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

Abstract

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.

Formulation of tunable size PLGA-PEG nanoparticles for drug delivery using microfluidic technology

“…The conjugated PEG allows to minimize the use of formulation stabilizers and importantly, it decreases the formation of protein corona after administration and results in extended systemic circulation of the NPs [33][34][35][36]. Furthermore, the PEG chain terminated with targeting ligands, demonstrated positive results in in vitro studies [22,37].…”

Effect of Physico-Chemical Properties of Nanoparticles on Their Intracellular Uptake

“…In a bid to examine the role of ligand mobility, cellular uptake of PLA-PEG nanoparticles bound to angiotensin-II was investigated using rat mesangial cells. It was found that a lower ligand density (20%) allowed more ligand mobility and enhanced binding to specific receptors, increasing it to 80%, and decreased cellular uptake, which may be associated with lower free movement of NPs [105].…”

Biomedical nanoparticle design: What we can learn from viruses

“… NP Ligands Targets Optimal ligand density/structure In vivo Therapy/Cargo Ref. Quantum dots Peptide NPY 1 receptor – – – [ 73 ] PAMAM dendrimers/Branched PEG Small molecule AT1R – – – [ 103 ] PEG-PLA/PLGA NPs “-” “-” 20% (+ high mobility) – – [ 113 ] PEG-PLGA NPs Folate Folate receptor >10% – DNA [ 110 ] Linear dendritic polymer NPs “-” “-” 20% KB/A375 tumors (mouse) – [ 114 ] Polystyrene/Ovalbumin NPs “-” “-” clustered – – [ 121 ] PLGA NPs Peptide ICAM-1 50% – – [ 111 ] Iron oxide NPs Antibody HER2/neu 23 ligands/NP (medium density) – – [ 112 ] PEG-Au NPs RGD αvβ3 integrin high – – [ 115 ] PEG-PLA/PLGA NPs c(RGDfK) “-” “-” – ...…”

“…Similarly, Elias et al [ 112 ] found that an intermediate ligand density was optimal for targeting purposes using antibodies against HER2/neu, overexpressed in cancer cells. Generally, decreases in targeting with higher grafting densities are explained by a steric hindrance of the ligands and decreased ligand mobility [ 113 ]. This may disrupt interaction with the receptors to a point where their internalization is impeded.…”

“…Second, it can alter the ligand disposition, which can be spaced out or tightly grouped by using longer or shorter tethers, respectively [ 116 ]. Thirdly, it can influence the ligand mobility on the particle surface, which has a tremendous influence on the cellular internalization of a NP [ 113 ].…”