110th Anniversary: Nanoparticle mediated drug delivery for the treatment of Alzheimer's disease: Crossing the blood-brain barrier

Abstract

Alzheimer's disease is an irreversible neurodegenerative disorder affecting approximately 6 million Americans, 90% of which are over the age of 65. The hallmarks of the disease are represented by amyloid plaques and neurofibrillary tangles. While the neuronal characteristics of Alzheimer's disease are well known, current treatments only provide temporary relief of the disease symptoms. Many of the approved therapeutic agents for the management of cognitive impairments associated with the disease are based on neurotransmitter or enzyme modulation. However, development of new treatment strategies is limited due to failures associated with poor drug solubility, low bioavailability, and the inability to overcome obstacles present along the drug delivery route. In addition, treatment technologies must overcome the challenges presented by the blood-brain barrier. This complex and highly regulated barrier surveys the biochemical, physicochemical, and structural features of nearby molecules at the periphery, only permitting passage of select molecules into the brain. To increase drug efficacy to the brain, many nanotechnology-based platforms have been developed. These methods for assisted drug delivery employ sophisticated design strategies and offer serveral advantages over traditional methods. For example, nanoparticles are generally low-cost technologies, which can be used for non-invasive administrations, and formulations are highly tunable to increase drug loading, targeting, and release efficacy. These nanoscale systems can facilitate passage of drugs through the blood-brain barrier, thus improving the bioavailability, pharmacokinetics, and pharmacodynamics of therapeutic agents. Examples of such nanocarriers which are discussed herein include polymeric nanoparticles, dendrimers, and lipid-based nanoparticles.

Keywords: Alzheimer’s disease; blood-brain barrier; drug delivery; nanoparticles.

Figure 1. Anatomy of nanocarriers used for Alzheimer’s disease drug delivery across the blood-brain barrier.

Dendrimers, polymeric nanoparticles, and liposomes are examples of nanocarriers which have been used to deliver therapeutic agents across the blood-brain barrier for the treatment of Alzheimer’s disease. To cross the blood-brain barrier, studies have shown optimal particle diameters ranging from 5–200 nm.

Figure 2. Overarching hypotheses of Alzheimer’s disease pathogenesis.

The two hypotheses which have been proposed regarding the pathophysiology of Alzheimer’s disease are the following: (i) the hypothesis on amyloid cascade neurodegeneration and (ii) the hypothesis on the impairment of the cholinergic system.

Figure 3. Key physicochemical characteristics for the development of nanomaterial technologies to cross the blood-brain barrier for Alzheimer’s disease treatment.

Size, shape, surface charge, and functionalization greatly influence the nanocarrier efficacy for drug delivery to the brain. Nanoparticles between 5–200 nm have shown to penetrate the brain more efficiently than larger particles, in addition to being efficaciously internalized by macrophages for cell-mediated delivery across the blood-brain barrier. The surface charge of the nanotechnologies used for brain delivery must be carefully controlled to minimize the potential toxicity of each platform. Furthermore, nanoparticle shape, can significantly enhance the circulation and uptake of nanomedicines. Finally, surface functionalization of the nanocarrier offers an extensive range of possibilities to improve brain penetration and target specific cell receptors with the use of small molecules, antibodies, or peptides.