Overcoming multidrug resistance in cancer: Recent progress in nanotechnology and new horizons

Abstract

Multidrug resistance (MDR), defined as the ability of cancer cells to gain resistance to both conventional and novel chemotherapy agents, is an important barrier in treating malignancies. Initially, it was discovered that cellular pumps dependent on ATP were the cause of resistance to chemotherapy, and further studies have found that other mechanisms such as increased metabolism of drugs, decreased drug entry, and defective apoptotic pathways are involved in this process. MDR has been the focus of numerous initiatives and countless studies have been undertaken to better understand MDR and formulate strategies to overcome its effects. The current review highlights various nano‐drug delivery systems including polymeric/solid lipid/mesoporous silica/metal nanoparticles, dendrimers, liposomes, micelles, and nanostructured lipid carriers to overcome the mechanism of MDR. Nanoparticles are novel gateways to enhance the therapeutic efficacy of anticancer agents at the target site of action due to their tumor‐targeting abilities, which can limit the unwanted systemic effects of chemotherapy agents and also reduce drug resistance. Additionally, other innovative strategies including RNA interference as a biological process used to inhibit or silence specific gene expression, natural products as MDR modulators with little systemic toxic effects, which interfere with the functions of proteins involved in drug efflux, and physical approaches such as combination of conventional drug administration with thermal/ultrasound/photodynamic strategies are also highlighted.

The Effect of Nanosystems on ATP-Binding Cassette Transporters: Understanding the Influence of Nanosystems on Multidrug Resistance Protein-1 and P-glycoprotein

“…Multidrug resistance is a multifactorial biological process that indicates a phenotype in malignant tumor cells in which they are resistant to structurally and functionally unrelated compounds, surviving chemotherapy [14]. MDR can be present on the get go of the first treatment for some tumors (e.g., pancreatic and lung cancer) or can be developed after a few cycles of chemotherapy [18].…”

“…A relatively new and more promising approach in cancer chemotherapy is the use of various nanosystems for drug delivery to achieve higher specificity and less toxicity [14]. In addition, nanomaterials are also a very powerful tool for tissue imaging for diagnostics and monitoring the progress of treatment [53].…”

“…It is a phenomenon that has been receiving great attention in the last 50 years [6,7] due to the sheer amount of mechanisms discovered and involved in the process of resistance which hinders the effectiveness of many anti-cancer drugs [8][9][10][11][12][13]. It is a challenge that needs to be further investigated and overcome and is a paramount factor in cancer recurrence and low survival rates [14][15][16][17]…”

“…ABC transporters have been used as targets by selective modulators aiming to reduce its activity or revert the resistant phenotype in cancer, increasing the concentration of anti-neoplastic drugs in cells [22,25,28]. This rationale can be achieved by using molecules and/or monoclonal antibodies that will interact directly with the transporters extracellularly or act as an antagonist in the cytoplasm [14]. Another strategy is to use interference RNA (RNAi) to silence the expression of ABC genes [5].…”

“…However, the first (e.g., Verapamil, Cyclosporin, Tamoxifen, Calmodulin) and second (e.g., Dexverapamil, Valspodar, Biricodar) generation of inhibitors were not successful in trials due to nonspecificity, the need of high concentrations that lead to toxicity, alteration of the pharmacokinetics of cytotoxic drugs due to drug-drug interactions in co-administration and formulation problems (e.g., solubility, biocompatibility, stability) [14,18]. The third (e.g., Laniquidar, Elacridar, Tariquidar) and fourth generation (e.g., Neochamaejasmin B, Curcumin) of modulators are promising candidates since they show less influence in pharmacokinetics and less toxicity [35,36].…”