Influences of nanocarrier morphology on therapeutic immunomodulation

Abstract

Nanomaterials provide numerous advantages for the administration of therapeutics, particularly as carriers of immunomodulatory agents targeting specific immune cell populations during immunotherapy. While the physicochemical characteristics of nanocarriers have long been linked to their therapeutic efficacy and applications, focus has primarily been placed on assessing influences of size and surface chemistry. In addition to these materials properties, the nanostructure morphology, in other words, shape and aspect ratio, has emerged as an equally important feature of nanocarriers that can dictate mechanisms of endocytosis, biodistribution and degree of cytotoxicity. In this review, we will highlight how the morphological features of nanostructures influence the immune responses elicited during therapeutic immunomodulation.

Keywords: antigen-presenting cells; biodistribution; drug delivery; immunomodulation; immunotherapy; nanocarrier; nanomaterial; nanoparticle; theranostics; vaccination.

Figure 1.. Schematics of the general structural classifications of nanomaterial morphologies discussed in this review, separated into spherical and nonspherical categories.

a: Area; AR: Aspect ratio; d: Diameter; L: Length.

Figure 2.. Inductively coupled plasma mass spectrometry analysis of gold from spherical (GNP2), rod (GNP3) and star-shaped (GNP4) AuNPs show morphology-dependent uptake over 120 h in treated mice.

Presented as the fraction of injected dose, significant differences between shapes were found (A) overall, (B–E) by organ, (F, G) route of excretion and (H) circulation. Statistical significance is represented as (∧) for spheres/rods, (§) for spheres/stars and (#) for rods/stars (p < *0.05, **0.005, ***0.0005). Reprinted with permission from [33] © ACS Publications (2017).

Figure 3.. Nanosphere and nanocube morphologies retained in lysosomes elicit a stronger antibody response through the increased release of proinflammatory cytokines.

Production of (A) TNF-α, (B) IL-6, (C) IL-12 and (D) GM-CSF in BMDCs was found to be significantly higher with 10 μg/ml of spherical and cubic nanoparticles compared with free drug, smaller spheres, rods, alum and PBS. (E)No difference was found in lower doses, or in IFN-α production among the groups. Statistical significance is represented by ***p < 0.001. BMDC: Bone marrow-derived dendritic cell; LPS: Lipopolysaccharide; PBS: Phosphate buffered saline. Reprinted with permission from [56] © ACS Publications (2013).

Figure 4.. Engineering of nanoparticle curvature determines the type and strength of immune cell binding.

Densely-packed ligands on a flat particle surface (A) allow for high affinity binding with multiple attachment points but inhibit access to deeper epitopes. Conversely, the loose packing found on highly curved particles (B) allows for deep penetration of immune cells but weaker binding due to the space between ligands. Reprinted with permission from [46] © Wiley (2016).

Figure 5.. Poly(ethylene glycol)-bl-poly(propylene sulfide) filomicelle-based scaffolds permit the sustained delivery of micellar delivery vehicles for immune cell uptake.

(A) Schematic depicting the individual components comprising the modular filomicelles. (B) Intravital fluorescence images comparing the release of free DyLight-755, uncrosslinked filomicelles and the in situ crosslinked filomicelle scaffold over the course of 1 month. (C) Cumulative release curves of the aforementioned groups representative of the loss of polymer from the injection site. (D) Flow cytometric analysis of micelle uptake within phagocytic immune cell populations within the draining lymph nodes of mice receiving either free DyLight, uncrosslinked filomicelles or the in situ crosslinked filomicelle scaffold 1 month post injection. Reprinted under the terms of the Creative Commons CC BY license [73] © Springer Nature (2018).