Self-assembled biocompatible heparin-based supramolecular hydrogel for doxorubicin delivery

An array of self-assembled biocompatible doxorubicin (DOX) loaded heparin--cyclodextrin supramolecular hydrogels (DOX@HGs) with highly encapsulated efficiency was constructed using heparin-β-cyclodextrin derivatives (Hep-β-CD), α-cyclodextrin (α-CD), pluronic F-127 and DOX via the synergy of host-guest and multiple hydrogen bonding interactions. These hydrogels were characterized by GPC measurements (GPC), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Size and zeta potential determinations, X-ray diffraction (XRD), and rheological characteristics; the data confirmed successful formation of the hydrogels. Furthermore, these hydrogels demonstrated distinctive thixotropy, indicating rapid self-repairing after continuously oscillatory shear stress. Variable release of DOX from DOX @HGs was obtained at various pH after 84 h depending on the strength of the hydrogels. At pH 7.4, cumulative DOX release was approximately 49.07% for DOX@HG 1, 32.15% for DOX@HG 2, and 27.12% for DOX@HG 3. While at pH 5.5, release of DOX was increased to 59.08% for DOX@HG 1 and to 43.2% for DOX@HG 3 after 84 h (P < 0.05). This information demonstrated that a higher DOX release rate was observed under a lower pH due to strong charge expansion of CDs and weakening of electrostatic interactions between heparin and DOX. Additionally, cytotoxicity of free DOX and DOX@HGs in ovarian cancer SKOV-3 cells was studied at various exposure durations. The results revealed that cytotoxicity of DOX@HG 1-3 toward ovarian cancer SKOV-3 cells was lower than that of free DOX (P < 0.05), suggesting prolonged DOX release from the hydrogels in SKOV-3 cells.