Abstract
The clinical outcomes of malignant melanoma have improved with the introduction of mitogen-activated protein kinase kinase (MEK) inhibitors. However, off-target toxicities of the MEK inhibitor trametinib (TMB) often result in dose interruption and discontinuation of therapy. The purpose of this study was to anchor a physically stable EphrinA1-mimicking peptide known as YSA (YSAYPDSVPMMS) on TMB-loaded PEGylated nanoliposomes (YTPLs), and evaluate them in BRAFV600E-mutated parent cells (lines A375 and SK-MEL-28) and vemurafenib-resistant cells lines (A375R and SK-MEL-28R) in melanoma. TMB-loaded PEGylated liposomes (TPL) functionalized with nickel-chelated phospholipids were prepared using a modified hydration method. The hydrodynamic diameter and zeta potential values of optimized YTPL were 91.20 ± 12.16 nm and –0.92 ± 3.27 mV, respectively. The drug release study showed TPL did not leak or burst release in 24 h. The hemolysis observed was negligible at therapeutic concentrations of TMB. A differential scanning calorimetry (DSC) study confirmed that TMB was retained in a solubilized state within lipid bilayers. YTPL showed higher intracellular uptake in parental cell lines compared to vemurafenib-resistant cell lines. Western blot analysis and a cytotoxicity study with the EphA2 inhibitor confirmed a reduction in EphA2 expression in resistant cell lines. Thus, EphA2 receptor-targeted nanoliposomes can be useful for metastatic melanoma-specific delivery of TMB.
Highlights
Melanoma is a malignant tumor formed from melanocytes, and is the sixth most common type of cancer in the United States [1]
Trametinib was purchased from LC Laboratories (Woburn, MA, USA); 1,2-Dioleoyl-sn-glycero-3 phosphocholine (DOPC) was purchased from Cordenpharma (Liestal, Switzerland); PE 18:0/18:0PEG2000 was obtained from Lipoid (Ludwigshafen, Germany); cholesterol, chloroform, and a Sephadex G50 column were purchased from Sigma-Aldrich
MO, USA); 6-histidine tagged PEGylated (PEG) YSA (6His-PEG-YSA) was obtained from GenScript Corporation (Piscataway, NJ, USA); DOGS-NTA-Ni was obtained from Avanti (Alabaster, AL, USA); Fetal Bovine Serum (FBS) was Pharmaceutics 2019, 11, 504 procured from Atlanta Biologics (Oakwood, GA, USA); Dulbecco’s modified Eagle’s medium (DMEM) and the BCA protein estimation kit were purchased from ThermoFisher Scientific Inc. (Waltham, MA, USA); Penicillin–Streptomycin–Amphotericin B (PSA) was purchased from MP Biomedicals, LLC (Solon, OH, USA); and ALW-II-41-27 was obtained from Cayman Chemical (Ann Arbor, MI, USA)
Summary
Melanoma is a malignant tumor formed from melanocytes (pigment-producing cells), and is the sixth most common type of cancer in the United States [1]. The survival rate is less than 10% for the patients with metastatic melanoma [2]. The introduction of BRAF-inhibitors like vemurafenib and dabrafenib and MEK-inhibitors (MEKi) like trametinib (TMB) has resulted in significant improvement in clinical outcomes; such therapeutic regimens have remarkably changed the survival statistics of malignant melanomas in recent years [3,4,5]. Dose-dependent side effects associated with TMB include: an absolute decrease of >10% in left ventricular ejection fraction (LVEF), ocular and interstitial lung disease, rash, hypertension, fatigue, peripheral edema, diarrhea, and acneiform dermatitis [6]. Management of decreased LVEF requires withholding TMB doses for up to four months, or in severe cases, permanent discontinuation of TMB. Drug delivery to the desired site is preferred for metastatic melanoma to reduce adverse drug effects
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