Take a look behind the scenes of a recent Systematic Review published in the journal Nanomedicine entitled, ‘Nanoparticles as contrast agents for the diagnosis of Alzheimer’s disease: a systematic review‘, as we ask corresponding author Nady Braidy (University of New South Wales, Sydney, Australia) about the use of magnetic nanoparticles for diagnosing Alzheimer’s disease (AD). Nady also speaks to us about nanomaterials that hold the most promise for the future of nano-based AD diagnosis, including the next steps that are required to move nano-based imaging strategies into the clinic.
Please can you introduce yourself and explain what stimulated your interest in using magnetic nanoparticles for diagnosing AD?
My name is Dr Nady Braidy. I am a senior lecturer and leader of the Brain Ageing Research Laboratory within the Centre for Healthy Brain Ageing (CHeBA) at UNSW Sydney (Australia). I am leading multiple research projects, collaborating both nationally and internationally, to explore the role of cellular energetics in aging and dementia, with the objective of developing interventions targeting nicotinamide adenine dinucleotide (NAD+) and other molecules, -omics based biomarker discovery and nanotheragnostics for widespread application to human health.
With the aging of the population, AD and other neurodegenerative disorders (e.g., Parkinson’s disease, dementia with Lewy bodies, frontotemporal dementia, etc.) have emerged as major public health problems. Currently, no treatments are available that can modify the course of AD and other neurodegenerative disorders, and dozens of trials, costing several billion dollars, have failed.
There are several possible reasons for such failures, which include the difficulty of early and precise diagnosis and limited access to the site of pathology in the brain due to the brain’s protective barriers such as the blood–brain barrier (BBB).
Working together with CHeBA’s co-director Scientia Professor Perminder Sachdev, our group has been collaborating with Dr Andre Bongers (Biomedical Resources Imaging Lab at UNSW), Professors Richard Tilley and Justin Gooding (Australian Centre for Nanomedicine at UNSW) and Professor Ashley Bush (Melbourne Dementia Research Centre, Australia) to use nanoparticles (NPs) for nanodiagnostic imaging and nanotherapy.
Over the last 7 years, our group has developed functionalized superparamagnetic iron oxide NPs (SPIONs) with a high density of iron atoms in the core that have more than 5x higher saturation magnetization than commercial SPIONs, resulting in a 3x enhanced MRI and MPI signal. They are superparamagnetic so are not attracted to each other, preventing irreversible aggregations that can create clots and block blood flow when used in vivo.
We have shown that these SPIONs have low toxicity and give increased contrast enhancement in MRI for imaging the liver, spleen and lymph nodes, improving accuracy in tumor diagnostics and enabling the detection of 2-mm tumors in animal models compared to that achieved using standard SPIONs. The denser iron cores mean that these SPIONs only require sizes up to 16 nm in diameter, which will enable them to more readily pass the BBB through various mechanisms such as the lipophilic pathway, carrier proteins, receptor-mediated transcytosis and adsorptive transcytosis.
We were recently awarded AUD$1 million from the Yulgibar Foundation/Dementia Australia to use nanotechnology for specific diagnosis and treatment of dementia. SPIONs are developed at the Australian Centre for Nanomedicine (UNSW Sydney) and the preclinical and clinical work is planned in CHeBA and the Melbourne Dementia Research Centre.
What are the drawbacks associated with the current approaches for diagnosing AD?
The theranostics of AD and other neurodegenerative disorders is highly challenging. The currently available diagnostic tests for AD – amyloid/tau imaging using positron emission tomography (PET) and cerebrospinal fluid (CSF) levels of amyloid-β (Aβ), phospho-tau (pTau) and total tau (tTau) – are either very expensive or invasive, and not suitable for screening or use in primary care. A recent advance in this field has been the development of ligands for amyloid and tau imaging using PET, which now permits a molecular diagnosis of AD pathology in vivo. PET, however, has a number of limitations, the salient ones being its low availability, high cost and exposure to radiation, thereby limiting its wide application. The alternative approach is to use CSF biomarkers, which is invasive and only available in specialized centers. One highly promising strategy to overcome these limitations is to develop novel imaging methods that leverage the potential of iron magnetic NPs as tracers for diagnostic imaging
Please give a brief overview of the main findings of your systematic review.
