New strategies in melanoma therapy: can nanoparticles overcome chemoresistance?

Melanoma is the deadliest form of skin cancer with the fastest growing incidence rate among all cancers. According to the National Cancer Institute, the incidence rate increased more than 60% in the past 20 years. Despite advances in therapy, the mortality rate remained constant in the same period [1]. Melanoma is extremely difficult to treat due to its high heterogeneity and ability to evade the immune system and develop multidrug resistance; rendering successive therapies ineffective [2]. Thus, there is a continuous need to develop new treatment strategies. The first nanotechnology approaches for cancer therapy were developed to improve the bioavailability and distribution profile of poorly soluble chemotherapeutic agents, leading to the first liposomal doxorubicin formulation on the market. In addition to drug encapsulation, nanoparticles are developed to carry their cargo specifically to tumor sites by passive targeting, capitalizing on the higher permeability of the blood vessels in tumors compared with the healthy endothelium (enhanced permeability and retention effect). To increase targeting specificity and efficiency, nanoparticles can be decorated with targeting moieties, increasing their uptake by the tumor cells and minimizing internalization, hence toxicity, by the surrounding healthy cells. Another advantage of nanoparticulate cancer therapy is that the building elements of the nanoparticles can be tailored to release their cargo only at the tumor site by responding to the specific conditions surrounding the tumors (e.g., pH, presence of certain enzymes, changes in oxygen pressure) [3]. One of the major benefits of encapsulating the drugs into nanoparticles is their potential for overcoming drug resistance [4]. Tumor resistance to therapy occurs due to complex phenomena including physical barriers, such as poor vascularization and increased tumor pressure; biochemical processes, such as upregulation of efflux enzymes and mutations that render targets inefficient; and, especially prominent for melanoma, intracellular sequestration of the drug that prevents its access to the intracellular target [5]. Nanoparticles can overcome these barriers by increasing drug permeation into solid tumors, using endocytotic pathways for cellular internalization and promoting escape of the endosomes. A significant number of studies address melanoma drug resistance, as novel chemotherapeutic compounds become inefficient as monotherapy quickly after initiation, thereby preventing their use for prolonged and repeated therapies.