Lucas A. Lane, the Lifenergy Associate Professor of Biomedical Engineering, has recently published a pioneering report on how employing knowledge of physical phenomena allows researchers to develop rationally design nanoparticles that can overcome current limitations of nanomedicine. The manuscript entitled, “Physics in nanomedicine: Phenomena governing the in vivo performance of nanoparticles” was published in the journal Applied Physics Reviews (IF=17.054). https://aip.scitation.org/doi/full/10.1063/1.5052455
Nanomedicine is a flourishing field with strong potential to offer better patient outcomes than current standards of care. In particular, nanoparticles can provide increased delivery efficiencies of therapeutic and diagnostic agents to cancerous tumors while decreasing healthy tissue accumulation. Conventional small molecule therapeutics and imaging agents, on the other hand, tend to distribute nonselectively among all tissues. In many cases, though, nanomedicine has provided mediocre improvements over small molecule compounds in terms of patient survival and care. Advancing nanomedicine far beyond marginal gains will require understanding and overcoming a series of physiological and technical obstacles. Physical phenomena governing the performance of nanoparticles encountering these physiological barriers remain poorly understood, and the nanomedicine field lacks an in-depth description of physical principles to guide rational nanoparticle designs to overcome biological obstacles. This work aims to provide the lacking description of physical phenomena present in nanomedicine.
One important concept presented in the manuscript is using a thermodynamic description to gain insight into how to prevent nonspecific protein adsorption on blood circulating nanoparticles. When proteins adsorb onto particles, they are signaled for removal by immune system organs, thus preventing these particles from locating to their intended target. Free energy diagrams of the nanoparticle protein interaction can indicate whether a particle is thermodynamically favored to resist protein adsorption (Figure 1). To prevent proteins from adsorbing to the particle surface requires the depths of the wells in the free energy curve to be comparable or smaller than the thermal energy. Creating energetic barriers to prevent protein adsorption can be accomplished by densely packing highly hydrophilic polymers or packing molecules that have a stronger attraction to water than proteins.
Figure 1. (a) Schematic illustration of the interparticle distance, d, defined as the distance from the nanoparticle surface to the protein surface. (b) A plot of a typical potential energy curve between a nanoparticle and a protein molecule, with the prominent features highlighted and discussed in the main text. (c) Potential energy plot of a particle with a deep primary energy well for adsorption and a small barrier for protein adsorption, leading to extensive protein adsorption that is thermodynamically stable. (d) Potential energy plot of a nanoparticle with a small primary well and a high-energy barrier for protein adsorption, leading to protein adsorption that is thermodynamically unstable. Note that even particles that are resistant to protein adsorption may still exhibit a secondary minimum; however, the adsorption states are short-lived as the potential well is close to the thermal energy.
The work also proposed a method to overcome the limited diffusion of particles into tumors with dense cellular networks by utilizing the process of transcytosis. In transcytosis, particles move through the tumor via a series of endocytotic and exocytotic events and are passed from cell to cell (Figure 2). Utilizing the transcytosis pathway may be the key to treating cancers known for poor drug penetration, such as pancreatic adenocarcinoma, which has particularly high death rates. By dimensional analysis carried out in the article, transcytosis seems to be even more critical as tumors increase in size.
Figure 2. (Left) In cases of tumors with high cellular density, it may be possible for particles to penetrate the tumor by being passed from cell to cell through a series of transcytotic events. (Right) The process of transcytosis through a cell where the particle is endocytosed, travels inside the cell within an endocytotic vesicle, then is exocytosed from the cell at a different location than the site of endocytosis.
Other concepts presented in the paper include the tradeoffs and targeting specificity of various actively targeted nanoparticle designs using statistical mechanical descriptions, and how nanoparticle size and porosity of tumors affect the transport of nanomedicine in tumors using fluid mechanics models. This work aims to provide more in-depth knowledge of the physical phenomena involved in the in vivo performance of nanomedicine to aid researchers in developing rationally designed constructs that overcome several biophysical barriers present in drug delivery and imaging. As more barriers are adequately addressed by future generations of nanoparticle designs, more favorable clinical outcomes may be attained.
Lucas A. Lane is an Associate Professor in the Department of Biomedical Engineering within the College of Engineering and Applied Sciences. The research was supported by the National Natural Science Foundation of China, the 1000 Global Talents Recruitment Program of China, and startup funding provided by Nanjing University.