PET imaging of tumor associated macrophages using mannose coated 64Cu liposomes

Abstract

Macrophages within the tumor microenvironment (TAMs) have been shown to play a major role in the growth and spread of many types of cancer. Cancer cells produce cytokines that cause macrophages to express scavenger receptors (e.g. the mannose receptor) and factors that facilitate tissue and blood vessel growth, suppress T cell mediated anti-tumor activity, and express enzymes that can break down the extracellular matrix, thereby promoting metastasis. We have designed a mannosylated liposome (MAN-LIPs) and show that it accumulates in TAMs in a mouse model of pulmonary adenocarcinoma. These liposomes are loaded with (64)Cu to allow tracking by PET imaging, and contain a fluorescent dye in the lipid bilayer permitting subsequent fluorescence microscopy. We injected these liposomes into a mouse model of lung cancer. In vivo PET images were acquired 6 h after injection followed by the imaging of select excised organs. MAN-LIPs accumulated in TAMs and exhibited little accumulation in remote lung areas. MAN-LIPs are a promising new vehicle for the delivery of imaging agents to lung TAMs. In addition to imaging, MAN-LIPs hold the potential for delivery of therapeutic agents to the tumor microenvironment.

Remote Loading of 64Cu2+ into Liposomes without the Use of Ion Transport Enhancers

“…[7][8][9][10][11][12] So far, only a few ionophore assisted loading (IAL) procedures have been developed for liposomal PET imaging applications. 1,12,13 Despite the generally high loading efficiencies, high radionuclide retention, rapid loading kinetics and successful in vivo liposomal performance there are disadvantages of using transporter molecules such as ionophores or lipophilic chelators (hereafter referred to as ionophores as a common term) for remote loading of radionuclides into liposomes. One drawback to consider is the penalty in Gibbs free energy, which derives from stripping the radionuclide from the ionophore upon transfer to the liposome-entrapped chelator (Figure 1, right).…”

“…Common practice is therefore to use ionophores to increase the trans-membrane ion diffusion rate, and thereby improve the loading kinetics of charged ions such as radionuclides into liposomes. [7][8][9][10][11][12][13] Despite previous knowledge and findings within this field, the present work describes a novel loading method of the PET radionuclide 64 Cu 2+ into liposomes, excluding the use of ionophores (an unassisted loading). In this method, 64 Cu 2+ (or copper) is added to preformed liposomes entrapping a high affinity copper chelator (Figure 1, left).…”

Optical In Vivo Imaging of the Alarmin S100A9 in Tumor Lesions Allows for Estimation of the Individual Malignant Potential by Evaluation of Tumor–Host Cell Interaction

“…Within cell-tracking studies featuring either iron oxide-mediated MR imaging (29,30) or radionuclide imaging, for example, using 64 Cu-liposome labels for PET (31), the abundance of macrophages and other phagocytes in the tumor microenvironment could already be shown. Within this study, we present an approach for visualization of monocyte activity beyond sheer abundance in the primary tumor.…”

Nanotechnology Approaches for Cancer Immunotherapy and Immunomodulation

“…To avoid recognition by peripheral macrophages, some studies have dealt with the shield of surface-decorated nanocarriers using polymers that degrade due to environmental changes in the tumor microenvironment, such as a more acidic pH (Huang et al 2012 ;Zhu et al 2013 ). Biomarkers aberrantly expressed at the surface of TAMs include the mannose receptor (Movahedi et al 2012 ;Locke et al 2012 ;Zhu et al 2013 ), the galactose-type lectin (Mgl) receptor (Huang et al 2012 ), the folate receptor beta ( Nagai et al 2009 ), scavenger receptors such as CD163 ( Etzerodt et al 2012 ), and legumain (Luo et al 2006 ;Gomez-Cabrero et al 2013 ;Zhang et al 2013 ).…”