Nanoparticles with dense poly(ethylene glycol) coatings with near neutral charge are maximally transported across lymphatics and to the lymph nodes

McCright, Jacob; Skeen, Colin; Yarmovsky, Jenny; Maisel, Katharina

doi:10.1016/j.actbio.2022.03.054

Cited by 33 publications

(47 citation statements)

References 62 publications

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“…Non-coated PS nanoparticles had a highly negative surface ζ-potential, due to functionalization with carboxylic acid groups (Table 1). Increasing amounts of PEG on nanoparticles reduced the surface ζ-potential to near neutral charge (Table 1) and we confirmed that nanoparticles were coated either with mushroom (Rf/D close to 1) or dense PEG (Rf/D > 4) PEG conformations (Table 1) [23]. ± 0.4 μm 2 /s for 100 nm and 200 nm nanoparticles, respectively.…”

Section: Dense Peg Coatings Enhance Nanoparticle Diffusion Through Ln...supporting

confidence: 70%

“…Additionally, using MPT for determining material properties like microrheology of a biological sample requires the nanoparticles to minimally interact with the native environment, as charge or hydrophilicity-based interactions can affect microrheological properties calculated via MPT [16]. PEGylation has been used to design nanoparticles that are able to cross biological barriers, including cellular barriers [22][23][24] and extracellular tissue structures such as mucus [21,[25][26][27] and brain and tumor ECM [28][29][30]. A key parameter to minimize nanoparticle-biological material interactions is the density of PEG on the nanoparticle surface [17].…”

Section: Dense Peg Coatings Enhance Nanoparticle Diffusion Through Ln...mentioning

confidence: 99%

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Multiple particle tracking (MPT) using PEGylated nanoparticles reveals heterogeneity within murine lymph nodes and between lymph nodes at different locations

Ramirez¹,

Merwitz²,

Lee³

et al. 2022

Preprint

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The lymph node (LN) is the main site where adaptive immunity is shaped, through education of B and T cells. LNs are highly structured lymphoid organs that compartmentalize B and T cells in the outer cortex and inner paracortex, respectively, and are supported by a collagen-rich reticular network. Tissue material properties like viscoelasticity and diffusion of materials within extracellular spaces and their implications on cellular behavior have been a recent hot topic of investigation. Researchers have shown that mechanical properties of LNs are dependent on reticular network and extracellular matrix, and the LN mesh spacing has been estimated at 10 - 20 um. Here, we developed a nanoparticle system to investigate the rheological properties, including pore size and viscoelasticity, through multiple particle tracking (MPT) combined with LN slice cultures. We first determined that dense coatings with polyethylene glycol (PEG) are necessary to allow nanoparticles to diffuse within the extracellular spaces of the LNs. We demonstrate that despite differences in functionality, extracellular tissue properties and mesh spacing do not change significantly in the cortex and paracortex, where B and T cells are educated, respectively, though nanoparticle diffusion was slightly reduced in B cell zones, indicating a higher viscosity. Our studies also confirm that LNs exhibit viscoelastic properties, with an initial solid-like response followed by stress-relaxation at higher frequencies. Finally, we found that nanoparticle diffusion is dependent on LN location, with nanoparticles in skin draining LNs (sdLNs) exhibiting higher diffusion compared to mesenteric LNs (mLNs). This phenomenon is also reflected in the slightly reduced nanoparticle diffusion coefficient and pore size in mLNs. Our data shed new light onto LN interstitial tissue properties, pore size, and define surface chemistry parameters required for nanoparticles to diffuse within LN interstitium. These studies provide both a tool for studying LNs interstitium and design criteria for nanoparticles targeting LN interstitial spaces, which has recently received increasing attention.

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Section: Dense Peg Coatings Enhance Nanoparticle Diffusion Through Ln...supporting

confidence: 70%

Section: Dense Peg Coatings Enhance Nanoparticle Diffusion Through Ln...mentioning

confidence: 99%

Multiple particle tracking (MPT) using PEGylated nanoparticles reveals heterogeneity within murine lymph nodes and between lymph nodes at different locations

Ramirez¹,

Merwitz²,

Lee³

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The conformational transition from a dumbbell to brush conformation at high grafting density has been thoroughly studied on surfaces, where the change in conformation is remarked by the relation between the distance between two grafts ( D ) and a polymer size-dependent Flory radius ( R f ) . However, experimental evidence of conformational changes at high degrees of PEGylation on protein surfaces has been scarcely observed, with reports limited to diPEGylation, − or simple globular structures such as nanoparticles, , although high density PEGylation has been achieved in lysozyme . Recently, high-density PEGylation of ovalbumin has been reported, with specific references toward a brush-like conformation at R f / D > 2.…”

