id_667. COPPER CHELATION VIA MITOCHONDRIA-TARGETED NANOSTRUCTURED LIPID CARRIERS TO MITIGATE OXIDATIVE STRESS IN NEURODEGENERATIVE DISORDERS
Akshada Mhaske1, Kamlinder K singh2,3, Rahul Shukla1
1 Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow, U.P., India-226002
2 School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, United Kingdom
3 Biomedical Evidence based Transdisciplinary (BEST) Health Research Institute, University of Central Lancashire, Preston PR1 2HE, United Kingdom
INTRODUCTION: Copper is an essential trace element critical for ATP production through the mitochondrial electron transport chain. Dysregulation and accumulation of copper, as observed in Wilson’s disease and several neurodegenerative disorders, disrupt cellular homeostasis, induce oxidative stress, and impair mitochondrial function. Strategies that selectively target mitochondria are therefore crucial to restore neuronal health.
AIM(S): To develop and evaluate a mitochondria-targeted nanostructured lipid carrier (NLC) capable of co-delivering a copper chelator and antioxidant to mitigate copper-induced mitochondrial dysfunction in neuronal cells.
METHOD(S): A mitochondria-targeted NLC was engineered with a mitochondrial-targeting ligand to enhance delivery to neuronal mitochondria. The NLC co-delivers D-penicillamine and kaempferol for synergistic copper chelation and antioxidant activity. Surface modification facilitated mitochondrial localization, and the lipid composition supported blood-brain barrier penetration in cellular models. Protective effects were assessed in SH-SY5Y and HepG2 cells. Copper chelation and cytoprotection were evaluated in ATP7B knockdown models. Mechanistic studies included RT-PCR for mitochondrial and oxidative stress markers, site-directed uptake assays, ATP quantification, and mitochondrial functional analyses.
RESULTS: The NLC effectively redirected excess copper and attenuated cytotoxicity in ATP7B knockdown cells. Mitochondrial protection was confirmed by restored ATP levels and functional assays, with reduced oxidative stress mediated via activation of the SIRT1/PGC-1α pathway.
CONCLUSIONS: This dual-function NLC enables prolonged circulation, controlled release, and efficient intracellular delivery. By combining copper chelation with antioxidant therapy, it represents a promising strategy to mitigate mitochondrial dysfunction and enhance neuronal survival in Wilson’s disease and related neurodegenerative disorders.
FINANCIAL SUPPORT: Commonwealth scholarship (United kingdom)