Rational design of polyglutamic acid delivering an optimized combination of drugs targeting melanoma

Targeted chemotherapy is an efficient approach to fight cancer, nonetheless, it still shares some of the problems associated with conventional chemotherapy such as limited therapeutic response. A more accurate and effective method is required in order to target the drug to the tumor, aiming to facilitate its accumulation in cancer tissues. Therefore, developing a novel targeted system is necessary, in which we can combine a number of active entities to increase the treatment efficacy. To meet these goals, we selected poly(α,L-glutamic acid) (PGA) polymer as a nanocarrier for selective delivery of a combination of drugs to the tumor tissue. Excellent biocompatibility and biodegradability in vivo make PGA an ideal biomedical material. In addition, the carboxylic acid sidechain can be modified for small drug conjugation for combined drug delivery. Here, we selected two drugs, a MEK1/2 inhibitor (Selumetinib) and a BRAF inhibitor (Dabrafenib), that exhibited synergism in vitro. The RAS/RAF/MEK/ERK pathway plays a role in normal organogenesis; however, it can lead to malignant cellular proliferation, inhibition of apoptosis, and invasion when aberrantly activated.

We report for the first time the conjugation of these two drugs to PGA with controlled drug loading up to 30 wt.% and a tailored diameter size around 10 nm. PGA-Selumetinib-mDabrafenib (modified Dabrafenib) inhibited the proliferation of human 131/4-5B1 and murine D4M.3a melanoma cells at an average IC₅₀ of 100 nM (mDabrafenib-equivalent) and decreased their migratory ability. Our novel combined conjugates showed no hemolytic effect and enhanced accumulation in the tumor compared to the free drugs following their intravenous administration. Comprehensive physico-chemical and biological characterization was performed in order to gain insights regarding the structure-activity relationship of the combined conjugates at different sizes and distinct loading for each drug.