Section: Resultsmentioning

confidence: 99%

Moving Protein PEGylation from an Art to a Data Science

2022

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PEGylation is a well-established and clinically proven half-life extension strategy for protein delivery. Protein modification with aminereactive poly(ethylene glycol) (PEG) generates heterogeneous and complex bioconjugate mixtures, often composed of several PEG positional isomers with varied therapeutic efficacy. Laborious and costly experiments for reaction optimization and purification are needed to generate a therapeutically useful PEG conjugate. Kinetic models which accurately predict the outcome of socalled "random" PEGylation reactions provide an opportunity to bypass extensive wet lab experimentation and streamline the bioconjugation process. In this study, we propose a protein tertiary structure-dependent reactivity model that describes the rate of protein-amine PEGylation and introduces "PEG chain coverage" as a tangible metric to assess the shielding effect of PEG chains. This structure-dependent reactivity model was implemented into three models (linear, structure-based, and machine-learned) to gain insight into how protein-specific molecular descriptors (exposed surface areas, pK a , and surface charge) impacted amine reactivity at each site. Linear and machine-learned models demonstrated over 75% prediction accuracy with butylcholinesterase. Model validation with Somavert, PEGASYS, and phenylalanine ammonia lyase showed good correlation between predicted and experimentally determined degrees of modification. Our structure-dependent reactivity model was also able to simulate PEGylation progress curves and estimate "PEGmer" distribution with accurate predictions across different proteins, PEG linker chemistry, and PEG molecular weights. Moreover, in-depth analysis of these simulated reaction curves highlighted possible PEG conformational transitions (from dumbbell to brush) on the surface of lysozyme, as a function of PEG molecular weight.

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“…Nanoparticles can be engineered to facilitate the controlled release of immunotherapies, and can limit negative immunogenic and toxic side effects through the encapsulation of delivered components and targeted delivery to tissues of interest (Reddy et al, 2007;Gutjahr et al, 2016;Chen et al, 2020). Research from the last decade has identified that nanomaterials between 10-250 nm in diameter (Kobayashi et al, 2006), and up to 1 micron in some studies, can also be taken up by LECs through transcellular and paracellular mechanisms (Srinivasan et al, 2016;McCright et al, 2022). In the gastrointestinal tract, lymphatics also play a special role in lipid absorption: lipids are taken up by lymphatic vessels via chylomicrons, small lipid vesicles into which dietary lipids are packaged by enterocytes.…”

Section: Targeting Lymphatics For Drug Deliverymentioning

confidence: 99%

Targeting Lymphatics for Nanoparticle Drug Delivery

et al. 2022

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The lymphatics transport material from peripheral tissues to lymph nodes, where immune responses are formed, before being transported into systemic circulation. With key roles in transport and fluid homeostasis, lymphatic dysregulation is linked to diseases, including lymphedema. Fluid within the interstitium passes into initial lymphatic vessels where a valve system prevents fluid backflow. Additionally, lymphatic endothelial cells produce key chemokines, such as CCL21, that direct the migration of dendritic cells and lymphocytes. As a result, lymphatics are an attractive delivery route for transporting immune modulatory treatments to lymph nodes where immunotherapies are potentiated in addition to being an alternative method of reaching systemic circulation. In this review, we discuss the physiology of lymphatic vessels and mechanisms used in the transport of materials from peripheral tissues to lymph nodes. We then summarize nanomaterial-based strategies to take advantage of lymphatic transport functions for delivering therapeutics to lymph nodes or systemic circulation. We also describe opportunities for targeting lymphatic endothelial cells to modulate transport and immune functions.

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Nanoparticles with dense poly(ethylene glycol) coatings with near neutral charge are maximally transported across lymphatics and to the lymph nodes

Cited by 33 publications

References 62 publications

Multiple particle tracking (MPT) using PEGylated nanoparticles reveals heterogeneity within murine lymph nodes and between lymph nodes at different locations

Multiple particle tracking (MPT) using PEGylated nanoparticles reveals heterogeneity within murine lymph nodes and between lymph nodes at different locations

Moving Protein PEGylation from an Art to a Data Science

Targeting Lymphatics for Nanoparticle Drug Delivery

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