William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, 151 W. Woodruff Avenue, Columbus, OH 43210, USA.
Department of Materials Science and Engineering, The Ohio State University, 2041 N. College Rd., Columbus, OH 43210, USA.
J Control Release. 2020 Apr 10;320:442-456. doi: 10.1016/j.jconrel.2020.01.036. Epub 2020 Jan 23.
Vascular endothelial growth factor (VEGF) is a key regulator of abnormal blood vessel growth. As such, bevacizumab-based inhibition of VEGF has been the clinically adopted strategy to treat colorectal and breast cancers as well as age-related macular degeneration (AMD). However, as the treatment of vascular diseases often requires a high drug concentration for a long period, the burst release of bevacizumab remains a critical limitation in anti-VEGF-based therapies. Maintaining bevacizumab at high concentrations over extended periods remains challenging due to insufficient drug loading capacity and drug-device interactions. We report the development of a polymeric based bi-layered capsule that could address these challenges by extending the release over one year, thereby providing an effective platform enabling treatment of chronic vascular diseases. Remarkably, the developed capsules have a bi-layered structure which ensures the structural integrity of the injectable capsules and appropriate diffusion of bevacizumab by providing optimal physical trapping and electrostatic interaction. Meanwhile, the central hollow design enables a higher drug loading to meet the need for long-term release of bevacizumab for several months to one year. Using an in vitro drug release assay, we demonstrated that the bi-layered capsule could produce longer-term local drug administration by intravitreal injection compared to previously reported devices. The capsules also present minimal toxicity and maintain anti-VEGF potency, suggesting that our approach may have the potential to treat vascular-related diseases using bevacizumab.
血管内皮生长因子（VEGF）是调节异常血管生长的关键因子。因此，基于贝伐单抗的 VEGF 抑制已被临床采用，用于治疗结直肠癌和乳腺癌以及与年龄相关的黄斑变性（AMD）。然而，由于治疗血管疾病通常需要长时间的高药物浓度，贝伐单抗的爆发释放仍然是抗 VEGF 治疗的一个关键限制。由于药物载药能力不足和药物-器械相互作用，将贝伐单抗维持在高浓度并延长释放时间仍然具有挑战性。我们报告了一种基于聚合物的双层胶囊的开发，该胶囊可以通过延长释放时间超过一年来解决这些挑战，从而提供一个有效的平台，实现慢性血管疾病的治疗。值得注意的是，所开发的胶囊具有双层结构，通过提供最佳的物理捕获和静电相互作用，确保了可注射胶囊的结构完整性和贝伐单抗的适当扩散。同时，中空的中心设计能够实现更高的载药量，以满足贝伐单抗数月至一年的长期释放需求。通过体外药物释放试验，我们证明与先前报道的装置相比，双层胶囊通过玻璃体内注射可以实现更长时间的局部药物给药。这些胶囊还表现出最小的毒性，并保持抗 VEGF 效力，这表明我们的方法可能有潜力利用贝伐单抗治疗与血管相关的疾病。
