EphA2-Receptor Targeted PEGylated Nanoliposomes for the Treatment of BRAF<sup>V600E</sup> Mutated Parent- and Vemurafenib-Resistant Melanoma
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 stud...
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MDPI AG
2019-10-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/11/10/504 |
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| author | Yige Fu Drishti Rathod Ehab M. Abo-Ali Vikas V. Dukhande Ketan Patel |
| author_facet | Yige Fu Drishti Rathod Ehab M. Abo-Ali Vikas V. Dukhande Ketan Patel |
| author_sort | Yige Fu |
| collection | DOAJ |
| description | 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 BRAF<sup>V600E</sup>-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. |
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| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-04-13T08:38:24Z |
| publishDate | 2019-10-01 |
| publisher | MDPI AG |
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| series | Pharmaceutics |
| spelling | doaj.art-f8c1d6f212b44efa9f9472addebc16942022-12-22T02:54:02ZengMDPI AGPharmaceutics1999-49232019-10-01111050410.3390/pharmaceutics11100504pharmaceutics11100504EphA2-Receptor Targeted PEGylated Nanoliposomes for the Treatment of BRAF<sup>V600E</sup> Mutated Parent- and Vemurafenib-Resistant MelanomaYige Fu0Drishti Rathod1Ehab M. Abo-Ali2Vikas V. Dukhande3Ketan Patel4Pharmaceutical Sciences, St. John’s University, Queens, NY 11439, USAPharmaceutical Sciences, St. John’s University, Queens, NY 11439, USAPharmaceutical Sciences, St. John’s University, Queens, NY 11439, USAPharmaceutical Sciences, St. John’s University, Queens, NY 11439, USAPharmaceutical Sciences, St. John’s University, Queens, NY 11439, USAThe 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 BRAF<sup>V600E</sup>-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.https://www.mdpi.com/1999-4923/11/10/504epha2 receptorpegylated nanoliposomesmelanoma cancertrametinib |
| spellingShingle | Yige Fu Drishti Rathod Ehab M. Abo-Ali Vikas V. Dukhande Ketan Patel EphA2-Receptor Targeted PEGylated Nanoliposomes for the Treatment of BRAF<sup>V600E</sup> Mutated Parent- and Vemurafenib-Resistant Melanoma Pharmaceutics epha2 receptor pegylated nanoliposomes melanoma cancer trametinib |
| title | EphA2-Receptor Targeted PEGylated Nanoliposomes for the Treatment of BRAF<sup>V600E</sup> Mutated Parent- and Vemurafenib-Resistant Melanoma |
| title_full | EphA2-Receptor Targeted PEGylated Nanoliposomes for the Treatment of BRAF<sup>V600E</sup> Mutated Parent- and Vemurafenib-Resistant Melanoma |
| title_fullStr | EphA2-Receptor Targeted PEGylated Nanoliposomes for the Treatment of BRAF<sup>V600E</sup> Mutated Parent- and Vemurafenib-Resistant Melanoma |
| title_full_unstemmed | EphA2-Receptor Targeted PEGylated Nanoliposomes for the Treatment of BRAF<sup>V600E</sup> Mutated Parent- and Vemurafenib-Resistant Melanoma |
| title_short | EphA2-Receptor Targeted PEGylated Nanoliposomes for the Treatment of BRAF<sup>V600E</sup> Mutated Parent- and Vemurafenib-Resistant Melanoma |
| title_sort | epha2 receptor targeted pegylated nanoliposomes for the treatment of braf sup v600e sup mutated parent and vemurafenib resistant melanoma |
| topic | epha2 receptor pegylated nanoliposomes melanoma cancer trametinib |
| url | https://www.mdpi.com/1999-4923/11/10/504 |
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