Nanoparticle Size

Size is important, especially for nanoparticles delivered to a tissue. Often nanoparticles are delivered intravenously, directly into the blood, upstream of the target tissue. One major tissue to distribute across is a cancerous solid tumour micro-environment. Nanoparticles are theorised to experience the enhanced permeability and retention (EPR) effect where particles are extravasated into the tissue due to the leaky vasculature and are retained in the micro-environment. Although the effect of the EPR effect is largely debated where immune cells in the tumour microenvironment are thought to affect the accumulation, retention and distribution1. Regardless, the size of nanoparticles can result in particles remaining near vessels and never penetrating deeper into a tissue therefore having minimal therapeutic effect2. This requires tailoring of the nanoparticle size to have adequate distribution.

What is a cancerous solid tumour micro-environment?

Figure 1: Cancerous solid tumour micro-environment. Image licensed by Cancer Research UK / Wikimedia Commons.

A cancerous tumour micro-environment forms when cancerous cells over-proliferate (grow unregulated) and create a solid tumour3. The micro-environment changes compared to health tissue (tissue being a collection of cells with similar structure), by becoming more densely packed due to the excess cells producing extra-cellular matrix products leading to increased pressure. The increased pressure is challenging to deliver drugs across as the micro-environment lacks convection where movement becomes almost only diffusive4.

Delivering nanomedicines to a cancerous solid tumour micro-environment

Assuming a cancerous tumour micro-environment is only diffusive, we can consider making nanoparticles smaller which means they will diffuse across the micro-environment faster. This is based upon the Stokes-Einstein equation, equation 1.

Equation 1: Stokes-Einstein equation5. The Stokes-Einstein equation calculates the diffusion co-efficient, m / s, for a spherical particle based on the Boltzmann’s constant, kB, temperature in Kelvin, T, the dynamic viscosity of the solution, η, and the particle radius, R.

Using the Stokes-Einstein equation as well as predictive models, we can optimise nanoparticle size to a desired micro-environment. The goal is to have full coverage and accumulation within the tumour micro-environment where particles do not remain near the vessels and leak out of the tumour before having a therapeutic effect.

These concepts formed the basis of my PhD research which was creating a microfluidic testbed to measure nanoparticle penetrations changing the size, shape, charge and coatings6. The nanoparticle size is something which can be tested against a variety of hydrogels acting as tumour-like mimics by replicating the diffusion and density7.

Conclusion

Nanoparticle size can be greatly controlled and has the potential for personalised treatment for cancerous solid tumour micro-environments as well as many other tissues. By controlling the nanoparticle size, distributions may be tailored for tissues leading to improved therapeutic and retention within the tissue.

References

  1. Shi, Y., van der Meel, R., Chen, X., & Lammers, T. (2020). The EPR effect and beyond: Strategies to improve tumor targeting and cancer nanomedicine treatment efficacy. Theranostics, Vol. 10, pp. 7921–7924. https://doi.org/10.7150/thno.49577
  2. Sykes, E. A., Chen, J., Zheng, G., & Chan, W. C. W. (2014). Investigating the impact of nanoparticle size on active and passive tumor targeting efficiency. ACS Nano, 8(6), 5696–5706. https://doi.org/10.1021/nn500299p
  3. Nunes, S. C. (2020). Tumor Microenvironment – Selective Pressures Boosting Cancer Progression. In Advances in Experimental Medicine and Biology (Vol. 1219, pp. 35–49). https://doi.org/10.1007/978-3-030-34025-4_2
  4. Stylianopoulos, T., Munn, L. L., & Jain, R. K. (2018). Reengineering the Physical Microenvironment of Tumors to Improve Drug Delivery and Efficacy: From Mathematical Modeling to Bench to Bedside. Trends in Cancer, Vol. 4, pp. 292–319. https://doi.org/10.1016/j.trecan.2018.02.005
  5. Einstein, A. (1905). Über die von der molekularkinetischen Theorie der Wärme geforderte Bewegung von in ruhenden Flüssigkeiten suspendierten Teilchen. Annalen Der Physik, 322(8), 549–560. https://doi.org/10.1002/andp.19053220806
  6. Hockley, M. (2018). Screening Nanoparticle Dynamics on Modular Tumours-on-a-chip devices (University of Bristol). [Accessed 17/10/2021] https://research-information.bris.ac.uk/en/studentTheses/screening-nanoparticle-dynamics-on-modular-tumours-on-a-chip-devi
  7. McCormick, S. C., Stillman, N., Hockley, M., Perriman, A. W., & Hauert, S. (2021). Measuring nanoparticle penetration through bio-mimetic gels. International Journal of Nanomedicine, 16, 2585–2595. https://doi.org/10.2147/IJN.S292131
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