Development of HLB-Adjustable Poly(γ-glutamic acid)-Vitamin E Conjugates as Enhanced TPGS Alternatives for Improved Solubilization, Biosafety, and Antioxidation.

d-α-tocopherol polyethylene glycol succinate (TPGS) is an FDA-approved polymeric solubilizer that is widely used in the pharmaceutical field; however, its limited solubilization capacity and high toxicity limit its wider application. Herein, a novel amphiphile─γ-PGAVE conjugate─was synthesized as a TPGS alternative by esterifying hydrophobic α-tocopherol (i.e., vitamin E; VE) to a hydrophilic γ-polyglutamic acid (γ-PGA) backbone. By achieving a tunable VE grafting ratio (2.5-13.5%) through varying the molar ratio of γ-PGA carboxyl groups to VE, the critical micelle concentration (CMC = 2.4-9.1 μg/mL) and hydrophilic-lipophilic balance (HLB = 4.45-13.39) could be controlled. Among the various γ-PGAVEs with differing graft ratios of VE, γ-PGAVE with a 2.5% grafting ratio (γ-PGAVE-2.5%) demonstrated superior solubilization capacity in aqueous environments. Additionally, antioxidant assays showed that γ-PGAVE-2.5% displayed an improved antioxidant capacity comparable to that of TPGS while exhibiting a significantly lower cytotoxicity. The enhanced biocompatibility and solubilization capability of γ-PGAVE-2.5% suggest that it could be a promising candidate for a range of applications, including food additives, dietary supplements, cosmetic ingredients, and pharmaceutical excipients.