2025
Cancer Lett. 2025 Apr 28:616:217522. doi: 10.1016/j.canlet.2025.217522. Epub 2025 Feb 7.
Lactoferrin-encapsulated dichloroacetophenone (DAP) nanoparticles enhance drug delivery and anti-tumor efficacy in prostate cancer
School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland (QLD), Australia; Translational Research Institute, Woolloongabba, QLD, Australia. School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland (QLD), Australia. School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland (QLD), Australia; Translational Research Institute, Woolloongabba, QLD, Australia; The Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, QLD, 4059, Australia. School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia. School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia; Mater Research Institute, Woolloongabba, QLD, Australia; Department of Functional Materials and Catalysis, Faculty of Chemistry, University of Vienna, Währinger Straße 42, 1090, Vienna, Austria. School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland (QLD), Australia; Translational Research Institute, Woolloongabba, QLD, Australia; The Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, QLD, 4059, Australia.
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Abstract
Pyruvate Dehydrogenase Kinase 1 (PDK1) regulates glycolysis and oxidative phosphorylation pathways and is linked to prostate cancer metastasis and poor prognosis. The therapeutic application of 2,2-dichloroacetophenone (DAP), a PDK1 inhibitor, remains underexplored in prostate cancer. In this study we demonstrated that DAP exhibited a superior ability to inhibit prostate cancer cell proliferation, migration and colony formation at a lower concentration (20 μM) compared to a previously established inhibitor, dichloroacetate (DCA), which required concentrations of 30 mM or higher. However, poor aqueous solubility and lower stability of DAP limits its therapeutic application. Nano formulation of DAP with natural lactoferrin enhanced its dispersion and stability by increasing polydispersity index and intensity, and reduced zeta potential values upon conjugation that overcame the solubility limitations of DAP. The lactoferrin-DAP nanoparticles exhibited enhanced therapeutic efficacy by precisely targeting prostate cancer cells that express high lactoferrin receptors and high anti-tumor activity in vitro (at 1 μM) and in mouse prostate tumor xenografts (20 mg/kg). Mechanistically, these nanoparticles induce apoptosis in cancer cells by inducing caspase3/7 activity and disrupting the glycolytic and oxidative phosphorylation pathways. Moreover, lactoferrin-conjugated DAP nanoparticles suppressed the viability of docetaxel-resistant cells exhibiting a higher inhibitory efficacy compared to free DAP and DCA. Targeting PDK1 through lactoferrin-conjugated DAP nanoparticles represents a potent targeted therapeutic strategy for disrupting prostate tumor metabolism and offers promising implications for overcoming drug resistance. Keywords: Dichloroacetophenone; Lactoferrin nanoparticles; Metabolism; Prostate cancer; Pyruvate dehydrogenase kinase 1.
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