Nanomedicine: A golden horizon.

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Diagnose, locate & treat. Earlier, easier & safer. This is the golden age of medicine, nanomedicine. Colloidal gold holds the future; state-of-the-art diagnosis, localisation and treatment of a variety of diseases, including cancer.

The first, accidental, use of nanoparticles dates back to the fourth century with the creation of the Lycurgus Cup. This magical beaker colours red or green when lit from the back or front respectively.  Attracted by the unique optical properties of nanoparticles, it was Michael Faraday in the mid-1800’s who gave the first sound description of this phenomenon.¹

A fairly old technology you might think, however, it’s only due to great efforts in the last 25 years that production of engineered gold nanoparticles has become practical. The synthesis of gold nanoparticles has evolved to the extent that one can control their size, shape and surface properties. Different morphologies give rise to unique chemical, electrical and optical properties. The applications for gold nanoparticles are extensive, encompassing multiple disciplines within life sciences.

Gold in Molecular Diagnostics

The unmatched versatility with impressive sensitivity makes gold a broadly applicable material. The capacity of gold nanoparticles complex with thiols and amines enables wide chemical, biomimetic and biologic functionalisation. The gamut of opportunities is enlarged through various transduction modes like localised surface plasmon resonance (e.g. absorption, scattering, fluorescence, quenching), surface-enhanced raman scattering and electrochemical methods.

Diagnostic platforms based upon gold nanoparticles have been widely commericialised. Immunoassays are ideal applications due to the high affinity between antibodies and antigens leading to outstanding sensitivities. A fascinating new challenge are regenerative immunosensors, allowing repeatability for statistical rigidity and semi-continuous monitoring. A thermal regenerative immunosensor utilising gold nanorods has recently been developed. With a detection limit of 8.4 fg/mL Troponin T concentration with a linear response between 7.6 x 10-15 and 9.1 x 10-4 gold nanoparticles proved to be a gem for biomedical engineering.²

Gold in Drug Delivery

Nanomedicine as a discipline within oncology is relatively immature and therefore the potential impact in the clinic is yet to be determined. However, there are quite a number of attractive applications prompting considerable research effort. For example, a major concern in current practise is the high cytotoxity of cytokines like Tumour Necrosis Factor-α. One approach to address this is to attach them to a drug-carrier to lower cytotoxity; this carrier can subsequently be modulated to accumulate in or near the tumour. Due to the high tailorability of gold nanoparticles they can be functionalised with tumour specific receptors, to explicitly target tumour cells. The enhanced permeability and retention effect allows gold nanoparticles to spontaneously penetrate the blood-brain barrier and enhance accumulation in tumor specific areas. Recently, Aurimune first generation nanotherapy platform CYT-6091 entered a Phase II clinical trial, emphasising the prospect of this approach. Results in the Phase I showed unmatched dose levels.³ ⁴

Gold in Therapy

Both established radiotherapy (RT) and the fairly new photothermal therapy (PTT) methods show great conjunction potential with gold nanoparticles. However, the combination with gold nanoparticles is still in its infancy. Both techniques benefit from the enhanced permeability and retention effect as well as the potenial to integrate drug delivery, with radio or thermal induced drug release.

RT is a common technique, treating ~50% of all oncology patients, with ionising radiation delivered to the tumour either via an inserted or external source. Through physical, chemical and biological pathways, cell death is induced. Although the mechanism of the gold nanoparticle induced enhancement remains unclear, the increased local dose of radiation is achieved through the high atomic number of gold.

PTT acts via exciting gold nanoparticles through near infra-red light. These nanoparticles are capable of translating light into thermal energy. This gives rise to a local temperature increase to ~55-60ºC, initiating cell death. Despite being a relatively new technique, three Phase 1 clinical trials are already underway.⁵ ⁶

Gold in Imaging

As a final application area, gold nanoparticles have been evaluated as contrast agents in X-ray, computed tomography(CT) and photoacoustic imaging. In current work, significant contrast enhancement has been observed. However, there are significant concerns relating to cytotoxicity. In addition to inherent cytotoxic effects of the gold nanoparticles, which can be shielded via chemical functionalisation of its surface, photoacoustic imaging shows adverse effects mimicking PPT, resulting from the heating of the gold nanoparticles due to the use of near infra-red light.

Through the ability to perform in a variety of fields, which may or may not be complementary, gold nanoparticles hold great potential. Yet, advancements in our understanding of the  inequalities between in vitro and in vivo and modes of toxicology are essential to achieve full impact. Likewise, a flexible synthesis and functionalisation platform for the production of gold nanoparticles with different morphologies and surface functionalities would significantly speed up development and, eventually, production. 7 8

There are still some clouds on the horizon, but the current advancement and momentum in research gives me confidence that the impact of gold nanoparticles could boost nanomedicine into being a key disruptive technology for modern healthcare.


michielMichiel Twisk

Michiel has a Biomedical Engineering background from University of Technology Eindhoven, specialising in biochemistry & molecular diagnostics. He is a skilled pragmatic problem-solver with a multidisciplinary approach to  support innovation in biotechnology.

Michiel’s personal interest is to miniaturize, simplify and develop low-cost solutions for (bio)molecular sensor platforms.

Michiel@ttp.com


References

1 Freestone, I, Meeks, N, Sax, M & Higgit, C (2007) The Lycurgus Cup – A roman nanotechnology. Gold Bulletin. 40/4. 270-277.

2 Ashaduzzaman, Md, Deshpande, SR, Murugan, NA, Mishra, YK, Turner, APF & Tiwar, A (2017) On/off-switchable LSPR nano-immunoassay for troponin-T. Scientific Reports 7. 

3 Sela, H, Cohen, H, Elia, H, Zach, R, Karpas, Z & Zeiri, Y (2015) Spontaneous penetration of gold nanoparticles through the blood brain barrier (BBB). J. Nanobiotechnology. 

4 Jain, S, Hirst, DG & O’Sullivan, JM (2012) Gold nanoparticles as novel agents for cancer therapy. Br. J. Radiol. 85. 101-113

5 Popp, MK, Oubou, I, Shepherd, C, Nagar, Z, Anderson, C & Pagliaro, L (2014) Photothermal Therapy Using Gold Nanorods and Near-Infrared Light in a Murine Melanoma Model Increases Survival and Decreases Tumor Volume. Journal of Nanomaterials.  

6 Her, S, Jaffray, DA & Allen, C (2017) Gold nanoparticles for applications in cancer therapy: Mechanisms and recent advancements. Advanced Drug Delivery Reviews. 109. 84-101. 

7 Cole, LE, Ross, RD, Tilley, JMR, Vargo-Gogola, T, Roeder, RK. (2015) Gold nanoparticles as contrast agents in x-ray imaging and computed tomography. Nanomedicine. Vol. 10. 321-341.

8 Li, W & Chen X. (2015) Gold nanoparticles for photoacoustic imaging. Nanomedicine. 10(2). 299-320 

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