Development of injectable hybrid biomaterials and investigation of controlled release efficiencies

Considering the clinical applications of cancer therapy, injectable, pH sensitive, and self-healable hybrid hydrogels stand out as promising biomaterial sets for localized, controlled, and sustained drug release systems. Within this scope, in this study, injectable hydrogel system was fabricated through the cross-linking of hydrazide functional groups in gelatin adipic acid dihydrazide (Gel-ADH) polymer and aldehyde functional groups in polyethylene glycol dibenzaldehyde (diBA-PEG2000) polymer with hydrazone bond. For this set of materials, to perform as a chemotherapeutic drug depot, laponite (LAP) nanodisc loaded with the anticancer drug doxorubicin (DOX) was integrated into the hydrogel during gel formation yielding to hybrid Gel-ADH/diBA-PEG/LAP@DOX. The synthesized hydrogels were characterized by ATR-FTIR, SEM-EDX and rheological analysis. The gelation time of hybrid hydrogel is 80 s while the gelation time of Gel-ADH/diBA-PEG2000 hydrogel is 137 s. With the integration of LAP into the hydrogel, the gelation time of hydrogel decreased, and mechanical strength increased. Additionally, the synthesized hybrid hydrogel exhibits self-healing, pH-sensitive, and injectable properties due to the reversibility of the hydrazone bond. In-vitro DOX release from hydrogels was evaluated in three different phosphate buffer environments (pH=5.0; 6.8; 7.4) at 37˚C. The release of DOX from the hybrid hydrogels was found to be pH sensitive and long-term sustained release continued for over 10 days. Compared to the Gel-ADH/diBA-PEG@DOX hydrogels, hybrid hydrogels exhibited a slower and longer release behaviour. The cytotoxicity of the gel precursor components (Gel-ADH, diBA-PEG2000, and LAP) and the hydrogels was determined using the human breast epithelial cell line (SVCT) and endothelial cell line (HUVEC). Gel precursors and hydrogels showed excellent biocompatibility as well as cell proliferation. Moreover, the cytotoxicity of DOX loaded hybrid hydrogels was investigated on human breast cancer cell lines (MCF-7 and MDA-MB-231). In conclusion, within the scope of this thesis, a new generation pH sensitive, self-healable, and injectable hybrid hydrogel system, which is capable of long-term and controlled drug release, has been developed with great promise for local cancer treatment.