Human mesenchymal stromal cells as cellular drug-delivery vectors for glioblastoma therapy: a good deal?

Abstract

BackgroundGlioblastoma (GB) is the most malignant brain tumor in adults. It is characterized by angiogenesis and a high proliferative and invasive capacity. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) is of limited efficacy. Innovative anticancer drugs targeting both tumor cells and angiogenesis are urgently required, together with effective systems for their delivery to the brain. We assessed the ability of human mesenchymal stromal cells (MSCs) to uptake the multikinase inhibitor, sorafenib (SFN), and to carry this drug to a brain tumor following intranasal administration.MethodMSCs were primed with SFN and drug content and release were quantified by analytical chemistry techniques. The ability of SFN-primed MSCs to inhibit the survival of the human U87MG GB cell line and endothelial cells was assessed in in vitro assays. These cells were then administered intranasally to nude mice bearing intracerebral U87MG xenografts. Their effect on tumor growth and angiogenesis was evaluated by magnetic resonance imaging and immunofluorescence analyses, and was compared with the intranasal administration of unprimed MSCs or SFN alone.ResultsMSCs took up about 9 pg SFN per cell, with no effect on viability, and were able to release 60% of the primed drug. The cytostatic activity of the released SFN was entirely conserved, resulting in a significant inhibition of U87MG and endothelial cell survival in vitro. Two intranasal administrations of SFN-primed MSCs in U87MG-bearing mice resulted in lower levels of tumor angiogenesis than the injection of unprimed MSCs or SFN alone, but had no effect on tumor volume. We also observed an increase in the proportion of small intratumoral vessels in animals treated with unprimed MSCs; this effect being abolished if the MSCs were primed with SFN.ConclusionWe show the potential of MSCs to carry SFN to brain tumors following an intranasal administration. However, the therapeutic effect is modest probably due to the pro-tumorigenic properties of MSCs, which may limit the action of the released SFN. This calls into question the suitability of MSCs for use in GB therapy and renders it necessary to find methods guaranteeing the safety of this cellular vector after drug delivery.

Development and characterization of sorafenib-loaded lipid nanocapsules for the treatment of glioblastoma

“…An HPLC-UV method was used to quantify SFN, as previously described (Clavreul et al., 2017 ). Briefly, HPLC was performed on a Waters modular system (600/717/996/2414) (Waters, Saint-Quentin-en-Yvelynes, France) with a SunFire ® C18 column (150 × 4.6 mm; 5 μm) at 37 °C.…”

“…A specific LC-MS/MS method was previously developed (Clavreul et al., 2017 ). Briefly, chromatography was performed on a Waters Alliance ® 2695 system with an Uptisphere ® 5 0DB (150 × 2.0 mm) column, at 25 °C, using an isocratic mixture of 0.1% formic acid in water/0.1% formic acid in acetonitrile: 20/80 (v/v) at a flow rate of 0.3 mL/min.…”

“…Systems for delivering SFN for local or systemic treatment are, therefore, required, to improve the anti-GB activity of this drug. We recently showed that mesenchymal stromal cells (MSCs) have the potential to transport SFN to brain tumors following intranasal administration (Clavreul et al., 2017 ). However, the therapeutic effect was modest, probably due to the pro-tumorigenic properties of the MSCs themselves, which may counteract the action of the released SFN.…”

<p>Nanocarriers and nonviral methods for delivering antiangiogenic factors for glioblastoma therapy: the story so far</p>

“…Several studies have indicated that MSCs promote angiogenesis by secreting angiogenic factors, such as VEGF, releasing exosomes, recruiting endothelial progenitors, and/or transdifferentiating into endothelial cells. 104,105 Our previous studies 96,106 showed no effect of unprimed MSCs on tumor volume or the proportion of Ki67 + tumor cells in the human U87MG GB model, but MSCs have been reported to facilitate tumor growth by secreting various anti-inflammatory cytokines and proangiogenic factors. [100][101][102][103] Furthermore, MSCs can differentiate into cancer-associated fibroblasts (CAFs), which have been detected in the stroma of carcinomas and are known to promote tumor growth.…”

“…We recently showed that MSCs can deliver the chemotherapy drug ferrociphenol and the antiangiogenic TKI SFN to brain tumors without the need for genetic modification. 95,96 MSCs can be primed in vitro with SFN, with no effect on viability, and can release 60% of the drug with which they are loaded. The cytostatic activity of the released SFN was entirely conserved, significantly decreasing the survival of human U87MG GB cells and endothelial cells in vitro.…”