Sparingly PEGylated Adipate Copolymers via Enzymatic Synthesis as Nano-Carriers for Solid Dispersions

Recent studies have highlighted the limitations of conventional high degrees of PEGylation in drug delivery systems, including immune recognition and reduced efficacy. Approaches such as poly(ethylene glycol) (PEG) isomerization and shortening of PEG chains have emerged as strategies to mitigate anti-PEG immune responses while preserving key physicochemical properties required for drug delivery. Inspired by these advancements, this study aims to enzymatically synthesize new hybrid polymers incorporating a limited fraction of PEG and biosourced polyols, such as glycerol and diglycerol, as the hydrophilic counterpart, minimizing the amount of PEG by 50% (compared to our previous work). These novel adipate-based tetrapolymers, generated using four different starting materials, outperformed previous systems, offering a tunable and sustainable design for nanomedicine. By strategically limiting the PEG fraction, we preserved the functional benefits of PEGylation, including stealth and amphiphilicity, while advancing toward greener chemistry. The resulting biodegradable PEGylated polyesters were formulated from film rehydration of solid dispersions and increased the water solubility of the model drug curcumin via direct encapsulation of the compound in polymeric nanoparticles. The best performing polymer variant consisted of diglycerol, 1,6-hexanediol, and PEG combined with divinyl adipate (PEGDGA-Hex 50%). Its drug interactions, colloidal stability, biodegradability, and biocompatibility, in both in vitro (Caco2, human intestinal epithelial cells MCF-7, human breast cancer cells, and MDA-MB-231 late-stage triple-negative breast cancer cells) and invertebrate in vivo models that align with 3R principles (Caenorhabditis elegans and Drosophila melanogaster), support its potential use in systemic drug delivery.