Controlled Functionalization of Poly(Glycerol Adipate) With N-Acetyl-Tryptophan Enables the Design of Dry Powder Nanoparticle Formulations

Poly(glycerol adipate) (PGA) is a glycerol-based biodegradable polyester that is emerging as a versatile platform for healthcare applications, owing to its biocompatibility, ease of functionalization, tunable physicochemical properties, and potential for enzymatic synthesis via green chemistry protocols. However, PGA is a viscous liquid with low glass transition temperature (~T_g −30°C) which limits its use in dry powder-based medicines formulations for inhalation or reconstitution for injection. Here, we report an efficient synthetic strategy that exploits the pendant hydroxyl groups on the PGA backbone to achieve > 90% functionalization with N-acetyl-tryptophan (NAcTrp). This approach enables precise tuning of the T_g and hydrophobicity (water contact angle) of PGA-NAcTrp polymers (60%–100% target substitution), with both properties exhibiting a strong linear correlation to the degree of NAcTrp functionalization. This strategy achieves T_g values in the 40°C–63°C range, making these materials suitable for dry powder formulations. The synthesized PGA-NAcTrp_60%–100% polymers can be formulated into spherical nanoparticles with a sub-100 nm particle size, which, using trehalose (5% w/v) as a cryoprotectant in the freeze-drying process, can be successfully reconstituted into nanoparticles suspensions. Overall, this study broadens the applicability of functionalized PGA polymers, establishing their potential for designing and fabricating dry powder particle-based formulations across diverse healthcare applications.