“It is a staggeringly small world that is below. In the year 2000, when they look back at this age, they will wonder why it was not until the year 1960 that anybody began seriously to move in this direction” (Feynman, 1960).

In 1959 the Nobel Prize-winning physicist, Richard P. Feynman, delivered his groundbreaking lecture “There’s Plenty of Room at The Bottom”, and from then, as the scientific world began to take action, the groundwork for a future built on the back of nanotechnology was laid out. Today, nanotechnology is ubiquitous, from zinc or titanium nanoparticles defending us from harmful UV rays in sunscreen to enhanced digital display screens and memory chips for our laptops and phones (Galligan, 2018). Notably, the healthcare industry illustrates nanotechnology’s impact on our lives, particularly in the field of drug delivery; and by looking more closely at some of the intricate mechanisms which make these technologies function we can see just how great their potential is.

Consider designing a high-tech suitcase to protect and transport your valuables. This suitcase, however, is unlike any other; it is so compact that it can navigate security checkpoints undetected and then, once on its journey it’s able to autonomously find its way to the intended final destination without needing any additional external guidance, delivering and unloading your possessions to you safe and intact. If this idea for a ‘suitcase’ were then shrunk down to around 100-500nm it could loosely represent the basic concept behind a successful nanoparticle drug delivery system. The motivation for developing this technology arises from nanoparticles having been shown to enhance the disposition of drugs in the body by increasing their solubility, bioavailability, and stability. Specific tissues and cells can also be targeted more precisely, increasing efficacy and reducing the side effects of certain drugs.

Developing these drug delivery systems presents immediate challenges. The size of the particle encapsulating the drug is a crucial consideration, influencing toxicity, distribution, targeting ability and detection by other cells in the body. As these particles become smaller their surface area to volume ratio gets larger, implying that there would be more of the drug near the surface of a smaller molecule compared to a larger one. This is important as, ideally, whatever drug is being carried should be located close to the periphery of the particle in order to enter target areas more effectively. It has been shown that particles 200nm or larger are more likely to activate the lymphatic system and be removed from circulation, so most are created with the optimum size being approximately 100nm (Prokop and Davidson, 2008). For reference, a human red blood cell is approximately 7000nm wide, making the average nanoparticle approximately 70 times smaller.

While size is an important factor that needs to be considered when designing one of these miniature systems, another that is equally, if not more, important is the surface characteristics of the nanoparticle. It would not serve well if the lymphatic system, which makes the nanoparticles subject to the body’s natural immune defence, detects and clears them from circulation entirely. So, in order to overcome this some basic principles are applied. The more hydrophobic a nanoparticle is the more likely it is to be cleared from circulation due to the increased binding of blood components. Therefore, the logical step would be to incorporate hydrophilic properties into their surface designs, which is exactly what happens. Surfactants, polymers, or copolymers such as polyethylene glycol (PEG), which are hydrophilic, are coated around the particle to provide the intended effect. Looking a little more closely, PEG is a relatively inert polymer that hinders the binding of plasma proteins (opsonisation) to the surface of the nanoparticle once incorporated (Li and Huang, 2010). Due to this, PEGylated nanoparticles can be referred to as “stealth” nanoparticles as they prevent opsonisation, which allows them to go undetected in the body.

Drug delivery merely scratches the surface of what nanotechnology is capable of. In fact, while still in its infancy, researchers are already beginning to manufacture and test experimental devices such as mechanical red blood cells. These are experimental nanorobots, referred to as respirocytes, which studies have shown to have the potential to deliver over 200 times more oxygen to the body’s tissues than natural red blood cells (Suhail et al., 2021). Faster recovery times, increased athletic performance, potential cures for a range of blood-linked disorders – one can only imagine the possibilities. With that being said, there is still some way for the technologies to progress before becoming widespread viable treatment options. Researchers must establish the ideal dosage range, frequency, and duration of nanoparticles to attain therapeutic objectives while mitigating potential side effects. While prior medical investigations have yielded highly sophisticated treatment modalities, there still remains a challenge in efficiently counteracting drug overdoses.

Feynman’s vision for “a hundred tiny hands” aiding us in our everyday lives and residing within us is no longer a fictional dream, and with the rapid development of technology, it would be no surprise if we will soon have to start replacing the word “hundreds” with thousands or even millions.

References

Feynman, R.P. (1960). There’s Plenty of Room at the Bottom. Engineering and Science,
[online] 23(5), pp.22-36. Available at: http://resolver.caltech.edu/CaltechES:23.5.1960Bottom
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Galligan, F. (2018). Exploring Nanotechnology’s Daily Applications. [online] ACS Publications
Chemistry Blog. Available at:
https://axial.acs.org/nanoscience/nanotechnology-daily-applications.

Li, S.-D. and Huang, L. (2010). Stealth nanoparticles: High density but sheddable PEG is a
key for tumor targeting. Journal of Controlled Release, 145(3), pp.178—-181.
doi:https://doi.org/10.1016/j.jconrel.2010.03.016.

Prokop, A. and Davidson, J.M. (2008). Nanovehicular Intracellular Delivery Systems. Journal
of Pharmaceutical Sciences, [online] 97(9), pp.3518—-3590.
doi:https://doi.org/10.1002/jps.21270.

Sahu, T., Ratre, Y.K., Chauhan, S., Bhaskar, L.V.K.S., Nair, M.P. and Verma, H.J. (2021).
Nanotechnology based drug delivery system: Current strategies and emerging therapeutic
potential for medical science. Journal of Drug Delivery Science and Technology, [online] 63,
p.102487. doi:https://doi.org/10.1016/j.jddst.2021.102487.

Suhail, M., Khan, A., Rahim, M.A., Naeem, A., Fahad, M., Badshah, S.F., Jabar, A. and
Janakiraman, A.K. (2021). Micro and nanorobot-based drug delivery: an overview. Journal of
Drug Targeting, pp.1—10. doi:https://doi.org/10.1080/1061186x.2021.1999962.