Nanomaterials for reversion of multidrug resistance in cancer: a new hope for an old idea?

Cancer is a major cause of mortality in the modern world, with more than 10 million new cases every year. This outline is expected to rise in the next few decades since the majority (59%) of people diagnosed with cancer is aged over 65. In fact, around one in three people will be diagnosed with cancer throughout their lifetime (Siegel et al., 2012; Bosetti et al., 2013). The foundation of cancer treatment is surgery, chemotherapy, radiation, antibody-blocking therapy, or a combination of these therapies (Hanahan and Weinberg, 2000). Still, many clinical chemotherapeutic and radiotherapeutic regimes are not exceptionally effective, due to multidrug resistance mechanisms, depending on the patient and the type of tumor. Therefore, there is an urgent need for more effective and valuable cancer therapeutics, in order to reduce the impact of the chemotherapeutic agents on the healthy tissues by creating more selective systems toward the cancerous cells (Alison, 2001; Perez-Tomas, 2006). Multi-drug resistance (MDR) in cancer refers to the capacity of cancer cells to survive or become resistant from treatment of a wide variety of drugs. Cancer chemotherapy has become progressively sophisticated within the last years; however there are not any cancer therapies 100% effective against disseminated cancer. This is in fact a major problem once approximately 70% of patients do not respond to initial chemotherapy and the five-year survival rate for these patients is a low 10–30%. Relapse is also frequent (Diseases, 2000). Mechanisms of MDR include decreased uptake of drugs, reduced intracellular drug concentration by activation of the efflux transporters, modifications in cellular pathways by altering cell cycle checkpoints, increased metabolism of drugs, induced emergency response genes to impair apoptotic pathways and altered DNA repair mechanisms (Gottesman, 2002). P-glycoprotein (P-gp) is the best known membrane transporter used in MDR and has been first described in the late 1970s (Juliano and Ling, 1976). Since then, the phenomenon of cancer drug resistance became a hotspot of cancer research (Gottesman, 2002; Ullah, 2008). Despite of the discovery of multiple new gene/protein expression signatures or factors associated with drug resistance by high throughput “-omics” technologies, none of these findings has been useful in producing efficient and specific diagnostic assays or for improvement of updated chemosensitizers. Clinical success has also been limited due to issues regarding safety, once one of the most common strategies against MDR is the development of ATP-binding cassette (ABC) transporter inhibitors, which are poorly effective and specific, increasing the toxicity associated with chemotherapy (Lage, 2008). Nanotechnology and nanomaterials in particular, are expected to provide a range of devices to treat cancer as their sizes are well matched in size to biologic molecules and structures found inside living cells (Conde et al., 2012). The development of nanoscale devices and structures has provided major breakthroughs in monitoring and fighting cancer (Qian et al., 2008; Ren et al., 2012; Conde et al., 2013). Cancer nanotechnology offers a wealth of safety and innovative tools to treat and diagnose cancer, such as multifunctional, targeted devices capable of bypassing crucial biological barriers and to deliver multiple therapeutic agents directly to cancer cells and adjacent tissues around tumor microenvironment (Sanvicens and Marco, 2008). Nanoparticles (NPs) are usually produced to deliver and enhance the drug concentration inside the cancer cells, using both active and passive targeting. (NPs) are excellent tumor-targeting vehicles because of the unique inherent property of solid tumors. Numerous tumors present with defective vasculature and poor lymphatic drainage, due to their rapid growth, resulting in an enhanced permeability and retention (EPR) effect. This effect allows (NPs) to accumulate preferably at the tumor site. Once the tumor is directly connected to the main blood circulation system, multifunctional (NPs) may exploit several characteristics of the newly formed vasculature and efficiently target tumors (Conde et al., 2012; Schroeder et al., 2012). This effect constitutes one of the major advantages of (NPs) against MDR mechanisms. In fact, lipid (NPs) and nanocapsules, polymeric (NPs), metal (NPs), dendrimers and liposomes have been reported to circumvent drug resistance (Dong and Mumper, 2010) (Figure 1). The most common nanomaterials to use against (P-gp) and ABC transporters resistance are non-ionic surfactants (i.e., poly(ethylene glycol), Tween 80® and Pluronics®) that usually form hydrogel bonds with the protein to escape from the recognition and therefore increase the uptake of the nanoformulated drug (Gao et al., 2012). The ABC transporters are also expressed in normal cells and so it