Mesenchymal STEM CELLS As Trojan Horses for the Selective Delivery of Nanoparticles to Tumors

A continuing challenge of cancer therapy is to attain sufficient selectivity by focusing the treatment in tumor cells, to avoid or minimize systemic side effects. Mesenchymal stem cells (MSCs) can be used as therapeutic vectors because of their ability to migrate and incorporate into inflammation areas such as tumors. Here, this homing ability is exploited to carry therapeutic nanoparticles (hollow Gold Nanoparticles (HGNs)) by a “Trojan-horse” strategy.

 Amongst the different nanoparticles that could be employed, HGNs have the capacity to resonate in the near infrared region when irradiated by a suitable light source. The absorbed energy is transformed into heat causing local hyperthermia and killing nearby tumor cells. At these wavelengths healthy tissues have a minimal light absorption, so the effect is restricted to the tissues containing HGNs. However, delivering a dose of HGNs to the tumor that is sufficient to achieve the desired thermal efects is challenging when the HGNs are intravenously administered, in spite of the so-called EPR effect that helps to accumulate nanoparticles of suitable size in tumors. This was clear in the results of our experiments with U251MG cell-line xenograft tumors, where a poor therapeutic result was obtained for PEG-HGNs injected intravenously in spite of their PEG coating. Two factors are likely contributing to this effect, on the one hand, the intrinsic heterogeneity of the EPR effect that leads to a variable distribution of plasmonic nanoparticles within the tumor. On the other, the fact that a significant fraction of the free PEG-HGNs injected intravenously are detected and cleared by RES macrophages, as shown by the gold accumulation found in the spleen and liver of the test animals, reducing the delivery of HGNs to the tumor Both problems were alleviated by using MSCs as carriers of those nanomaterials.

On the other hand, a successful internalization of both bare and PEGylated hollow gold nanoparticles was demonstrated in murine MSCs incubated with HGNs under suitable conditions. The HGNs remain inside the cells for at least one week, a period sufficient for the MSCs to reach tumor sites. Taking advantage of the tumor-homing ability of nanoparticle-loaded MSCs, a more homogeneous nanoparticle distribution across the tumoral tissue was obtained, as demonstrated by histological analysis of treated tumors, and this phenomenon increased the efficiency obtained when applying photothermal therapy on subcutaneous xenograft glioma. The immunohistochemical analysis also confirmed the efficiency of photothermal theraphy, especially in those tumors where gold nanoparticles had been delivered by MSCs. Therefore the Trojan Horse strategy outperforms the EPR (Enhanced Permeation and Retention) effect, commonly exploited in the delivery of nanoparticles to tumors.

Finally, in this work we also demonstrate how MSCs internalize the HGNs and after intravenous administration they reach the tumors still loaded with HGNs. Interestingly, internalization of HGNs affects the motility of MSCs (as evidenced by would healing experiments) and the expression of some key constituent proteins. This opens up numerous opportunities to exploit MSCs as carriers of different functional nanoparticles.