Effect of the Polymer Architecture on the Structural and Biophysical Properties of PEG–PLA Nanoparticles

Abstract

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.

Nanoparticle stability in biologically relevant media: influence of polymer architecture

“…S11-S14, ESI †). 13 Overall, these results are consistent with nanoparticles exhibiting a solid-like PLA core, stabilized by a solubilized PEG corona. 40 The use of an external standard (methanol) allowed for quantification of PEG on nanoparticle surfaces relative to the total PEG content.…”

“…42 This was also observed to be the case for PEG/PLA nanoparticles made from grafted copolymers, as shown by Banquy et al 13 At higher temperatures, increased disruption of the hydrogen bonding between PEG and water would further contribute to agglomeration. 42 This was also observed to be the case for PEG/PLA nanoparticles made from grafted copolymers, as shown by Banquy et al 13 At higher temperatures, increased disruption of the hydrogen bonding between PEG and water would further contribute to agglomeration.…”

“…13 Binding stoichiometry ranged from B0.2-2, indicating only a small number of binding events per nanoparticle. This was recently suggested, albeit not quantified, for the interaction between bovine serum albumin (BSA, a protein similar to HSA) and PEG/PLA nanoparticles from graft copolymers.…”

“…[5][6][7][8] It is generally agreed that high molecular weight PEG (42000 Da) will endow nanoparticles with stealth properties, 9 and that higher PEG surface density will reduce protein binding and macrophage uptake, hence prolonging circulation half-lives. 1,12,13 Yet other examples of complex macromolecular architectures are linear-dendritic polymers or dendron-coils, which self-assemble into micelles at concentrations 1-2 orders of magnitude lower than their linear counterparts (B10 À8 M), and are reported to have high surface coverage of the hydrophilic component. However, less so is known regarding the interactions of proteins with nanoparticles from polymers with more complex molecular architectures, which are gaining popularity as a consequence of their unique physicochemical properties; a recent example is Banquy's work on nanoparticles from graft copolymers.…”

Role of self‐assembly conditions and amphiphilic balance on nanoparticle formation of PEG‐PDLLA copolymers in aqueous environments

“…Due to their intrinsic amphiphilic balance, PEGylated block copolymers are perfect candidates to be formulated into NPs via simple nanoprecipitation techniques. In this regard, previous studies have demonstrated that the amphiphilic balance of the copolymers can impact the size, stability, surface charge, and protein corona formation on the final NPs . However, there are a series of physicochemical parameters that drive the nucleation, growth, and aggregation of the polymers into NPs during the nanoprecipitation process that have not yet been fully understood .…”