ICRS 2018

Rational design of polyglutamic acid delivering a combination of drugs targeting melanoma brain metastases

Evgeni Pisarevsky 1 Yana Epshtein 1 Rachel Blau 1 Dikla Ben-Shushan 1 Anat Eldar-Boock 1 Galia Tiram 1 Adva Krivitsky 1 Anna Scomparin 1 Sabina Pozzi 1 Richard White 2 Ronit Satchi-Fainaro 1
1Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
2Cancer Biology & Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

INTRODUCTION

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 [1]. To meet these goals, we selected to exploit 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[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.

RESULTS AND DISCUSSION

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 range of 5-15 nm. PGA-Selumetinib-Dabrafenib-diol inhibited the proliferation of human 131/4-5B1, murine D4M.3a and zebrafish ZMEL melanoma cells at an IC50 of 80 nM (Dabrafenib-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.

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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