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Targeted Brain Delivery of Nrf-2 Gene and α-Synuclein Binding Peptide using Functionalised Gold Nanoparticles for Disease-modifying Therapy of Parkinson’s Disease

Final Report Summary - NANOGOLD4PARKINSONS (Targeted Brain Delivery of Nrf-2 Gene and α-Synuclein Binding Peptide using Functionalised Gold Nanoparticles for Disease-modifying Therapy of Parkinson’s Disease)

The overall goal of this project is to develop functionalised AuNPs for targeted delivery of α-synuclein peptide inhibitor and Nrf-2 therapeutic gene (pNrf-2) across the BBB to confer potential neuroprotective and disease modifying effects for Parkinson’s disease (PD) treatment. In this project, highly uniform gold nanoparticles (AuNPs) were synthesized and functionalized with poly(ethylene imine) (PEI), leptin-derived peptides and α-synuclein binding peptides. The subsequent functionalization of the AuNP-PEIs with poly(ethylene glycol) (PEG) led to enhanced colloidal stabilities without inducing significant toxicities to the C6 astrocytic cell line. It was found that the AuNP-PEI-PEG effectively inhibited insulin, which is a common amyloid model protein due to its characteristic cross-β sheet structure, and its resultant DNA complex could effectively protect neuronal cells from oxidative stress induced by hydrogen peroxide. During the course of this project, the large neutral amino acid transporter-1 (LAT-1) emerged as a highly promising target to mediate targeting of AuNPs across the blood brain barrier (BBB). As such, we designed and synthesized functionalized AuNPs bearing molecules recognized by the LAT-1. As the LAT-1 has also been found to be overexpressed in breast cancer, the cell targeting capabilities of the functionalized AuNPs were investigated using several immortalized breast cancer cell lines as a model. In these studies, it was found that the LAT-1 ligand functionalized AuNPs mediated significantly higher uptake in the MCF-7. MDA-MB-231, MDA-MB-453, and MDA-MB-468 breast cancer cell lines as compared to the non-tumorigenic MCF-10A breast epithelial cell line. The anisotropic nature of the functionalized AuNPs also offered an unprecedented opportunity to mediate targeted photothermal therapy of breast cancer via the LAT-1. This application is important as breast cancer is a significant cause of morbidity and mortality among women worldwide, and current clinical treatments against advanced breast cancer, particularly the triple negative subtypes which are not responsive to most conventional chemotherapeutic agents remain inadequate. The selective uptake of the functionalized AuNPs by breast cancer cells, and the subsequent conversion of photon energy into heat by an incident laser beam offers a non-invasive and highly targeted method to kill breast cancer cells, without inducing toxicities in other tissues. Indeed, it was found in this study that AuNPs functionalized with LAT-1 ligand absorbs light strongly in the near infrared region, and effectively resulted in a dose-dependent killing effect of MDA-MB-231 breast cancer cells, whereas minimal or no changes in cell viability were observed with the untreated and non-LAT-1 targeting control AuNPs. Notably, the use of this strategy effectively sensitized the breast cancer cells to conventional chemotherapeutic drugs such as docetaxel and cisplatin. In the light of the promising results observed with targeting the LAT-1 in breast cancer, studies are currently underway in the host laboratory to evaluate the targeting capabilities of the functionalized AuNPs developed in this project in an in vitro BBB model derived from primary rat brain endothelial cells. The successful demonstration of the ability to target nanoparticles across the BBB via the LAT-1 would be the first of its kind and would be expected to open up avenues for the treatment of numerous difficult to treat diseases of the brain such as PD, Alzheimer’s disease and cancer, leading to reduced healthcare costs and improved quality of life in patients.