Fast dissolving nanofiber (NF) composed of poly(vinyl alcohol) (PVA) and D-alpha-tocopheryl polyethylene glycol succinate (TPGS) was developed for locoregional delivery of phloretin to oral cancers. PVA/TPGS/phloretin NF with 321 nm mean diameter and >90% drug entrapment efficiency was fabricated by an electrospinning method. Transformation of drug from crystalline to amorphous state was identified by solid-state studies. NF structure was changed to nanoparticles after its dispersing in the aqueous medium. PVA/TPGS/phloretin NF exhibited fast wetting property and smaller hydrodynamic size of dispersion, compared with PVA/phloretin NF. The amphiphilic property of TPGS also contributed to the improved drug release from PVA/TPGS/phloretin NF. The anticancer activities of phloretin, via the inhibition of glucose uptake into the cancer cells, in NFs were assessed in YD-9 cells (oral squamous cell carcinoma from buccal cheek). The antiproliferation efficacy of PVA/TPGS/phloretin NF was significantly higher than that of phloretin solution and PVA/phloretin NF (p < 0.05). Higher apoptotic events were also observed in PVA/TPGS/phloretin NF group rather than phloretin solution and PVA/phloretin NF groups (p < 0.05). All these results support that PVA/TPGS/phloretin NF can be a promising fast dissolving formulation for the treatment of oral cancers. (C) 2017 Elsevier Inc. All rights reserved.