Metastases are responsible for 90% of human cancer deaths.[1] Most solid tumors metastasize through the circulation system, and the sentinel lymph node (LN) is typically the first site reached by the disseminating malignant cancer cells.[2] The detection of LN metastases is therefore crucial for accurate tumor staging and therapeutic decisionmaking.[3] The current standard method for LN assessment is lymphography using a vital blue dye. However, this method is invasive, involving extended nodal dissection, and can give a false negative result if a LN is missed in surgery.[4] A non-invasive LN imaging technique is urgently needed to improve the accuracy of tumor staging.[5] Various techniques for sentinel LN imaging have been investigated, such as near-infrared (NIR) fluorescence imaging, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and ultrasound and photoacoustic imaging.[4b, 5b, 6] However, each technique has its drawbacks, and none is sufficient to provide all the necessary information for LN assessment.[4b] PET is the most sensitive and specific technique for in vivo molecular imaging,[7] but it suffers from low spatial resolution. In contrast, fluorescence imaging has high resolution and allows spatial visualization, which is helpful for intraoperative guidance; but its application is limited by poor tissue penetration. Therefore, combination of both PET and fluorescence imaging together potentially permit non-invasive assessment of LNs with high sensitivity and excellent spatial resolution.

Silica nanoparticles (NPs) are widely used for biomedical imaging applications because of the good biocompatibility and optically transparency of silica.[8] We recently developed a versatile, size-controlled, monodisperse drug/dye–silica nanoconjugate (NC) platform that allows for conjugation with a variety of functional moieties.[9] The robust silane chemistry and the formulation strategy permit the construction of multifunctional NCs, such as multimodal imaging probes for in vivo applications. It is generally accepted that the physicochemical properties of NPs, especially their size, play a vital role in the systemic and lymphatic biodistribution.[10] Because the size of the silica NCs can be precisely controlled, they are ideal for investigating size effects on their trafficking behavior in the lymphatic system. The silica NCs provide a unique platform with multifunctionality and excellent size control for the preparation of nanoparticulate probes with optimized properties for improved imaging of LN metastases.[10c]