Nanomedicinal strategies to treat multidrug-resistant tumors: current progress

Abstract

Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. P-glycoprotein is an important and the best-known membrane transporter involved in MDR. Several strategies have been used to address MDR, especially P-glycoprotein-mediated drug resistance in tumors. However, clinical success has been limited, largely due to issues regarding lack of efficacy and/or safety. Nanoparticles have shown the ability to target tumors based on their unique physical and biological properties. To date, nanoparticles have been investigated primarily to address P-glycoprotein and the observed improved anticancer efficacy suggests that nanomedicinal strategies provide a new opportunity to overcome MDR. This article focuses on nanotechnology-based formulations and current nanomedicine approaches to address MDR in tumors and discusses the proposed mechanisms of action.

Figure 1. Summary of the mechanisms in which cultured cancer cells have been shown to become resistant to cytotoxic anticancer drugs

The efflux pumps at the plasma membrane include P-glycoprotein, multidrug resistance protein family members and breast cancer resistance protein. Adapted from [42].

Figure 2. Topology model of P-glycoprotein

Each hydrophobic domain is followed by a hydrophilic domain (ATP-binding domain) containing a nucleotide-binding site that is located at the cytoplasmic face of the membrane and couples ATP hydrolysis.

Figure 3. Enhanced drug delivery to solid tumors using nanoparticles

(A) Passive targeted delivery. After intravenous injection, nanoparticles accumulate in tumors through leaky and permeable tumor vasculature and impaired lymphatic system (e.g., enhanced permeability and retention effect). (B) Active targeted delivery. Ligand-coated nanoparticles bind to a cancer cell receptor resulting in cell-specific recognition and improved drug delivery to solid tumors.