MRI Detection of Lymph Node Metastasis through Molecular Targeting of C–C Chemokine Receptor Type 2 and Monocyte Hitchhiking

Abstract

Biopsy is the clinical standard for diagnosing lymph node (LN) metastasis, but it is invasive and poses significant risk to patient health. Magnetic resonance imaging (MRI) has been utilized as a noninvasive alternative but is limited by low sensitivity, with only ∼35% of LN metastases detected, as clinical contrast agents cannot discriminate between healthy and metastatic LNs due to nonspecific accumulation. Nanoparticles targeted to the C−C chemokine receptor 2 (CCR2), a biomarker highly expressed in metastatic LNs, have the potential to guide the delivery of contrast agents, improving the sensitivity of MRI. Additionally, cancer cells in metastatic LNs produce monocyte chemotactic protein 1 (MCP1), which binds to CCR2 + inflammatory monocytes and stimulates their migration. Thus, the molecular targeting of CCR2 may enable nanoparticle hitchhiking onto monocytes, providing an additional mechanism for metastatic LN targeting and early detection. Hence, we developed micelles incorporating gadolinium (Gd) and peptides derived from the CCR2-binding motif of MCP1 (MCP1-Gd) and evaluated the potential of MCP1-Gd to detect LN metastasis. When incubated with migrating monocytes in vitro, MCP1-Gd transport across lymphatic endothelium increased 2-fold relative to nontargeting controls. After administration into mouse models with initial LN metastasis and recurrent LN metastasis, MCP1-Gd detected metastatic LNs by increasing MRI signal by 30−50% relative to healthy LNs. Furthermore, LN targeting was dependent on monocyte hitchhiking, as monocyte depletion decreased accumulation by >70%. Herein, we present a nanoparticle contrast agent for MRI detection of LN metastasis mediated by CCR2-targeting and demonstrate the potential of monocyte hitchhiking for enhanced nanoparticle delivery.

Porphyrin-Based Self-Assembled Nanoparticles for PET/MR Imaging of Sentinel Lymph Node Metastasis

“…Similarly, the mean T 1 relaxation time of T-SLN decreased from 887.2 to 623.3 ms, with a color change from turquoise to light blue with an uneven color distribution. The uneven distribution of T 1 relaxation time in the lymph nodes in MRI images may be related to the distribution of macrophages and tumor cells; similar phenomena have been reported previously. , MRI can effectively visualize the contrast agent, so the change rate of mean T 1 relaxation time (Δ T 1 (%), calculated as Δ T 1 = ( T 1pre – T 1post )/ T 1pre × 100%) was measured. It can be seen from Figure E that (1) Δ T 1 of T-SLN was consistently lower than that of N-LN.…”

Investigation of Basolateral Targeting Micelles for Drug Delivery Applications in Polycystic Kidney Disease

“…Next, this study used only Cy7 to label the micelle for imaging in biodistribution studies. Additional labeling methods, such as through the use of gadolinium for MRI and isotope labeling for PET imaging, should be conducted to further quantify and measure the in vivo biodistribution and in vivo stability of micelles at different injection time points. Lastly, it is important to investigate the mechanism by which RGD micelles are taken up by both normal and diseased tubular cells and how the loading of drugs into micelles influences drug pharmacokinetics and their accumulation in the kidneys.…”