A Dual‐Bioresponsive Drug‐Delivery Depot for Combination of Epigenetic Modulation and Immune Checkpoint Blockade,Advanced Materials

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A Dual‐Bioresponsive Drug‐Delivery Depot for Combination of Epigenetic Modulation and Immune Checkpoint Blockade
Advanced Materials ( IF 27.4 ) Pub Date : 2019-03-11 , DOI: 10.1002/adma.201806957
Huitong Ruan _{1,

2,

3,

4} , Quanyin Hu _{1,

3,

4} , Di Wen _{1,

3,

4} , Qian Chen _{1,

3,

4} , Guojun Chen _{1,

3,

4} , Yifei Lu _{1,

3,

4} , Jinqiang Wang _{1,

3,

4} , Hao Cheng ₅ , Weiyue Lu ₂ , Zhen Gu _{1,

3,

4}

Affiliation

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 (CaCO₃ 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.

中文翻译：

结合表观遗传调控和免疫检查点封锁的双重生物反应药物递送库。

肿瘤相关抗原（TAA）表达低的晚期黑色素瘤患者通常对PD-1 / PD-L1阻断疗法的反应较差。表观遗传调节剂，例如低甲基化剂（HMA），可以通过诱导TAA表达来增强抗肿瘤免疫应答。在这里，设计了一个双生物响应凝胶库，该储库可以对肿瘤微环境（TME）中的酸性pH和活性氧（ROS）进行响应，以实现抗PD1抗体（aPD1）和HMA的Zebularine（Zeb）的代码传递。首先将aPD1装入对pH敏感的碳酸钙纳米颗粒（CaCO ₃（NPs），然后与Zeb（Zeb-aPD1-NPs-Gel）一起封装在ROS响应水凝胶中。事实证明，这种联合疗法可提高癌细胞的免疫原性，并在逆转免疫抑制TME中发挥作用，从而有助于抑制肿瘤生长并延长B16F10黑色素瘤小鼠的存活时间。

更新日期：2019-03-11

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