Dendrimers and Derivatives as Multifunctional Nanotherapeutics for Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia. It affects more than 30 million people worldwide and costs over US$ 1.3 trillion annually. AD is characterized by the brain accumulation of amyloid β peptide in fibrillar structures and the accumulation of hyperphosphorylated tau aggregates in neurons, both leading to toxicity and neuronal death. At present, there are only seven drugs approved for the treatment of AD, of which only two can slow down cognitive decline. Moreover, their use is only recommended for the early stages of AD, meaning that the major portion of AD patients still have no disease-modifying treatment options. Therefore, there is an urgent need to develop efficient therapies for AD. In this context, nanobiomaterials, and dendrimers in particular, offer the possibility of developing multifunctional and multitargeted therapies. Due to their intrinsic characteristics, dendrimers are first-in-class macromolecules for drug delivery. They have a globular, well-defined, and hyperbranched structure, controllable nanosize and multivalency, which allows them to act as efficient and versatile nanocarriers of different therapeutic molecules. In addition, different types of dendrimers display antioxidant, anti-inflammatory, anti-bacterial, anti-viral, anti-prion, and most importantly for the AD field, anti-amyloidogenic properties. Therefore, dendrimers can not only be excellent nanocarriers, but also be used as drugs per se. Here, the outstanding properties of dendrimers and derivatives that make them excellent AD nanotherapeutics are reviewed and critically discussed. The biological properties of several dendritic structures (dendrimers, derivatives, and dendrimer-like polymers) that enable them to be used as drugs for AD treatment will be pointed out and the chemical and structural characteristics behind those properties will be analysed. The reported use of these nanomaterials as nanocarriers in AD preclinical research is also presented. Finally, future perspectives and challenges that need to be overcome to make their use in the clinic a reality are discussed.

Keywords: Alzheimer’s disease; acetylcholinesterase; amyloid β; dendrimer; drug delivery; inflammation; nanomedicine; oxidative stress; tau peptide.

Figure 1

Amyloid fibril formation. The kinetic curve of a nucleation-dependent mechanism and the species expected in each moment. Created with BioRender.com.

Figure 2

Two-dimensional representation of a spherical structure of generation 3 (G3) dendrimer.

Figure 3

Classical strategies for the synthesis of dendrimers. Both strategies include growth reactions (R1) and deprotection/activation of the branching points (R2) to create a new generation of dendrimer/dendron. Squares represent protected/inactive functional groups and circles represent free/active functional groups. Adapted from Leiro et al. [14] © John Wiley & Sons, Inc.

Figure 4

Chemical structure of the most researched dendrimers/dendrons in the biomedical field: (a) Generation 2 (G2) poly(amido amine) (PAMAM), (b) G2 poly(L-lysine) (PLL), (c) G2 carbosilane, (d) G2 poly(propylene imine) (PPI), (e) G2 poly(ether imine) (PETIM), (f) G1 azabisphosphonate-terminated (ABP) phosphorus, (g) G2 gallic acid-triethylene glycol (GATG) dendron, and (h) poly(ether)-copoly(ester) (PEPE) dendrimers.

Figure 5

Equilibrated configurations of seven families of dendrimers—PAMAM (7a,b-Gn), PPI (6a,b-Gn), carbosilane dendrimers (4-G1), PLL (8a-G2) and phosphorus-containing dendrimers (1-G1, 2-G1,3-Gn, 5a,b-G1) bearing azabisphosphonate (ABP) groups at their surface obtained by molecular dynamics simulations. (a) Bioactivity of dendrimers to alternatively activate human monocytes in vitro in function of the number of ABP groups (END groups). Efficiency of activation of monocytes from 0 (no activation) to +++ (the highest activation). (b) Equilibrated MD configurations of different dendrimers. Adapted from Caminade et al. [185] (licensed under CC BY 4.0).

Figure 6

Synthesis of G4 phosphorous-containing dendrimers via the orthogonal coupling method. Synthetic route described in Brauge et al. [265].

Figure 7

Synthetic route of polyethylene glycol–based dendrimer (PEGOL-60). Adapted from Sharma et al. [178] (licensed under CC BY 4.0).