ORCID

https://orcid.org/0000-0001-7072-5910

Date of Award

2025

Document Type

Thesis

Degree Name

MS in Pharmaceutical Science

Department

Pharmaceutical Sciences

First Advisor

Hyunah HC Cho

Second Advisor

Nitesh NK Kunda

Third Advisor

Sei SH Higuchi

Abstract

Alzheimer’s disease (AD) is a long-term neurological disorder associated with neuroinflammation and amyloid-beta (Aβ) aggregation, which leads to a decline in cognitive and behavioral changes. Rapamycin (Rapa) is an immunosuppressive drug effective in preventing organ rejection after a kidney transplant. In the last few years, orally delivered Rapa has emerged as a potential candidate for improving cognitive function in patients with AD. However, it is evident that long-term oral treatment of Rapa causes systemic toxicity, and although controversial, it may even trigger the aggregation of Aβ deposition. This study investigated the therapeutic potential of intranasally delivered brain-targeting polymeric micelles carrying Rapa. We successfully prepared Fibronectin CS1 peptide-conjugated poly(ethylene glycol)-block-poly(D, L-lactic acid) (FibCS1-PEG-b-PLA) micelles carrying Rapa, which were 98.08 ± 1.15 nm in particle size with a polydispersity index of 0.21± 0.01. FibCS1-PEG-b-PLA micelles showed a significant improvement in the nasal permeation of Rapa across RPMI-2650 epithelial cells. Behavioral studies such as the corner, novel object recognition, and Morris Water Maze tests showed promising results towards the improvement of cognitive function in a 3xTg-AD mice model when treated with intranasal FibCS1-PEG-b-PLA micelles carrying RAPA at a dose of 0.2 mg/kg (q4d x 5). The western blot and ELISA results of the brain tissues of 3xTg-AD mice treated with intranasal FibCS1-PEG-b-PLA micelles carrying Rapa showed significant reductions in Aβ and two pro-inflammation markers (e.g., interleukin (IL)-1β, tumor necrosis factor (TNF-α). Here, we conclude that brain-targeting FibCS1-PEG-b-PLA micelles carrying Rapa were effective in reaching the brain via the intranasal route, reduced pro-inflammatory markers and Aβ, and improved cognitive function in AD-induced mice.

Available for download on Sunday, August 10, 2025

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