Macrophages Homing to Metastatic Lymph Nodes Can Be Monitored with Ultrasensitive Ferromagnetic Iron-Oxide Nanocubes and a 1.5T Clinical MR Scanner

Abstract

BackgroundDue to the ability of macrophages to specifically home to tumors, their potential use as a delivery vehicle for cancer therapeutics has been suggested. Tracking the delivery and engraftment of macrophages into human tumors with a 1.5T clinical MR scanner requires the development of sensitive contrast agents for cell labeling. Therefore, this study aimed to determine whether intravenously injected macrophages could target a primary tumor as well as metastatic LNs, and whether these cells could be detected in vivo by MRI.MethodologyPeritoneal macrophages were obtained from BALB/c nude mice. The viability, phagocytotic capacity and migratory activity of the macrophages were assessed. MR imaging was performed using a clinical 1.5 T MR scanner and we estimated the T2* of the labeled macrophages. Metastatic lymph nodes were produced in BALB/c nude mice. We administrated 2×106 macrophages labeled with 50 µg Fe/mL FIONs intravenously into the mice. In the 3D T2* GRE MR images obtained one day after the injection of the labeled macrophages or FION solution, the percentages of pixels in the tumors or LNs below the minimum normalized SI (signal intensity) threshold were summated and reported as the black pixel count (%) for the FION hypointensity. Tumors in the main tumor model as well as the brachial, axillary and inguinal lymph nodes in the metastatic LN models were removed and stained. For all statistical analyses, single-group data were assessed using t test or the Mann-Whitney test. Repeated measurements analysis of variance (ANOVA) with Tukey–Kramer post hoc comparisons were performed for multiple comparisons.ConclusionsThe FION-labeled macrophages, which could be non-invasively monitored using a 1.5 T clinical MR scanner, targeted both the main tumors and LN metastases. Overall, the results of this study suggest that the use of macrophages may have many future applications in the clinic for vectorizing therapeutic agents toward main tumors as well as LN metastases.

The Smart Targeting of Nanoparticles

“…Basel and coworkers demonstrated that targeting ligands may not always be necessary for effective nanoparticle targeting via the exploitation of high concentrations of cancer-associated protease (CAP), such as urokinase plasminogen activator (uPA), matrix metalloproteases (MMPs), and some cathepsins, in dysplastic tissues [95]. In a radical shift of nanoparticle targeting strategy, Choi and Kennedy demonstrated that macrophages and human T cells could be loaded with gold nanoparticles (AuNPs) and used to deliver those AuNPs to tumor sites [96, 97]. Building off early bacteriophage work by Smith [98], many studies have used bacteriophages as nanoparticle platforms presenting weakly immunogenic targets for the purpose of provoking immune responses [99-102].…”

A block copolymer-stabilized co-precipitation approach to magnetic iron oxide nanoparticles for potential use as MRI contrast agents

“…Feridex® and Resovist®) have been FDA-approved and used in the clinic as T 2 -weighted MRI contrast agents to detect hepatic lesions and hypervascular hepatocellular carcinoma. [5][6][7][8] Gadolinium contrast agents are currently favoured over IONP contrast agents as the images they produce are easily interpreted by radiologists, however, iron oxide-based contrast agents have a potentially lower toxicity than gadolinium [9][10][11][12] and IONPs have been successfully used to study the role of macrophages in inammatory processes [13][14][15] and to label stem cells in vivo. 16,17 'Naked' IONPs in solution are susceptible to agglomeration and precipitation as they are unstable in biological media.…”

Metastatic breast cancer cells in lymph nodes increase nodal collagen density

“…A separate clinical study of fifty breast cancer patients and 34 healthy controls showed higher levels of gelatinase-A (MMP-2) and gelatinase-B (MMP-9) in sentinel lymph nodes containing macroscopic metastatic nodules with respect to lymph nodes that were free of cancer cells 19 . An increased number of macrophages was observed in the draining lymph nodes of breast cancer patients, in which these macrophages were shown to phagocytose keratinic debris 20 .…”