Ligand density on nanoparticles: A parameter with critical impact on nanomedicine

Alkilany, Alaaldin M.; Zhu, Lin; Weller, Horst; Mews, Alf; Parak, Wolfgang J.; Barz, Matthias; Feliu, Neus

doi:10.1016/j.addr.2019.05.010

Cited by 157 publications

(148 citation statements)

References 146 publications

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“…The establishment of multivalent interactions between NPs and their target cells is a complex multifactorial process. Different particle attributes, such as size or ligand‐ type and density [ 5 ] are essential for determining the binding avidity. However, our work suggests that a high particle avidity for the targeted receptors does not unequivocally predict a particle's fate after binding.…”

Section: Resultsmentioning

confidence: 99%

“…There are several factors that are known to influence a nanomaterial's multivalent binding, and thus the targeting capacity of NPs, such as particle size and receptor‐ or ligand density. [ 4,5 ] The latter not only determines the ability of a NP to bind to the target cell surface, but also the thermodynamic feasibility of cellular uptake [ 6 ] and its precise pathway. [ 7 ] Still, there are several other elements that contribute to the thermodynamic favorability of a multivalent interaction, among which flexibility was noted to be crucial by several publications.…”

Section: Introductionmentioning

confidence: 99%

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The Effect of Ligand Mobility on the Cellular Interaction of Multivalent Nanoparticles

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Fleischmann

Beck

et al. 2020

Macromolecular Bioscience

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Multivalent nanoparticle binding to cells can be of picomolar avidity making such interactions almost as intense as those seen with antibodies. However, reducing nanoparticle design exclusively to avidity optimization by the choice of ligand and its surface density does not sufficiently account for controlling and understanding cell–particle interactions. Cell uptake, for example, is of paramount significance for a plethora of biomedical applications and does not exclusively depend on the intensity of multivalency. In this study, it is shown that the mobility of ligands tethered to particle surfaces has a substantial impact on particle fate upon binding. Nanoparticles carrying angiotensin‐II tethered to highly mobile 5 kDa long poly(ethylene glycol) (PEG) chains separated by ligand‐free 2 kDa short PEG chains show a superior accumulation in angiotensin‐II receptor type 1 positive cells. In contrast, when ligand mobility is constrained by densely packing the nanoparticle surface with 5 kDa PEG chains only, cell uptake decreases by 50%. Remarkably, irrespective of ligand mobility and density both particle types have similar EC50 values in the 1–3 × 10−9 m range. These findings demonstrate that ligand mobility on the nanoparticle corona is an indispensable attribute to be considered in particle design to achieve optimal cell uptake via multivalent interactions.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Effect of Ligand Mobility on the Cellular Interaction of Multivalent Nanoparticles

Figueroa

Fleischmann

Beck

et al. 2020

Macromolecular Bioscience

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“…One of the most relevant ones is ligand density, which is frequently neglected in nanomaterial design. In their excellent recent review Alkilany et al [ 109 ] calculated the number of ligands displayed by viruses on their surface. Depending on the virus, they obtained a range between 7 and 659 ligands per virus particle.…”

Section: Ligand Display and Cell Recognitionmentioning

confidence: 99%

“…Despite generally addressing disease-related overexpressed receptors, they are often also prevalent in “healthy” off-target tissues, which leads to poor material bioavailabilities and deleterious side effects. One of the elements that can negatively impact the specificity of multivalent NPs is the elevated number of ligands displayed on their corona, which is usually higher than the one presented by viruses [ 109 ]. In vivo this may additionally cause a particle stealth loss and increased protein corona formation, which also hinders targeting.…”

Section: Ligand Display and Cell Recognitionmentioning

confidence: 99%

“…However, for most published formulations there is a lack of information regarding these parameters ( Table 3 ). As they have enormous influence on the establishment of receptor interactions [ 109 , 132 ], it should come as no surprise that heteromultivalent NPs frequently achieve only moderate improvements, regarding targeting and specificity, compared to “simple” multivalent systems [ 126 , 133 ]. The addition of a second ligand type increases the complexity of the system and does not equal the rise in number of a single ligand.…”

Section: Ligand Display and Cell Recognitionmentioning

confidence: 99%

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Biomedical nanoparticle design: What we can learn from viruses

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Fleischmann

Goepferich

2021

Journal of Controlled Release

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Viruses are nanomaterials with a number of properties that surpass those of many synthetic nanoparticles (NPs) for biomedical applications. They possess a rigorously ordered structure, come in a variety of shapes, and present unique surface elements, such as spikes. These attributes facilitate propitious biodistribution, the crossing of complex biological barriers and a minutely coordinated interaction with cells. Due to the orchestrated sequence of interactions of their stringently arranged particle corona with cellular surface receptors they effectively identify and infect their host cells with utmost specificity, while evading the immune system at the same time. Furthermore, their efficacy is enhanced by their response to stimuli and the ability to spread from cell to cell. Over the years, great efforts have been made to mimic distinct viral traits to improve biomedical nanomaterial performance. However, a closer look at the literature reveals that no comprehensive evaluation of the benefit of virus-mimetic material design on the targeting efficiency of nanomaterials exists. In this review we, therefore, elucidate the impact that viral properties had on fundamental advances in outfitting nanomaterials with the ability to interact specifically with their target cells. We give a comprehensive overview of the diverse design strategies and identify critical steps on the way to reducing them to practice. More so, we discuss the advantages and future perspectives of a virus-mimetic nanomaterial design and try to elucidate if viral mimicry holds the key for better NP targeting.

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Ligand Density Controls C‐Type Lectin‐Like Molecule‐1 Receptor–Specific Uptake of Polymer Nanoparticles

et al. 2020

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Ligand density on nanoparticles: A parameter with critical impact on nanomedicine

Cited by 157 publications

References 146 publications

The Effect of Ligand Mobility on the Cellular Interaction of Multivalent Nanoparticles

The Effect of Ligand Mobility on the Cellular Interaction of Multivalent Nanoparticles

Biomedical nanoparticle design: What we can learn from viruses

Ligand Density Controls C‐Type Lectin‐Like Molecule‐1 Receptor–Specific Uptake of Polymer Nanoparticles

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