Drug-loaded nanoparticle systems and adult stem cells: a potential marriage for the treatment of malignant glioma?

Abstract

Despite all recent advances in malignant glioma research, only modest progress has been achieved in improving patient prognosis and quality of life. Such a clinical scenario underscores the importance of investing in new therapeutic approaches that, when combined with conventional therapies, are able to effectively eradicate glioma infiltration and target distant tumor foci. Nanoparticle-loaded delivery systems have recently arisen as an exciting alternative to improve targeted anti-glioma drug delivery. As drug carriers, they are able to efficiently protect the therapeutic agent and allow for sustained drug release. In addition, their surface can be easily manipulated with the addition of special ligands, which are responsible for enhancing tumor-specific nanoparticle permeability. However, their inefficient intratumoral distribution and failure to target disseminated tumor burden still pose a big challenge for their implementation as a therapeutic option in the clinical setting. Stem cell-based delivery of drug-loaded nanoparticles offers an interesting option to overcome such issues. Their ability to incorporate nanoparticles and migrate throughout interstitial barriers, together with their inherent tumor-tropic properties and synergistic anti-tumor effects make these stem cell carriers a good fit for such combined therapy. In this review, we will describe the main nanoparticle delivery systems that are presently available in preclinical and clinical studies. We will discuss their mechanisms of targeting, current delivery methods, attractive features and pitfalls. We will also debate the potential applications of stem cell carriers loaded with therapeutic nanoparticles in anticancer therapy and why such an attractive combined approach has not yet reached clinical trials.

Figure 1. Incorporation, trafficking, endosomal escape and sustained drug release of nanoplatforms into stem cell carriers

Three mechanisms of nanoparticle incorporation into cell carriers are depicted here: caveolin-mediated endocytosis, clathrin-mediated endocytosis and passive transport. Drug-loaded nanocarriers coated with cationic charges or tumor-specific ligands are incorporated into stem cells. By different mechanisms (see text) endo-lysosomal escape takes place. Drug-loaded nanoparticles then accumulate in the cytosol. Nanoparticle accumulation and sustained drug release in the cytoplasm of the cell carrier leads to membrane disruption and targeted drug release to tumor cells.

Figure 2. Intraoperative transplantation of stem cells carrying drug-loaded nanoparticles into the human brain post-tumor resection

Chronological order of the events that take place post-surgical transplantation. Here, stem cell carriers' tumor-tropic migration results in a targeted drug release in infiltrative tumor zones. Modified cell carriers contribute to the local toxic effects caused by the drug-loaded system in neoplastic areas. Stem cells' immunosuppressive properties hide loaded nanocarriers from the host-immune system and facilitate targeted anti-glioma therapy.