Neurotheranostics as personalized medicines

Abstract

The discipline of neurotheranostics was forged to improve diagnostic and therapeutic clinical outcomes for neurological disorders. Research was facilitated, in largest measure, by the creation of pharmacologically effective multimodal pharmaceutical formulations. Deployment of neurotheranostic agents could revolutionize staging and improve nervous system disease therapeutic outcomes. However, obstacles in formulation design, drug loading and payload delivery still remain. These will certainly be aided by multidisciplinary basic research and clinical teams with pharmacology, nanotechnology, neuroscience and pharmaceutic expertise. When successful the end results will provide "optimal" therapeutic delivery platforms. The current report reviews an extensive body of knowledge of the natural history, epidemiology, pathogenesis and therapeutics of neurologic disease with an eye on how, when and under what circumstances neurotheranostics will soon be used as personalized medicines for a broad range of neurodegenerative, neuroinflammatory and neuroinfectious diseases.

Keywords: Alzheimer's disease (AD); Blood brain barrier (BBB); Brain-targeted nanoparticles; Magnetic resonance imaging (MRI); Nanomedicine; Neurodegenerative disorders; Neuroimaging; Neurotheranostics; Parkinson's disease (PD); Single photon emission computed tomography (SPECT/CT); Theranostics.

Fig. 1.. An historical overview of theranostics.

(A) Timed events recorded during the development of theranostics until the present. (B) The role of the theranostics in the diagnosis, staging and treatment of neurodegenerative diseases are outlined in this chart. Abbreviations are as follows: DDS; drug delivery system, MRI; magnetic resonance imaging, MRS; magnetic resonance spectroscopy, DTI; diffusion tensor Imaging, PET; positron emission tomography, SPECT CT; single photon emission computed tomography, IVIS; in vivo optical imaging system and NIR; near infrared fluorescence.

Fig. 2.. Design, physicochemical properties and applications of multimodal theranostic nanoparticles.

An outline is provided of the physicochemical properties, payload options, imaging agent labeling and surface decoration designed to improve clinical outcomes.

Fig. 3.. Molecular mechanisms of neurodegenerative diseases: Role of protein aggregation and neuronal network dysfunction.

Protein aggregates deposited in brain subregions are a common characteristic of neurodegenerative diseases [180]. Extracellular and intracellular protein aggregates are commonly observed. The intracellular protein aggregation consists of (a) tau, (b) α-synuclein, (c) huntingtin protein, (d) SOD1 and (e) self-harm to neurons [181, 182]. Each of these proteins are actively involved with cellular processes that play key roles in affecting microtubule and synaptic function [183]. However, amyloid-β, α-synuclein, and tau are also part of extracellular protein aggregates and stimulate astrocyte and oligodendrocyte responses. These occur with immunocytes to affect neuronal function and vitality [184]. Astrocytes, microglia and oligodendrocyte cytokines and ROS and generate a spectrum of immune cell responses that leads to BBB and neural and glial damage [184, 200]. Schematic illustration concept was adopted from [201].

Fig. 4.. The structural and functional components of the BBB.

(A) Human brain cross-section and (B) cellular structure, and schematic representation of the BBB including, endothelial cells, astrocytes, tight junctions and transporters. (C) Several putative mechanisms for theranostic nanoparticles trafficking across the BBB. This includes, but is not limited to, passive transport of hydrophilic nanoparticles by paracellular diffusion and limited by endothelial tight junctions. Targeting insulin and transferrin receptors mediates transcytosis by functionalization of nanoparticles with antibody and ligands [73, 236]. Nanoparticles with high positive zeta potential (> 15 mV) show facilitated BBB passage [–239]. Smaller hydrophobic and lipophilic nanoparticles cross the BBB by diffusion across endothelial cells [240, 241].

Fig. 5.. Schematic representation of the clinical role of theranostic nanoparticles.

Schematic representation of tau pathogenesis with theranostic nanoparticles: Formation of neurofibrillary tangles by the tau protein in Alzheimer’s disease (AD) tauopathies. In pathological states tau becomes hyperphosphorylated and detaches from microtubules. Phosphorylated tau then aggregates to form paired helical filaments and neurofibrillary tangles. Here multifunctional theranostic nanoparticles injected into an AD patient precisely target hyperphosphorylated tau. Particles can have ROS scavenging, drug release and bioimaging capabilities. These nanoparticles can scavenge ROS to inhibit hyperphosphorylation of tau, aggregation and release drug. This leads to neuroprotection from ROS mediated cell damage.

Fig. 6.. Bio-barcode amplification.

This assay was developed with the aim to isolate amyloid-β-derived diffusible ligands (ADDLs) concentrated in the CSF. First step, anti ADDLs mAbs were decorated onto magnetic nanoparticles. Second step, double-stranded DNA functionalized gold nanoparticles were allowed to bind the target antigen to create a magnetic nanoparticles complex. Last step, the sandwich complexes were then magnetically separated and collected as barcode DNA (Concept of assay form reference number [351]).

Fig. 7.. Schematic illustration of theranostic nanoparticle biodistribution.

Biodistribution of multifunctional theranostic nanoparticles loaded in cells. Metal nanoparticle-loaded macrophages are shown here. Nanoparticle loaded macrophages are transported through the intestinal epithelium and are capable of systematic biodistribution to organs susceptible to infection including lung, liver, spleen and lymph nodes. The ultimate fate of theranostic nanoparticles depends on their specific physicochemical properties, targeting moieties on nanoparticles, and the route of administration, as well as altered biochemical processes in disease states [, –683].

Fig. 8.. Cell-based bioimaging.

Schematic illustration of multimodal cell based bioimaging. Theranostic nanoparticles loaded into cells can be monitored for brain distribution by using SPECT/CT, PET, and MRI.