Development and In-Vitro Evaluation of Doxorubicin-Loaded Methacrylate Gelatin (GelMa)-Acrylamide Hydrogels for the Treatment of Malignant Pleural Mesothelioma.

Objective: Malignant pleural mesothelioma (MPM) is the most prevalent subtype of malignant mesothelioma that affects the pleural lining of the lungs. Conventionally, chemotherapy via systemic injections has shown limited efficacy due to off-target effects, and inefficacious deposition at the disease site. In our previous study, we reported the development and optimization of UV-initiated methacrylate gelatin (GelMa)-acrylamide based hydrogel formulation for local intracavitary administration of therapies. The current study utilizes a pre-established GelMa formulation for delivering a small molecule chemotherapeutic agent, Doxorubicin (Dox), against in-vitro MPM models.

Methods: Dox-loaded hydrogel (DLH) precursor solution was prepared by dissolving Dox in the precursor solution. The gels were characterized for physical properties such as gelling time, swelling index, bio adhesion, and injectability and were compared to blank hydrogels. Dox-loaded hydrogels were also tested for therapeutic efficacy in MPM cells in various 2D and 3D cell culture models.

Results: It was revealed that Dox-loaded hydrogels retained similar physical properties, including gelling time (< 25 s), swelling index (~ 1,200%), bio-adhesion (> 20 g detachment force), and injectability (< 2N force for injecting precursor), compared to blank hydrogels. Moreover, the gel formulation effectively sustained the release of hydrophilic Dox HCl over a period of 12 days by increasing the degree of crosslinking between GelMa and its crosslinkers. Further, the therapeutic efficacy of Dox was retained even after loading into hydrogels, indicating that no chemical interactions took place between gel excipients and the drug. Studies in MPM cell-based models revealed that DLH showed excellent potential in inhibiting 2D and 3D cell growth, with DLH being more effective than plain Dox in suppressing tumor growth in 3D spheroid models.

Conclusions: Overall, the results of the present study suggest that Dox-loaded hydrogels (DLH) may be a good candidate for efficacy study in preclinical mesothelioma models, with strong potential for clinical translation.