Beyond Trial and Error: A Systematic Development of Liposomes Targeting Primary Macrophages

Abstract

Monocytes/macrophages are phagocytic innate immune cells playing a pivotal role in tissue homeostasis, inflammation, and antitumor immunity in a microenvironment‐dependent manner. By expressing pattern recognition and scavenger receptors on their surface, macrophages selectively take up pathogens, cellular debris, and often—undesirably—drug delivery systems. On the other hand, the propensity of phagocytic cells to internalize particulate drug carriers is used to load them with a cargo of choice, turning the monocytes/macrophages into a diagnostic or therapeutic Trojan horse. Identifying the ideal physicochemical properties of particulate carriers such as liposomes to achieve the most efficient macrophage‐mediated drug delivery has been object of extensive research in the past, but the studies reported so far rely solely on trial‐and‐error approaches. Herein, a design of experiment (DoE) strategy to identify the optimal liposomal formulation is proposed, fully characterized in terms of size, surface charge, and membrane fluidity, to maximize macrophage targeting. The findings are validated using mouse bone marrow‐derived macrophages, a primary preparation modeling in vivo monocyte‐derived macrophages, thus confirming the robustness and versatility of the systematic and iterative approach and suggesting the promising potential of the DoE approach for the design of cell‐targeting delivery systems.

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“…Particle size and shape are important characteristics in directing phagocytic endocytosis, and can also be used to enhance uptake into specific immune cells. [141][142][143][144] When the attachment and internalization rate of a range of 1 to 6 mm polystyrene microspheres was assessed in macrophages, 2-3 mm diameter particles were consistently taken up to a greater extent. 145 It was hypothesized that this size preference is mediated by the intrinsic structure of macrophages' ruffled membrane, as this behavior was lost after the elimination of ruffles via osmotic swelling and is consistent among multiple macrophage populations.…”

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“…In other cases, the therapeutic strategy may benefit from reduced interactions with macrophages, as they are primarily responsible for nanoparticle degradation and clearance, thereby reducing circulation and retention times. , Notably, high concentrations (>45 mol %) of cholesterol in liposome formulations have been correlated with decreased macrophage uptake in vitro due to increased particle rigidity. , However, liposomes with up to 40 mol % cholesterol are taken up to a greater extent by macrophages compared to cholesterol-free ones . The increased cellular internalization may be due to liposome resemblance to cholesterol-containing chylomicrons that are naturally taken up by phagocytes . The incorporation of polyethylene glycol (PEG) in liposomes can prolong retention and circulation times, which leads to improved efficacy.…”

“…100,101 However, liposomes with up to 40 mol % cholesterol are taken up to a greater extent by macrophages compared to cholesterol-free ones. 102 The increased cellular internalization may be due to liposome resemblance to cholesterol-containing chylomicrons that are naturally taken up by phagocytes. 102 The incorporation of polyethylene glycol (PEG) in liposomes can prolong retention and circulation times, which leads to improved efficacy.…”

“…102 The increased cellular internalization may be due to liposome resemblance to cholesterol-containing chylomicrons that are naturally taken up by phagocytes. 102 The incorporation of polyethylene glycol (PEG) in liposomes can prolong retention and circulation times, which leads to improved efficacy. PEG alters the biomolecular corona of liposomes, causing reduced interactions with macrophages.…”