Directing cell therapy to anatomic target sites in vivo with magnetic resonance targeting.

Munitta Muthana,Mark F Lythgoe,Craig Murdoch,Joe Conner,Russell Hughes,Neil Farrow,Aneurin J Kennerley,Christopher Payne,Claire Lewis,Melanie Paul,Ester Fagnano,Jon Dobson,Jim M Wild,Jay Richardson,Fiona Wright

doi:10.1038/ncomms9009

Abstract

Cell-based therapy exploits modified human cells to treat diseases but its targeted application in specific tissues, particularly those lying deep in the body where direct injection is not possible, has been problematic. Here we use a magnetic resonance imaging (MRI) system to direct macrophages carrying an oncolytic virus, Seprehvir, into primary and metastatic tumour sites in mice. To achieve this, we magnetically label macrophages with super-paramagnetic iron oxide nanoparticles and apply pulsed magnetic field gradients in the direction of the tumour sites. Magnetic resonance targeting guides macrophages from the bloodstream into tumours, resulting in increased tumour macrophage infiltration and reduction in tumour burden and metastasis. Our study indicates that clinical MRI scanners can not only track the location of magnetically labelled cells but also have the potential to steer them into one or more target tissues.

Highlights

Cell-based therapy exploits modified human cells to treat diseases but its targeted application in specific tissues, those lying deep in the body where direct injection is not possible, has been problematic
When macrophages were found to accumulate in large numbers in avascular hypoxic/necrotic areas of such tissues in mice and humans[17,25,26], we suggested that these cells could be used to deliver therapeutic agents such as oncolytic viruses (OVs) to these poorly vascularized, and relatively inaccessible, areas of tumours[17]
We show that magnetic resonance targeting (MRT) can be used to increase the number of OV-loaded macrophages in primary and metastatic tumours in mice

Summary

Introduction

Cell-based therapy exploits modified human cells to treat diseases but its targeted application in specific tissues, those lying deep in the body where direct injection is not possible, has been problematic. Previous studies have shown that magnetic particles or cells loaded with super-paramagnetic iron oxide nanoparticles (SPIOs) can be injected systemically and attracted to a target tissue in mice by the application of a local external magnet[2,3,4,5,6]. Bone marrow-derived cells are increasingly being used in cell-based therapies for such diseases as infarcted myocardium[11], spinal cord injury[12], cerebral ischaemia[13] and degenerative diseases such as Parkinson’s disease[14], Alzheimer’s disease[15] and cancer[16,17,18] In the latter disease, numerous clinical trials have administered bone marrow-derived cells systemically in an attempt to treat malignant tumours, including T cells[19,20], dendritic cells[21], macrophages[22,23] and stem cells[24]. This lack of targeting reduces the therapeutic efficacy and increases the risk of side effects

Methods

Results

Conclusion