Nanoparticle-macrophage interactions: A balance between clearance and cell-specific targeting

Abstract

The surface properties of nanoparticles (NPs) are a major factor that influences how these nanomaterials interact with biological systems. Interactions between NPs and macrophages of the reticuloendothelial system (RES) can reduce the efficacy of NP diagnostics and therapeutics. Traditionally, to limit NP clearance by the RES system, the NP surface is neutralized with molecules like poly(ethylene glycol) (PEG) which are known to resist protein adsorption and RES clearance. Unfortunately, PEG modification is not without drawbacks including difficulties with the synthesis and associations with immune reactions. To overcome some of these obstacles, we neutralized the NP surface by acetylation and compared this modification to PEGylation for RES clearance and tumor-specific targeting. We found that acetylation was comparable to PEGylation in reducing RES clearance. Additionally, we found that dendrimer acetylation did not impact folic acid (FA)-mediated targeting of tumor cells whereas PEG surface modification reduced the targeting ability of the NP. These results clarify the impact of different NP surface modifications on RES clearance and cell-specific targeting and provide insights into the design of more effective NPs.

pH-responsive high stability polymeric nanoparticles for targeted delivery of anticancer therapeutics

“…Opsonization of NPs and their subsequent uptake by monocytes and macrophages of the mononuclear phagocyte system (MPS) leads to accumulation of the NPs in healthy organs (e.g., spleen and liver) rather than at the target solid malignant tumors (tumor-associated macrophages are discussed in Supplementary Note 4) 71 . To overcome this issue, the surface of NPs is often functionalized with neutral molecules, e.g., PEG, known to resist protein adsorption and MPS clearance 72 . However, studies have reported that surface modification with compounds such as PEG may trigger an immune reaction 62 .…”

Limitations of Pegylated Nanocarriers: Unfavourable Physicochemical Properties, Biodistribution Patterns and Cellular and Subcellular Fates

“…Also, PEG synthesis and purification are difficult processes that give rise to an inherent polydispersity of the polymer which eventually causes batch-to-batch variability [20].…”

“…For example, intracellular uptake of PEGylated NPs was noted to drop to one-third of the uptake of non-PEGylated ones [46,47]. Also, PEGylation of folic acid (FA)-targeted dendrimers has been also reported decreasing the tumour-specific targeting by FA [20].…”

“…The mechanism by which acetylation reduces RES clearance was hypothesized to occur by neutralizing the cationic surface of the dendrimers and reducing the electrostatic interactions with serum proteins that are required for uptake by RES macrophages. Acetylation is also potentially applicable for modification of other types of nanocarriers and possesses an added advantage of better control over the size and polydispersity of the NP compared to PEGylation [20].…”

Overcoming tumor cell chemoresistance using nanoparticles: lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles

“…90,91 Many approaches have been utilized to limit the clearance of nanomedicines, either by delaying of RES clearance or by altering the surface properties of nanomedicines. 92,93 The physiological barriers are another obstacle that needs to be overcome for nanomedicines to effectively overcome cancer chemoresistance in vivo. 89 The accessibility of nanomedicines to solid tumors is determined by various mechanisms, such as the efficiency of the blood and lymphatic networks in tumor tissues, the permeability of the vascular barriers in tumors, and the constitution of the tumor stroma.…”