Monodisperse PEG engineering for quantifiable surface conjugation on PLGA nanoparticles.

Authors

Ezgi Basavci, Alvja Mali, Marjan Kalati, Raphael Marques Marcilli, Mangala Srinivas

Published in

Nanoscale advances. Jun 30, 2026. Epub Jun 30, 2026.

Abstract

Surface PEGylation is a well-established strategy to enhance the stability, functionality, and bioavailability of nanoparticles (NPs) in biomedical applications. However, the widespread use of polydisperse PEG derivatives limits the ability to precisely quantify surface PEGylation efficiency (mol%) and evaluate its effect on NP properties. In this study, we present a systematic approach to engineer PLGA NPs using structurally defined monodisperse PEG-diamine derivatives of varying chain lengths (PEG6, PEG26, PEG45), synthesized and purified by chromatographic methods and covalently attached via EDC/NHS-mediated amide bond formation under mild conditions. PEGylation was quantified by ¹H NMR through integrating the PEG methylene and PLGA lactide signals, taking advantage of the defined chain length of the monodisperse PEGs to calculate the molar degree of PEGylation. PEGylation was strongly influenced by surface purification protocols, particularly the removal of residual surfactant (PVA). Thermogravimetric analysis (TGA) and derivative thermogravimetric analysis (DTGA) demonstrated that PEGs with higher molar mass conferred greater thermal stability to both free PEGs and PEGylated NPs. PEGylated NPs exhibited improved PFCE encapsulation (up to 18.2%) under the tested lyophilization and washing conditions. Incubation in an albumin-containing medium showed that PEGylated NPs maintained a narrow size distribution and low PDI over 20 hours, suggesting that extended PEG chains provided more effective surface shielding in a protein-rich environment. Long-term stability studies over 60 days revealed condition-dependent improvements in colloidal stability under physiologically relevant conditions. In PBMCs, all formulations maintained over 80% cell viability after 24 hours, while RAW macrophages displayed moderate formulation-dependent responses after 4 hours, with PEG45-PLGA NPs showing slightly higher viability than the other NP formulations. Overall, this work highlights that monodisperse PEG engineering enables reproducible and quantitative surface modification of PLGA NPs. This approach offers a robust platform for the rational design of advanced polymeric nanocarriers, exemplified here for ¹⁹F MRI applications.

PMID:
42438481
Bibliographic data and abstract were imported from PubMed on 13 Jul 2026.

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