentiate between benign and malignant breast tissues in the mammary tumor transgenic mice. Interestingly, the ingenious tailoring of HBc VLP could not only endow its tumor-targeting ability towards integrin αvß3 but also significantly reduce the humoral and cellular immune response. Conclusion: The RGD-HBc160/ICG holds promise as an effective tool to delineate tumor margin. These results have translational potential to achieve margin-negative resection and improve the stratification of patients for a potentially curative.

In vivo visualization of fluorescence reflecting CDK4 activity in a breast cancer mouse model.

The CDK4/6-Rb axis is a crucial target of cancer therapy and several selective inhibitors of it have been approved for clinical application. However, current therapeutic efficacy evaluation mostly relies on anatomical imaging, which cannot directly reflect changes in drug targets, leading to a delay in the selection of optimal treatment. In this study, we constructed a novel fluorescent probe, CPP30-Lipo/CDKACT4, for real-time monitoring of CDK4 activity and the therapeutic efficacy of its inhibitor in HR+/HER2- breast cancer. CPP30-Lipo/CDKACT4 exhibited good optical stability and targetability. The signal of the probe in living cells decreased after CDK4 knockdown or palbociclib treatment. Moreover, the fluorescence intensity of the tumors after 7 days of palbociclib treatment was significantly lower than that before treatment, while no significant change in tumor diameter was observed under magnetic resonance imaging. Overall, we developed an innovative fluorescent probe that can monitor CDK4 activity and the early therapeutic response to CDK4 inhibitors in living cells and in vivo. It may provide a new strategy for evaluating antitumor therapeutic efficacy in a clinical context and for drug development.

Biodegradable Nanoprobe for NIR-II Fluorescence Image-Guided Surgery and Enhanced Breast Cancer Radiotherapy Efficacy.

Positive resection margin frequently exists in breast-conserving treatment (BCT) of early-stage breast cancer, and insufficient therapeutic efficacy is common during radiotherapy (RT) in advanced breast cancer patients. Moreover, a multimodal nanotherapy platform is urgently required for precision cancer medicine. Therefore, a biodegradable cyclic RGD pentapeptide/hollow virus-like gadolinium (Gd)-based indocyanine green (R&HV-Gd@ICG) nanoprobe is developed to improve fluorescence image-guided surgery and breast cancer RT efficacy. R&HV-Gd exhibits remarkably improved aqueous stability, tumor retention, and target specificity of ICG, and achieves outstanding magnetic resonance/second near-infrared (NIR-II) window multimodal imaging in vivo. The nanoprobe-based NIR-II fluorescence image guidance facilitates complete tumor resection, improves the overall mouse survival rate, and effectively discriminates between benign and malignant breast tissues in spontaneous breast cancer transgenic mice (area under the curve = 0.978; 95% confidence interval: 0.952, 1.0). Moreover, introducing the nanoprobe to tumors generated more reactive oxygen species under X-ray irradiation, improved RT sensitivity, and reduced mouse tumor progression. Notably, the nanoprobe is biodegradable in vivo and exhibits accelerated bodily clearance, which is expected to reduce the potential long-term inorganic nanoparticle toxicity. Overall, the nanoprobe provides a basis for developing precision breast cancer treatment strategies.