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Despite the progress in cancer treatment over the past years advanced cancer is still an incurable disease. Special attention is pointed toward cancer stem cell (CSC)-targeted therapies, because this minor cell population is responsible for the treatment resistance, metastatic growth and tumor recurrence. The recently described CSC dynamic phenotype and interconversion model of cancer growth hamper even more the possible success of current cancer treatments in advanced cancer stages. Accordingly, CSCs can be generated through dedifferentiation processes from non-CSCs, in particular, when CSC populations are depleted after treatment. In this context, the use of targeted CSC nanomedicines should be considered as a promising tool to increase CSC sensitivity and efficacy of specific anti-CSC therapies.

Aim: The design of novel F3-targeted liposomes with adequate features for systemic administration, to enable efficient intracellular delivery of siRNA toward both cancer and endothelial cells from angiogenic blood vessels. Materials & methods: Cellular association studies were performed by flow cytometry. Gene silencing was evaluated with eGFP-overexpressing cells, by flow cytometry and real-time reverse-transcription PCR. Safety and immunogenicity was assessed in CD1 mice. Results: A strong improvement on siRNA internalization by the target cells was achieved, which was correlated with effective downregulation of eGFP. In addition, the F3-targeted liposomes were nonimmunogenic, even in a multiadministration schedule. Conclusion: Overall, the developed F3-targeted nanocarrier constitutes a valuable tool for the specific and safe systemic delivery of siRNA to solid tumors. Original submitted 19 April 2012; Revised submitted 12 September 2012; Published online 8 February 2013

The presence of highly resistant cancer stem cells (CSCs) within tumors as drivers of metastatic spread has been commonly accepted. Nonetheless, the likelihood of its dynamic phenotype has been strongly discussed. Importantly, intratumoral cell-to-cell communication seems to act as the main regulatory mechanism of CSC reversion. Today, new strategies for cancer treatment focusing into modulating tumor cell intercommunication and the possibility to modulate the composition of the tumor microenvironment are being explored. In this review, we summarize the literature describing the phenomenon of CSC reversion and the factors known to influence this phenotypic switch. Furthermore, we will discuss the possible role of nanomedicine toward altering this reversion, and to influence the tumor microenvironment composition and the metastatic spread of the disease.