Hyperthermia treatment of tumors by mesenchymal stem cell-delivered superparamagnetic iron oxide nanoparticles

Abstract

Magnetic hyperthermia – a potential cancer treatment in which superparamagnetic iron oxide nanoparticles (SPIONs) are made to resonantly respond to an alternating magnetic field (AMF) and thereby produce heat – is of significant current interest. We have previously shown that mesenchymal stem cells (MSCs) can be labeled with SPIONs with no effect on cell proliferation or survival and that within an hour of systemic administration, they migrate to and integrate into tumors in vivo. Here, we report on some longer term (up to 3 weeks) post-integration characteristics of magnetically labeled human MSCs in an immunocompromized mouse model. We initially assessed how the size and coating of SPIONs dictated the loading capacity and cellular heating of MSCs. Ferucarbotran ® was the best of those tested, having the best like-for-like heating capability and being the only one to retain that capability after cell internalization. A mouse model was created by subcutaneous flank injection of a combination of 0.5 million Ferucarbotran-loaded MSCs and 1.0 million OVCAR-3 ovarian tumor cells. After 2 weeks, the tumors reached ~100 µL in volume and then entered a rapid growth phase over the third week to reach ~300 µL. In the control mice that received no AMF treatment, magnetic resonance imaging (MRI) data showed that the labeled MSCs were both incorporated into and retained within the tumors over the entire 3-week period. In the AMF-treated mice, heat increases of ~4°C were observed during the first application, after which MRI indicated a loss of negative contrast, suggesting that the MSCs had died and been cleared from the tumor. This post-AMF removal of cells was confirmed by histological examination and also by a reduced level of subsequent magnetic heating effect. Despite this evidence for an AMF-elicited response in the SPION-loaded MSCs, and in contrast to previous reports on tumor remission in immunocompetent mouse models, in this case, no significant differences were measured regarding the overall tumor size or growth characteristics. We discuss the implications of these results on the clinical delivery of hyperthermia therapy to tumors and on the possibility that a preferred therapeutic route may involve AMF as an adjuvant to an autologous immune response.

Human mesenchymal stem cell-derived iron oxide exosomes allow targeted ablation of tumor cells via magnetic hyperthermia

“…Kalber et al reported migration and integration of systemically administered SPION-labeled MSCs in ovarian tumor nude mouse model. 3 They found that even though the nanocarrier was able to accumulate into tumors, the amount of magnetic nanoparticles was not necessarily enough to promote hyperthermia in order to treat cancer exclusively by heat delivery 14 days after the administration of labeled MSCs. Studies of biodistribution, migration, and homing of systemically applied MSCs revealed that 80% of cells are immediately entrapped in the lung tissue and then cleared to the liver within 1 day.…”

“…[1][2][3] This approach involves targeting magnetic nanoparticles to tumors and then inducing cytotoxic hyperthermia by applying an alternating magnetic field (AMF). Iron oxide nanoparticles are optimal for inducing hyperthermia, and their effectiveness as a cancer therapeutic should be evaluated according to the following criteria: 1) they should selectively target tumor cells, 2) they should easily penetrate tumor cells, 3) they should be internalized by tumor cells, 4) they should be biocompatible and nontoxic across a wide range of concentrations, 5) they should be easy to administer in the clinic, 6) they should be likely to be approved for clinical use, and 7) they should be targetable to specific tumor types or to organs with metastases.…”

“…Iron oxide-labeled cells migrate to and integrate into tumors. 3,15 Recently, we reported a simple procedure to label MSCs of the human dental pulp (DP-MSCs) and DP-MSCs expressing the yCD::UPRT fusion gene with iron oxide (Venofer). We found that both Venoferlabeled and Venofer-unlabeled DP-MSCs and yCD::UPRT-DP-MSCs released exosomes into the conditioned medium (CM).…”

Molecular Imaging in Nanotechnology and Theranostics

“…Aminosilane-coated iron oxide (NanoTherm), significantly polarized under external magnetic fields to selectively ablate tumors by heat generation, is undergoing clinical trials in the USA [118-120]. FDA-approved SPIONs were also found to inhibit tumor growth by hyperthermia under magnetic fields at preclinical levels [121-123]. The integration of multiple energies and modalities is a unique characteristic of nanoparticles that will make them invaluable for detection and therapy in a wide variety of diseases.…”

Dynamic imaging of allogeneic adipose-derived regenerative cells transplanted in ischemic hind limb of apolipoprotein E mouse model

“…15,16 The superiority of MRI in tracking and monitoring transplanted stem cells has been established using different cell types, such as bone mesenchymal stem cells (BMSCs), peripheral blood stem cells, and embryonic stem cells. 17 Superparamagnetic iron oxide (SPIO) nanoparticles are the most sensitive MRI contrast agents used in cell labeling. They are safe and biodegradable, and they do not affect the proliferation and differentiation capacity of implanted cells in vitro and in vivo.…”