Department of Bioengineering, University of California, Los Angeles, CA, 90095, USA.
Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Fudan University, Shanghai, 201203, China.
Adv Mater. 2019 Apr;31(17):e1806957. doi: 10.1002/adma.201806957. Epub 2019 Mar 11.
Patients with advanced melanoma that is of low tumor-associated antigen (TAA) expression often respond poorly to PD-1/PD-L1 blockade therapy. Epigenetic modulators, such as hypomethylation agents (HMAs), can enhance the antitumor immune response by inducing TAA expression. Here, a dual bioresponsive gel depot that can respond to the acidic pH and reactive oxygen species (ROS) within the tumor microenvironment (TME) for codelivery of anti-PD1 antibody (aPD1) and Zebularine (Zeb), an HMA, is engineered. aPD1 is first loaded into pH-sensitive calcium carbonate nanoparticles (CaCO NPs), which are then encapsulated in the ROS-responsive hydrogel together with Zeb (Zeb-aPD1-NPs-Gel). It is demonstrated that this combination therapy increases the immunogenicity of cancer cells, and also plays roles in reversing immunosuppressive TME, which contributes to inhibiting the tumor growth and prolonging the survival time of B16F10-melanoma-bearing mice.
低肿瘤相关抗原 (TAA) 表达的晚期黑色素瘤患者对 PD-1/PD-L1 阻断疗法的反应往往较差。表观遗传调节剂，如低甲基化剂 (HMAs)，可以通过诱导 TAA 表达来增强抗肿瘤免疫反应。在这里，设计了一种双生物响应性凝胶库，该凝胶库可以响应肿瘤微环境 (TME) 中的酸性 pH 和活性氧 (ROS)，用于共递送抗 PD-1 抗体 (aPD1) 和 Zebularine (Zeb)，一种 HMA。aPD1 首先被加载到 pH 敏感的碳酸钙纳米粒子 (CaCO NPs) 中，然后与 Zeb（Zeb-aPD1-NPs-Gel）一起封装在 ROS 响应性水凝胶中。结果表明，这种联合治疗方法提高了癌细胞的免疫原性，同时也在逆转免疫抑制性 TME 方面发挥作用，有助于抑制肿瘤生长并延长 B16F10-黑色素瘤荷瘤小鼠的存活时间。
