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首页> 外文期刊>Biomaterials Science >Tumor localization of oncolytic adenovirus assisted by pH-degradable microgels with JQ1-mediated boosting replication and PD-L1 suppression for enhanced cancer therapy
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Tumor localization of oncolytic adenovirus assisted by pH-degradable microgels with JQ1-mediated boosting replication and PD-L1 suppression for enhanced cancer therapy

机译：肿瘤腺瘤的肿瘤定位通过具有JQ1介导的促进复制和PD-L1抑制的PH-可降解微凝胶辅助，抑制增强癌症治疗

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Oncolytic therapy is a fast-developing cancer treatment field based on the promising clinical performance from the selective tumor cell killing and induction of systemic antitumor immunity. The virotherapy efficacy, however, is strongly hindered by the limited virus propagation and negative immune regulation in the tumor microenvironments. To enhance the antitumor activity, we developed injectable pH-degradable PVA microgels encapsulated with oncolytic adenovirus (OA) by microfluidics for localized OA delivery and cancer treatments. PVA microgels were tailored with an OA encapsulation efficiency of 68% and exhibited a pH-dependent OA release as the microgel degradation at mildly acidic conditions. PVA microgels mediated fast viral release and increased replication in HEK293T and A549 cells at a lower pH, and the replication efficiency could be further reinforced by co-loading with one BET bromodomain inhibitor JQ1, inducing significant cytotoxicity against A549 cells. An in vivo study revealed that OA release was highly located at the tumor tissue assisted by PVA microgels, and the OA infection was also enhanced with the addition of JQ1 treatment, meanwhile greatly inhibiting the PD-L1 expression to overcome the immune suppression. OA/JQ1 co-encapsulated injectable microgels exhibited a superior in vivo antitumor activity on the A549 lung tumor-bearing mice by the combination of inhibited proliferation, amplified oncolysis, and potential immune regulation.
机译：溶瘤治疗是一种快速发展的癌症处理领域，基于来自选择性肿瘤细胞杀伤和诱导全身抗肿瘤免疫的临床表现。然而，在肿瘤微环境中的病毒繁殖和阴性免疫调节有限的病毒繁殖和阴性免疫调节受到了病症的疗效。为了增强抗肿瘤活性，我们开发了通过微流体封装的可注射的pH-可降解PVA微凝胶，用于通过微流体用于局部OA递送和癌症治疗方法。 PVA微凝胶以68％的OA封装效率量身定制，并在温和的酸性条件下表现为微凝胶降解的pH依赖性OA释放。 PVA MICROGELS介导的快速病毒释放和HEK293T和A549细胞在较低的pH下的复制，并且通过用一个BET BROMODOMAIN抑制剂JQ1加载，可以进一步加强复制效率，诱导显着的细胞毒性对A549细胞进行显着的细胞毒性。体内研究表明，OA释放高度位于PVA微凝胶辅助的肿瘤组织，并且通过添加JQ1处理也增强了OA感染，同时大大抑制PD-L1表达以克服免疫抑制。通过抑制增殖，扩增溶解和潜在的免疫调节，oA / JQ1共封装的可注射微凝胶在A549肺肿瘤的小鼠上表现出A549肺肿瘤的小鼠的优越性。

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