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Review
. 2021 Aug;11(8):2243-2264.
doi: 10.1016/j.apsb.2021.01.012. Epub 2021 Jan 24.

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

Edgar Pérez-Herrero  1   2   3 , Alberto Fernández-Medarde  4
Affiliations
Review

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

Edgar Pérez-Herrero et al. Acta Pharm Sin B. 2021 Aug.

Abstract

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.

Keywords: Cancer; Chemotherapy; Metabolism of glucose; Proton transport inhibitors; Proton-caged carriers; _targeted drug delivery; Warburg effect; pH-Gradient inversion; pH-Sensitive nanocarriers.

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Conflict of interest statement

These authors have no conflicts of interest to declare in this work.

Figures

Image 1
Graphical abstract
Figure 1
Figure 1
An increase in aerobic glycolysis to lactate in the tumor cells leads to an accumulation of protons that are actively removed from the cell by proton pumps (in light orange) and transporters (green). This activity produces an accumulation of protons in the extracellular media and a concomitant pH increase at the cytosol. The augmented glycolytic flux is driven by the action of several oncogenes (in bold red letters), that induce the expression and activation of most of the glycolytic enzymes. For a comprehensive review on the role of oncogenic signals in the control of glycolysis see reference 9. HK2: hexokinase 2; PFK1: phosphofructokinase 1; LDHA: lactate dehydrogenase A; GLUT1: glucose transporter 1; pHi: intracellular pH; pHe: extracellular pH.
Figure 2
Figure 2
Mechanism of action of lansoprazole. In acidic environments the sulfoxide residue in lansoprazole is transformed into a sulfenic acid, which can bind to cysteine 813 in the ATPase and inhibit proton transport to the stomach lumen. These inhibitors can be used in cancer to block acidification of the tumor microenvironment, but also to induce a reduction in intracellular pH that would lead to cell death.
Figure 3
Figure 3
Preparation protocol of paclitaxel (PTX) and lansoprazole (LPZ) loaded PLGA-based NPs by the double emulsion solvent evaporation method. The use of LPZ as PPI in combination with the protection provided by the PLGA-based NPs reduces the PTX resistance.
Figure 4
Figure 4
Carbonic anhydrases (CAs) as possible molecular _targets in cancer treatment (A) The family of the carbonic anhydrases comprise several members located either at the plasma membrane, in the cytosol or in the mitochondria. Among these pH regulators, CA9 and CA12 seem to have an important role in cancer, where they are usually overexpressed (B) Mechanism of action of sulphonamides in CA inhibition. CAs need a zinc residue bound to three histidines for the catalytic reaction. Sulphonamides bind to this zinc atom and displaces a molecule of water that is needed for the transformation of CO2 into NCO3–.
Figure 5
Figure 5
Scheme of PEGylated CAI-conjugated Au-NPs for a pH-dependent and selective intracellular delivery of DOX. Reprinted with modifications by permission from Ref. 60. Copyright © 2018 American Chemical Society.
Figure 6
Figure 6
Mechanism of action of NBA-conjugated up-converting NPs. They absorb low-energy NIR light (980 nm) and emit high-energy UV light (350–400 nm) to generate intracellular acidification by the cleavage of NBA and the consequent release of protons inside the cancerous cell.
Figure 7
Figure 7
Mechanisms of action of pH-sensitive nanocarriers. Reprinted from Ref. 92. Copyright © 2015 with permission from Elsevier.
Figure 8
Figure 8
Scheme of siRNA-loaded PEGylated NPs that shows reduced non-specific interactions with blood proteins at physiological pH. However, at the slightly acidic pHe, PEG molecules are removed from the surface of the NPs because of their acid-cleavable DMMA linker, promoting the intracellular delivery of the siRNA. Reprinted with permission from Ref. 106. Copyright © 2012 American Chemical Society.
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