Influence of PEGylation on nanoparticle mobility in different models of the extracellular matrix

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Abstract

Nanoparticle transport inside the extracellular matrix (ECM) is a crucial factor affecting the therapeutic success. In this work, two in vitro ECM models – a neutrally charged collagen I network with an effective pore size of 0.47 μm and Matrigel, a basement membrane matrix with strong negative charge and effective pore size of 0.14 μm – were assessed for barrier function in the context of diffusing nanoparticles. Nanoparticles with a size of 120 nm were coated with poly(ethylene glycol) (PEG) of different molecular weights – 2, 5 and 20 kDa – over a range of gradually increasing coating densities – precisely 0.2, 2, 8 and 20 PEG/nm2. The PEG corona was imaged in its native state without any drying process by atomic force microscopy, revealing that the experimentally determined arrangement of PEG at the surface did not match with what was theoretically expected. In a systematic investigation of nanoparticle mobility via fluorescence recovery after photobleaching, increasing both PEG MW and PEGylation density gradually improved diffusion properties predominately in collagen. Due to its smaller pore size and electrostatic obstruction, diffusion coefficients were about ten times lower in Matrigel than in the collagen network and an extension of the PEG MW and density did not necessarily lead to better diffusing particles. Consequently, collagen gels were revealed to be a poor model for nanoparticle mobility assessment, as neither their pore size nor their electrostatic properties reflect the expected in vivo conditions. In Matrigel, diffusion proceeded according to a sigmoidal increase with gradually increasing PEG densities showing threshold zeta potentials of 11.6 mV (PEG2kDa) and 13.8 mV (PEG5kDa), below which particles were regarded as mobile. Irrespective of the molecular weight particles with a PEGylation density lower than 2 PEG/nm2 were defined as immobile and those with a PEG coverage of more than 8 PEG/nm2 as mobile.

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