In our systematic review, we examined the current progress of research in this field using PubMed, Medline, EMBASE, PsychINFO and Scopus databases. We found 33 studies that described the development and utility of various NPs for AD imaging, including their coating, functionalization, MRI relaxivity, toxicity and bioavailability. We found that NPs show immense promise for neuroimaging, due to superior relaxivity and biocompatibility compared to currently available imaging agents. Consistent reporting is imperative for further progress in this field. The functionalization of NPs with peptides, immunotargeting ligands, fluorescent dyes, sialic acid and curcumin render them promising alternatives to current amyloid imaging techniques. However, appropriate surface coatings and structural characteristics are essential to maintain the stability of the NP, prevent toxicity and enable effective biodistribution and permeation of the BBB.
A range of different nanomaterials are discussed in the article. In your opinion, which hold the most promise for the future of nano-based Alzheimer’s diagnosis and why?
The theranostics of AD and other neurodegenerative disorders is highly challenging. The currently available diagnostic tests for AD – amyloid/tau imaging using PET and CSF levels of Aβ, pTau and tTau – are either very expensive or invasive, and not suitable for screening or use in primary care.
Nanotechnology has the potential to make a major impact on early diagnosis and treatment of neurodegenerative diseases. Magnetic NPs, in particular SPIONs, are special iron oxide NPs that can cross the BBB and be imaged using MRI and the newly developed technique of magnetic particle imaging (MPI).
When appropriately labelled, they can target specific brain pathology (e.g., amyloid plaques, tangles, Lewy bodies) and potentially provide a cheap and accessible contrast agent for molecular imaging.
NPs can also act as vehicles for specific drugs across the brain’s protective barriers and deliver treatments to the site of pathology. These developments have the potential to transform our approach to diagnosis and treatment of AD and other neurodegenerative disorders.
What steps need to be taken to move nano-based imaging strategies into the clinic?
Several challenges need to be overcome before use of NPs in diagnosis can be widespread. For nanotherapeutics, reaching the interstitial space for pathology-directed drug release is sufficient. This explains the commercial and clinical success of nanotherapeutic agents over nanodiagnostics, which require adequate circulation time, but rapid elimination and low accumulation in other tissues. Furthermore, the lack of expertise of radiologists in interpreting SPION-enhanced images results in a lower likelihood of its selection over other imaging agents. This can be easily overcome with specialized additional training as well as the use of specialized imaging centers.
Exciting future directions for nanomedicine involve a combined theranostic approach, in which medications are functionalized to NPs specific to the pathogenic target, which can subsequently be monitored with the use of imaging modalities.
Congo Red/Rutin nanotheranostics demonstrated an ability to enhance MRI detection of amyloid plaques and prevent oxidative stress in both in vitro and in vivo experiments. Aβ-induced production of H2O2 resulted in controlled release of the drug Rutin, resulting in a therapeutic effect. Alternative imaging targets such as activated microglia, ferritin accumulation and cholesterol in AD have also been explored. No studies to our knowledge have functionalized a tau-targeting ligand to a NP for MR imaging. The intracellular location of tau is an additional challenge to targeting this biomarker.
Finally, MPI is a novel technology which utilizes magnetic NPs. As a true tracer method, it confers several important advantages over MRI. While MRI contrast agents deliver their contrast indirectly through influencing relaxivities of surrounding tissue protons, MPI directly images SPION magnetization with very high sensitivity. This enables depth independent observation of NP distribution and density with high spatial and temporal resolution without obscuring background. Due to the extremely linear behavior of MPI signal with local particle concentrations, the technology is highly quantifiable. We have demonstrated that zero valent iron core iron oxide shell NPs are effective MPI tracers. The use of MPI tracers to gain additional quantitative diagnostic information about AD disease load is promising.
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Neuro Central or Future Science Group.
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