Nanocarriers targeting cancer stem cells: how to help drugs to find their way home.

Abstract

The concept of tumor-initiating cells, or cancer stem cells (CSCs), has gained significant attention in recent years in the field of cancer research. Although the CSC theory was suggested several decades ago, the identification of small subpopulations of CSCs from blood mononuclear cells in human acute myeloid leukemia in 1997 was a milestone discovery that recognizes the potential function of CSCs in tumor aggressiveness [1]. Afterwards, CSCs have been found in several different types of cancer, and their presence has been, at least in part, related to the development of cancer resistance, together with rapid tumor growth, disease progression/recurrence and migration/invasion [2]. CSCs share some common properties with normal stem cells. Two of them are relevant for the development and recurrence of both solid and liquid tumors: their self-renewal capacity and their highly uncontrolled differentiation capacity into multiple different cancer cell lineages. Moreover, CSCs also express characteristic surface markers, which can be used for subpopulation identification. These findings suggest that CSCs may be interesting therapeutic targets for the treatment of cancer progression/recurrence, as they seem to be implicated in cancer cell migration, invasion, metastasis and treatment resistance, all of which lead to poor clinical outcomes [2,3]. However, it has been demonstrated that CSCs are substantially more resistant to standard forms of chemotherapy than bulk cancer cell populations, mainly, but not only, due to their quiescent nature. For example, acute myeloid leukemia stem cells profit of peculiar, spatial niches, with ‘commodities’, like different oxygen tension, different pH, as well as different ‘spatial gradients’, all contributing to their preservation from external harming. The current treatment modalities fail poorly in tackling CSCs and, paradoxically, chemotherapy [4] and radiation therapy [5] have been shown to increase CSC population [2]. More than a few small molecular compounds are able to efficiently target CSCs in vitro, and some of them, such as tariquidar, piperine, curcumin and metformin, have been used, alone or in combination, with conventional chemotherapeutic agents in clinical trials. However, given the promising potential of these small compounds to increase drug exposure in chemo-resistant cancers, they are hampered by a high rate of severe nonhematological toxicities, short half-life and lack of water solubility. Therefore, as well as the major hurdles in treating cancer are the limits and disadvantages of most chemotherapeutic drugs, such as the lack of specificity toward cancer cells, high dosages associated toxicity, nontargeted accumulation, fast elimination, poor solubility and short in vivo half-lives, all the same this limits reduce the wide clinical application of small molecules targeting CSCs. The use of drug delivery systems has reduced most of the potential disadvantages Nanocarriers targeting cancer stem cells: how to help drugs to find their way home