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The MEK 1/2 inhibitor PD98059 exhibits synergistic anti-endometrial cancer activity with paclitaxel in vitro and enhanced tissue distribution in vivo when formulated into PAMAM-coated PLGA-PEG nanoparticles

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Abstract

Endometrial cancer is the most common gynecological cancer that affects the female reproductive organs. The standard therapy for EC for the past two decades has been chemotherapy and/or radiotherapy. PD98059 is a reversible MEK inhibitor that was found in these studies to increase the cytotoxicity of paclitaxel (PTX) against human endometrial cancer cells (Hec50co) in a synergistic and dose-dependent manner. Additionally, while PD98059 arrested Hec50co cells at the G0/G1 phase, and PTX increased accumulation of cells at the G2/M phase, the combination treatment increased accumulation at both the G0/G1 and G2/M phases at low PTX concentrations. We recently developed poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) modified with polyethylene glycol (PEG) and coated with polyamidoamine (PAMAM) (referred to here as PGM NPs) which have favorable biodistribution profiles in mice, compared to PD98059 solution. Here, in order to enhance tissue distribution of PD98059, PD98059-loaded PGM NPs were prepared and characterized. The average size, zeta potential, and % encapsulation efficiency (%EE) of these NPs was approximately 184 nm, + 18 mV, and 23%, respectively. The PD98059-loaded PGM NPs released ~ 25% of the total load within 3 days in vitro. In vivo murine studies revealed that the pharmacokinetics and biodistribution profile of intravenous (IV) injected PD98059 was improved when delivered as PD98059-loaded PGM NPs as opposed to soluble PD98059. Further investigation of the in vivo efficacy and safety of this formulation is expected to emphasize the potential of its clinical application in combination with commercial PTX formulations against different cancers.

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Acknowledgements

K.W. acknowledges support from the Government Pharmaceutical Organization (GPO) scholarship. J.C.Q. acknowledges support from the Alfred P. Sloan Foundation, the University of Iowa Graduate College, and the American Association for University Women. A.K.S acknowledges support from the Cancer Center support grant (P30 CA086862) and the Lyle and Sharon Bighley Chair of Pharmaceutical Sciences.

Funding

This work was supported by the Cancer Center support grant (P30 CA086862).

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Author notes

  1. Kanawat Wiwatchaitawee and Aml I. Mekkawy contributed equally.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, 52242, USA

    Kanawat Wiwatchaitawee, Aml I. Mekkawy, Juliana C. Quarterman, Youssef W. Naguib, Kareem Ebeid, Sean M. Geary & Aliasger K. Salem

  2. Department of Pharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, Sohag University, Sohag, 82524, Egypt

    Aml I. Mekkawy

  3. Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt

    Youssef W. Naguib & Kareem Ebeid

  4. Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Manufacturing, Deraya University, New Minia City, 61768, Minia, Egypt

    Youssef W. Naguib & Kareem Ebeid

  5. Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242, USA

    Aliasger K. Salem

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  1. Kanawat Wiwatchaitawee
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Contributions

K.W., A.I.M., and A.K.S. had the idea for the article. K.W., A.I.M., Y.W.N., and K.E. performed the experiments and data analysis. K.W., A.I.M., J.C.Q., Y.W.N., and S.M.G. drafted and critically revised the work.

Corresponding author

Correspondence to Aliasger K. Salem.

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Animal studies were carried out by Kanawat Wiwatchaitawee, Youssef W. Naguib, and Kareem Ebeid for this article. Animal husbandry and veterinary care were provided by the Office of Animal Resources at the University of Iowa. All animal protocols used in these studies were in agreement with and approved by Institutional Animal Care and Use Committee (IACUC).

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Wiwatchaitawee, K., Mekkawy, A.I., Quarterman, J.C. et al. The MEK 1/2 inhibitor PD98059 exhibits synergistic anti-endometrial cancer activity with paclitaxel in vitro and enhanced tissue distribution in vivo when formulated into PAMAM-coated PLGA-PEG nanoparticles. Drug Deliv. and Transl. Res. 12, 1684–1696 (2022). https://doi.org/10.1007/s13346-021-01065-7

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