(676b) Mechanistic Understanding of the Biological Responses to Polymeric Nanoparticles

Polymeric nanoparticles have demonstrated tremendous potential for theranostic and nanomedicine applications due their central role in the delivery of a wide range of therapeutic and imaging agents [1-4]. Nonetheless, increasing studies have reported the failures of these nanomaterials in realizing their designed objectives because of a single or combination of factors, notably non-specific biomolecule adsorption, inefficient cellular internalization, triggered immune response, and fast body excretion, which have collectively challenged the merit of nanomedicine for disease theranostics [5-7]. Although numerous efforts have attempted to regulate the biological behaviors of polymeric nanoparticles by controlling their physicochemical properties, a large number of the demonstrated studies have focused solely on either the biological effects induced through the regulation of a single nanoparticle parameter or the separate molecular, cellular, and in vivo behaviors of nanoparticles. Crucially, the interdependency of multiple physicochemical properties of polymeric nanoparticles in determining their biological effects from molecular to organism levels is still largely unclear, which warrants a thorough investigation.

In this work, we prepared a series of polymeric nanoparticles consisting of various biocompatible polymeric nanocarriers (i.e., polystyrene (PS), poly(lactic-co-glycolic acid) (PLGA), and polyethylene glycol (PEG)) encapsulating organic fluorophores [8]. Subsequent to the synthesis of these nanoparticles, we evaluated their physicochemical properties, such as surface morphology, size distribution, zeta potential, lipophilicity, optical absorbance, and fluorescence. Next, through a range of experimental characterization and molecular simulation, we systematically probed the interdependent effect of nanoparticle lipophilicity, zeta potential, and size on the formation of protein corona around the nanoparticles as well as the in vitro cellular uptake and in vivo biodistribution of nanoparticles in a zebrafish model.

We observed that nanoparticle lipophilicity influenced the recruitment of non-specific biomolecules, where the adsorption of biomolecules could be reduced by decreasing nanoparticle lipophilicity and vice versa. For a given lipophilicity, the nanoparticle size had a more significant effect in determining biomolecule adsorption than the nanoparticle surface charge. However, irrespective of size, the surface charge of nanoparticles was noted to affect their endothelium and macrophage uptake as well as circulation lifetime. More clearly, the negatively charged nanoparticles could be internalized preferentially by endothelial cells without the need for targeting ligands. Additionally, these nanoparticles were minimally internalized by macrophages and showed a much prolonged in vivo circulation lifetime. Based on our experimental data, we proposed a two-step framework to rationally design a single polymeric nanoparticle system with highly regulated in vitro and in vivo biological behaviors.

In summary, the optimization of the interplay between nanoparticle lipophilicity and surface charge is necessary to control the overall biological behaviors of polymeric nanoparticles. Our study has offered a strong basis for the engineering of enhanced polymeric nanoparticle systems to regulate multiple biological events simultaneously for in vivo theranostic and nanomedicine applications.

References

[1] Elsabahy et al., Chemical Reviews 115 (2015), 10967-11011.

[2] Ulbrich et al., Chemical Reviews 116 (2016), 5338-5431.

[3] Kenry et al., Advanced Materials 30 (2018), 1802394.

[4] Kenry et al., Accounts of Chemical Research 52 (2019), 3051-3063.

[5] Wilhelm et al., Nature Review Materials 1 (2016), 16014.

[6] Rosenblum et al., Nature Communications 9 (2018), 1410.

[7] Nature Nanotechnology 14 (2019), 1083.

[8] Kenry et al., ACS Nano 14 (2020), 4509-4522.