Abstract
Despite advances in cancer therapies, nanomedicine approaches including the treatment of glioblastoma (GBM), the most common, aggressive brain tumor, remains inefficient. These failures are likely attributable to the complex and not yet completely known biology of this tumor, which is responsible for its strong invasiveness, high degree of metastasis, high proliferation potential, and resistance to radiation and chemotherapy. The intimate connection through which the cells communicate between them plays an important role in these biological processes. In this scenario, tunneling nanotubes (TnTs) are recently gaining importance as a key feature in tumor progression and in particular in the re-growth of GBM after surgery. In this context, we firstly identified structural differences of TnTs formed by U87-MG cells, as model of GBM cells, in comparison with those formed by normal human astrocytes (NHA), used as a model of healthy cells. Successively, we have studied the possibility to exploit U87-MG TnTs as drug-delivery channels in cancer therapy, using liposomes composed of cholesterol/sphingomyelin and surface functionalized with mApoE and chlorotoxin peptides (Mf-LIP) as nanovehicle model. The results showed that U87-MG cells formed almost exclusively thick and long protrusions, whereas NHA formed more thin and short TnTs. Considering that thick TnTs are more efficient in transport of vesicles and organelles, we showed that fluorescent-labeled Mf-LIP can be transported via TnTs between U87-MG cells and with less extent through the protrusions formed by NHA cells. Our results demonstrate that nanotubes are potentially useful as drug-delivery channels for cancer therapy, facilitating the intercellular redistribution of this drug in close and far away cells, thus reaching isolated tumor niches that are hardly targeted by simple drug diffusion in the brain parenchyma. Moreover, the differences identified in TnTs formed by GBM and NHA cells can be exploited to increase treatment precision and specificity.
Highlights
The limits of conventional therapies against tumors, in terms of effectiveness/damage ratio, lead to the development and application in clinics of different nanotechnological drugs in the last 25 years (Stupp et al, 2009)
The results showed that DOX-LIP displayed a diameter of 121 ± 6 nm with a polydispersity index (PDI) value of 0.098 ± 0.01; the ζ -potential was −19.32 ± 0.58 mV
In the context of searching more effective therapies against GBM, which remains an incurable brain tumor, we focus our attention on the cell communication
Summary
The limits of conventional therapies against tumors, in terms of effectiveness/damage ratio, lead to the development and application in clinics of different nanotechnological drugs in the last 25 years (Stupp et al, 2009). Intrinsic brain tumors, are a dissimilar group of oncological diseases for which there is currently no cure, and only very limited progress has been made in the control of the disease course over the past three decades (Westphal and Lamszus, 2011). Glioblastoma multiforme (GBM, called grade IV astrocytoma) is one of the most deadly brain tumors, with a short median patient survival and a very limited response to therapies (Louis et al, 2016). In this context, many efforts are underway toward the development of new therapeutic approaches and nanomedicine seems to be one of the most promising. An important component of tumor growth is communication within cancer cells and with other cells in the microenvironments, which strengthen tumor progression and resistance to radiotherapy and chemotherapy (Broekman et al, 2018)
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