Targeting cellular and microenvironmental multidrug resistance

Abstract

Multidrug resistance (MDR) is one of the major factors restricting the efficacy of chemotherapy. Several pathophysiological mechanisms contribute to MDR, including the overexpression of drug efflux pumps. Strategies to overcome MDR have mostly focused on the modulation of cellular resistance, such as the use of drugs and drug delivery systems to inhibit or bypass drug efflux pumps. Much less attention has been devoted to microenvironmental resistance, both mechanistically and therapeutically. As a reciprocal response to cellular MDR, cancer cells might remodel their microenvironment, resulting in changes in vascularization and oxygenation, as well as in the expression of cell adhesion molecules, extracellular matrix components and matrix metalloproteinases. We here describe the basic principles of cellular and microenvironmental MDR, and discuss drug delivery systems and drug targeting strategies to more efficiently deal with cellular and microenvironmental resistance.

Keywords: Multi drug resistance; cancer; drug delivery; nanomedicine; tumor microenvironment.

Figure 1

Schematic representation of nanomedicine-based strategies for overcoming cellular MDR. (A) Classical approach using drug-loaded nanomedicines which are endocytosed to bypass drug efflux pumps. (B) Pluronic-based nanomedicines possess multiple intrinsic anti-MDR properties which are schematically indicated by numbers (see [4] for details). (C) Combinatorial nanotherapy with a drug efflux pump inhibitor and a chemotherapeutic agent. (D) Co-encapsulation of anti-MDR siRNA together with a chemotherapeutic drug. Images adapted, with permission, from [, and 12].

Figure 2

The reciprocal interaction between cancer cells and their tumor microenvironment (TME) is schematically depicted. The microenvironment promotes cellular resistance via mechanisms such as low pH, hypoxia and cell adhesion-mediated drug resistance (CAM-DR). Vice versa, cancer cells promote microenvironmental resistance via the expression of cell adhesion molecules and matrix metalloproteinases (MMPs).