Rational Design of Polyglutamic Acid Delivering an Optimized Combination of Drugs targeting Melanoma Brain Metastases

Evgeni Pisarevsky jalchemic@gmail.com Yana Epshtein Dikla Ben-Shushan Anat Eldar-Boock,
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

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 required, in which we can combine a number of active entities to increase the treatment efficacy [1]. To meet these goals, we selected to exploit poly (α,L-glutamic acid) (PGA) polymer as a nanocarrier for selective delivery to the tumor. Excellent biocompatibility and biodegradability in vivo make PGA an ideal biomedical material[2]. 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)[3] and a BRAF inhibitor (Dabrafenib)[4], 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 diameter size range of 5-15 nm. PGA-Selumetinib-Dabrafenib-diol inhibited the proliferation of 131/4-5B1 and D4M melanoma cells at an IC50 of 80 nM (Dabrafenib-equivalent) and decreased their migratory ability. Our novel conjugates showed no hemolytic effect. Comprehensive physico-chemical and biological characterization was performed for better understanding of the structure-activity relationship of the combined conjugate.

References

[1] Markovsky, E.; Baabur-Cohen, H.; Satchi-Fainaro, R., J. Controlled Release, (2014) 187, 145.

[2] Deming, T. J., Prog. Polym. Sci., (2007) 32, 858.

[3] Chapman, P. B et al., New England Journal of Medicine, (2011) 364, 2507.

[4] Falchook, G. S et al., The Lancet, 379, 1893.









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