Rational Design of Polyglutamic Acid Delivering an Optimized Combination of Drugs Targeting Mutated BRAF and MEK in Melanoma

Targeted therapies against cancer can relieve symptoms and induce remission; however, they often present limited duration of disease control, cause side effects, and may induce acquired resistance. Therefore, there is great motivation to develop a unique delivery system, targeted to the tumor, in which several active entities can be combined, the therapeutic index can be increased by reducing systemic exposure, and their synergistic activity can be enhanced. To meet these goals, the biocompatible and biodegradable poly(alpha,l-glutamic acid) (PGA) is chosen as a nanocarrier that facilitates extravasation-dependent tumor targeting delivery. The RAS/RAF/MEK/ERK pathway when aberrantly activated in melanoma, can lead to uncontrolled cell proliferation, induced invasion, and reduced apoptosis. Here, two drugs targeting this pathway are selected: a MEK1/2 inhibitor (selumetinib, SLM) and a modified BRAF inhibitor (modified dabrafenib, mDBF) that exhibit synergism in vitro. The combination of PGA conjugated to SLM and mDBF (PGA-SLM-mDBF) is synthesized and characterized. PGA-SLM-mDBF inhibits the proliferation of melanoma cells and decreases their migratory and sprouting abilities without inducing a hemolytic effect. Moreover, it exhibits superior antitumor activity in a mouse model of primary melanoma and prolonged survival at a lower dose than the free drugs.