Modulating Phagocytic Cell Sequestration by Tailoring Nanoconstruct Softness

Abstract

The effect of nanoparticle size, shape, and surface properties on cellular uptake has been extensively investigated for its basic science and translational implications. Recently, softness is emerging as a design parameter for modulating the interaction of nanoparticles with cells and the biological microenvironment. Here, circular, quadrangular, and elliptical polymeric nanoconstructs of different sizes are realized with a Young's modulus ranging from ∼100 kPa (soft) to 10 MPa (rigid). The interaction of these nanoconstructs with professional phagocytic cells is assessed via confocal microscopy and flow cytometry analyses. Regardless of the size and shape, softer nanoconstructs evade cellular uptake up to 5 times more efficiently, by bone-marrow-derived monocytes, as compared to rigid nanoconstructs. Soft circular and quadrangular nanoconstructs are equally uptaken by professional phagocytic cells (<15%); soft elliptical particles are more avidly internalized (<60%) possibly because of the larger size and elongated shape, whereas over 70% of rigid nanoconstructs of any shape and size are uptaken. Inhibition of actin polymerization via cytochalasin D reduces the internalization propensity for all nanoconstruct types. High-resolution live cell microscopy documents that soft nanoconstructs mostly establish short-lived (<30 s) interactions with macrophages, thus diminishing the likelihood of recognition and internalization. The bending stiffness is identified as a discriminating factor for internalization, whereby particles with a bending stiffness slightly higher than cells would more efficiently oppose internalization as compared to stiffer or softer particles. These results confirm that softness is a key parameter in modulating the behavior of nanoparticles and are expected to inspire the design of more efficient nanoconstructs for drug delivery, biomedical imaging, and immunomodulatory therapies.

Optimizing the Pharmacological Properties of Discoidal Polymeric Nanoconstructs Against Triple-Negative Breast Cancer Cells

“…A versatile fabrication strategy was used to realize polymeric nanoconstructs with controlled geometrical and mechanical features, including the size, shape, surface properties, and mechanical stiffness-the 4S parameters. These features can be independently tuned in the fabrication process to affect the therapeutic and imaging performances, as shown by the authors and other investigators (Key et al, 2013;Palomba et al, 2018). The first step in DPNs fabrication is the realization of a master silicon template through a Direct Laser Writer lithographic process.…”

“…Within this scenario, the authors have previously demonstrated a new nanotechnological platform-the Discoidal Polymeric Nanoconstructs (DPNs). Similarly to red blood cells, DPNs tend to resist sequestration by professional phagocytic cells, such us hepatic Kupffer cells and splenic macrophages (Palomba et al, 2018). This DPN feature results in longer circulation times and increased probability to lodge within the tortuous and low perfused tumor microvasculature (Key et al, 2015).…”

“…The Discoidal Polymeric Nanoconstructs are realized with a top-down, template-based approach, where the size, shape, surface properties and mechanical stiffness can be readily and independently modulated (Key et al, 2013;Palange et al, 2017;Palomba et al, 2018). DPNs are made out of poly(lactic-coglycolic acid) (PLGA) and polyethylene glycol (PEG) chains entangled together to form a hydrogel matrix.…”

Materials for Immunotherapy

“…[381] Afterward, work by Decuzzi and coworkers revealed that the softness of backpacks also plays a role in suppressing their phagocytosis. [382] Guan and co-workers leveraged these concepts to fabricate different types of backpacks with various payloads using microcontact printing. [383] In 2015, Mitragotri and co-workers advanced their earlier work by showing that monocytes can deliver backpacks to inflamed areas in the body as a step toward immunotherapeutic applications (see Figure 14f for more recent iterations of backpacks made from PLGA).…”

Branched and Dendritic Polymer Architectures: Functional Nanomaterials for Therapeutic Delivery

“…[14][15][16] Materials chemists can elegantly engineer materials of various sizes, shapes, compositions and physicochemical properties. [17][18][19][20] Inorganic materials such as iron oxide nanoparticles, carbon nanotubes, metal organic frameworks, and mesoporous silica constructs, have been applied with good effect. 21 Biological materials are also being investigated including viral vectors for the delivery of gene-based therapeutics, and more recently extracellular vesicles have been receiving interest for drug delivery.…”