Polymers made of poly(ethylene glycol) chains grafted to poly(lactic acid) chains (PEG-g-PLA) were used to produce stealth drug nanocarriers. A library of comblike PEG-g-PLA polymers with different PEG grafting densities was prepared in order to obtain nanocarriers with dense PEG brushes at their surface, stability in suspension, and resistance to protein adsorption. The structural properties of nanoparticles (NPs) produced from these polymers by a surfactant-free method were assessed by dynamic light scattering, ζ potential, and transmission electron microscopy and found to be controlled by the amount of PEG present in the polymers. A critical transition from a solid NP structure to a soft particle with either a "micellelike" or a "polymer nanoaggregate" structure was observed when the PEG content was between 15 and 25% w/w. This structural transition was found to have a profound impact on the size of the NPs, their surface charge, their stability in suspension in the presence of salts, and the binding of proteins to the surface of the NPs. The arrangement of the PEG-g-PLA chains at the surface of the NPs was investigated by (1)H NMR and X-ray photoelectron spectroscopy (XPS). NMR results confirmed that the PEG chains were mostly segregated at the NP surface. Moreover, XPS and quantitative NMR allowed quantification of the PEG chain coverage density at the surface of the solid NPs. Concordance of the results between the two methods was found to be remarkable. Physical-chemical properties of the NPs such as resistance to aggregation in a saline environment as well as antifouling efficacy were related to the PEG surface density and ultimately to the polymer architecture. Resistance to protein adsorption was assessed by isothermal titration calorimetry using lysozyme. The results indicate a correlation between the PEG surface coverage and level of protein interactions. The results obtained lead us to propose such PEG-g-PLA polymers for nanomedicine development as an alternative to the predominant polyester-PEG diblock polymers.

Improving nanoparticles (NPs) transport across biological barriers is a significant challenge that could be addressed through understanding NPs diffusion in dense and confined media. Here, we report the ability of soft NPs to shrink in confined environments, therefore boosting their diffusion compared to hard, non-deformable particles. We demonstrate this behavior by embedding microgel NPs in agarose gels. The origin of the shrinking appears to be related to the overlap of the electrostatic double layers (EDL) surrounding the NPs and the agarose fibres. Indeed, it is shown that screening the EDL interactions, by increasing the ionic strength of the medium, prevents the soft particle shrinkage. The shrunken NPs diffuse up to 2 orders of magnitude faster in agarose gel than their hard NP counterparts. These findings provide valuable insights on the role of long range interactions on soft NPs dynamics in crowded environments, and help rationalize the design of more efficient NP-based transport systems.

The present study establishes the scaling laws describing the structure of spherical nanoparticles formed by diffusion-limited coalescence. We produced drug-loaded nanoparticles from a poly(ethylene glycol)-poly(d,l-lactic acid) diblock polymer (PEG- b-PLA) by the nanoprecipitation method using different types of micromixing chambers to explore multiple mixing regimes and characteristic times. We first show that the drug loading of the nanoparticles is not controlled by the mixing time but solely by the drug-to-polymer ratio (D:P) in the feed and the hydrophobicity of the drug scaled via the partition coefficient P. We then procure compelling evidence that particles formed via diffusion/coalescence exhibit a relative distribution of PEG blocks between the particle core and its shell that depends only on mixing conditions (not on D:P). Scaling laws of PEG relative distribution and chain surface density were derived in different mixing regimes and showed excellent agreement with experimental data. In particular, results made evident that PEG blocks entrapment in the core of the particles occurs in the slow-mixing regime and favors the overloading (above the thermodynamic limit) of the particles with hydrophilic drugs. The present analysis compiles effective guidelines for the scale up of nanoparticles structure and properties with mixing conditions, which should facilitate their future translation to medical and industrial settings.

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