Kulkarni Nishant S, Chauhan Gautam, Quadros Mural, Gadhave Dnyandev G, Gupta Vivek
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY, 11439, USA.
Pharm Res. 2024 Dec;41(12):2331-2345. doi: 10.1007/s11095-024-03794-z. Epub 2024 Dec 4.
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.
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.
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.
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.
恶性胸膜间皮瘤（MPM）是影响肺胸膜的最常见的恶性间皮瘤亚型。传统上，通过全身注射进行化疗由于存在脱靶效应以及在疾病部位的无效沉积，疗效有限。在我们之前的研究中，我们报道了用于局部腔内给药治疗的紫外线引发的甲基丙烯酸明胶（GelMa）-丙烯酰胺基水凝胶制剂的开发和优化。本研究利用预先建立的GelMa制剂来递送小分子化疗药物阿霉素（Dox），用于体外MPM模型。
通过将阿霉素溶解在前体溶液中来制备载药阿霉素水凝胶（DLH）前体溶液。对凝胶的物理性质如胶凝时间、溶胀指数、生物粘附性和可注射性进行表征，并与空白水凝胶进行比较。还在各种二维和三维细胞培养模型中测试了载药阿霉素水凝胶对MPM细胞的治疗效果。
结果表明，与空白水凝胶相比，载药阿霉素水凝胶保留了相似的物理性质，包括胶凝时间（<25秒）、溶胀指数（~1200%）、生物粘附性（> 20g的脱离力）和可注射性（注射前体所需力<2N）。此外，通过增加GelMa与其交联剂之间的交联程度，凝胶制剂在12天内有效地维持了亲水性阿霉素盐酸盐的释放。此外，即使将阿霉素载入水凝胶后，其治疗效果仍然保留，这表明凝胶辅料与药物之间没有发生化学相互作用。在基于MPM细胞的模型中的研究表明，DLH在抑制二维和三维细胞生长方面显示出优异的潜力，在三维球体模型中，DLH在抑制肿瘤生长方面比普通阿霉素更有效。
总体而言，本研究结果表明，载药阿霉素水凝胶（DLH）可能是临床前间皮瘤模型疗效研究的良好候选者，具有很强的临床转化潜力。
