The reversed intra- and extracellular pH in tumors as a unified strategy to chemotherapeutic delivery using targeted nanocarriers.

Solid tumors are complex entities, comprising a wide variety of malignancies with very different molecular alterations. Despite this, they share a set of characteristics known as "hallmarks of cancer" that can be used as common therapeutic targets. Thus, every tumor needs to change its metabolism in order to obtain the energy levels required for its high proliferative rates, and these adaptations lead to alterations in extra- and intracellular pH. These changes in pH are common to all solid tumors, and can be used either as therapeutic targets, blocking the cell proton transporters and reversing the pH changes, or as means to specifically deliver anticancer drugs. In this review we will describe how proton transport inhibitors in association with nanocarriers have been designed to block the pH changes that are needed for cancer cells to survive after their metabolic adaptations. We will also describe studies aiming to decrease intracellular pH in cancer using nanoparticles as molecular cages for protons which will be released upon UV or IR light exposure. Finally, we will comment on several studies that have used the extracellular pH in cancer for an enhanced cell internalization and tumor penetration of nanocarriers and a controlled drug delivery, describing how nanocarriers are being used to increase drug stability and specificity.