Effect of salt-induced structural changes in hydroxypropyl methylcellulose gels on 5-fluorouracil release

Localized chemotherapy represents a promising strategy for enhancing tumor-targeted drug delivery while minimizing systemic toxicity. In this study, we investigated thermosensitive hydroxypropyl methylcellulose (HPMC)-based hydrogels for the prolonged localized delivery of 5-fluorouracil (5-FU). The sol-gel transition temperature of the formulations was modulated within the physiological range (32-37) using Hofmeister salts. Rheological analysis revealed that 5-FU alone decreased the gelation temperature of HPMC from 47 ± 0.8 °C to 44 ± 0.7 °C due to the competitive disruption of polymer hydration shells. Salt addition further decreased sol-gel transition temperatures following the salting-out order PO₄^3- > SO₄^2- > Cl^-. Synergistic effects in HPMC/salt/5-FU systems were observed. 5-FU increased the viscoelastic moduli and promoted a more compact, homogeneous microstructure exclusively in gels with K₂SO₄ content. FTIR spectroscopy confirmed the absence of covalent interactions between the gel components, indicating physical crosslinking In vitro release studies demonstrated that drug transport is governed by both the specific nature of the anions and the ionic strength. The HPMC/K₂SO_{4_0.2M}/5-FU formulation provided the most prolonged release profile, which correlated with superior mechanical strength and a homogeneous gel network structure. These findings highlight the potential of Hofmeister salt modulated HPMC hydrogels for tailored, long-acting localized drug delivery in cancer therapy.