Lactoferrin-encapsulated dichloroacetophenone (DAP) nanoparticles enhance drug delivery and anti-tumor efficacy in prostate cancer.

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.