Project Summary Alzheimer’s disease (AD) is the principal cause of dementia worldwide with its incidence anticipated to double every 20 years as the population ages. It represents an ongoing public health crisis, compounded by the lack of effective therapeutics to attenuate or reverse its progression. The principal obstacles to treatment are the inability of drugs to penetrate the blood brain barrier (BBB) and their potential to cause adverse effects when administered systemically. The unmet need of effective drug delivery systems for AD and AD-related dementias (ADRD) led to the application of a variety of nanomaterials including carbon-based nanotubes and intranasal delivery systems in order to encapsulate noxious drugs during their delivery and reduce drug toxicity. Unfortunately, many of these alternatives, like carbon nanotubes, are themselves toxic, reducing their applicability. To surmount these obstacles, Somatoceutics, LLC aims to utilize nanotechnology to apply materials, functionalized structures or devices having novel properties in order to generate tools that may serve as new diagnostics, therapeutics and preventatives. To this end, we identified a natural peptide-based nanomaterial derived from the C-terminal 41 residues of insulin-like growth factor binding protein-2 (IGFBP2 residues 249-289), which we named SMC-101 nanotubes (NTs). We have shown that SMC-101 peptides self-assemble into NTs that are 35 nm wide by 10 – 1,000 nm long driven by disulfide bond formation. They are stable and can be loaded with drugs such as doxorubicin for cell delivery mediated by an intrinsic RGD motif, targeting them to integrins. Thus, SMC-101 NTs represent natural, peptide-based drug delivery agents that provide a safe, non-toxic advantage over current nanoparticles for delivery of drugs across the BBB. In this Phase I proof of principle application we hypothesize that SMC-101 NTs will exhibit high stability and the ability to transcytose the BBB endothelium for efficient CNS penetration. The objective of this application is to demonstrate the in vitro and in vivo effectiveness of SMC-101 NTs by completing the following two Specific Aims. The goal of AIM 1 is to optimize and standardize SMC-101 NT assembly, drug-loading, and BBB transcytosis in vitro. We will standardize SMC-101 NT assembly to generate 100 nm long NTs. Immortalized human hCMEC3/D3 endothelial cells on Transwell inserts will be used to demonstrate SMC-101 NT transcytosis as a model of the BBB. RGD-dependence for SMC-101 NT cellular uptake and transcytosis will be determined. In AIM 2 we will evaluate the toxicity of SMC-101 NTs in mice and their ability to deliver galantamine (GAL) to the CNS. We will compare the effectiveness of SMC-101 NT encapsulated vs. “free” GAL in improving CNS penetration. These studies will provide strong proof of principle demonstrating the efficacy of SMC-101 NTs as drug delivery agents for the treatment of AD. This will establish SMC-101 NTs as safe, ef...