PDF(Pubmed)
Abstract：
Tumor-promoting niche after incomplete surgery resection (SR) can lead to more aggressive local progression and distant metastasis with augmented angiogenesis-immunosuppressive tumor microenvironment (TME). Herein, elevated neutrophil extracellular traps (NETs) and cancer-associated neurotransmitters (CANTs, e.g., catecholamines) are firstly identified as two of the dominant inducements. Further, an injectable fibrin-alginate hydrogel with high tissue adhesion has been constructed to specifically co-deliver NETs inhibitor (DNase I)-encapsulated PLGA nanoparticles and an unselective β-adrenergic receptor blocker (propranolol). The two components (i.e., fibrin and alginate) can respond to two triggers (thrombin and Ca2+, respectively) in postoperative bleeding to gelate, shaping into an interpenetrating network (IPN) featuring high strength. The continuous release of DNase I and PR can wreck NETs and antagonize catecholamines to decrease microvessel density, blockade myeloid-derived suppressor cells, secrete various proinflammatory cytokines, potentiate natural killer cell function and hamper cytotoxic T cell exhaustion. The reprogrammed TME significantly suppress locally residual and distant tumors, induce strong immune memory effects and thus inhibit lung metastasis. Thus, targetedly degrading NETs and blocking CANTs enabled by this in-situ IPN-based hydrogel drug depot provides a simple and efficient approach against SR-induced cancer recurrence and metastasis.
摘要：
不完全手术切除（SR）后的促肿瘤小生境可导致血管生成免疫抑制肿瘤微环境（TME）增强的局部进展和远处转移。在这里，中性粒细胞胞外诱捕网(NETs)和癌症相关神经递质(CANTs，例如，儿茶酚胺）首先被确定为两种主要诱因。Further,具有高组织粘附性的可注射纤维蛋白-藻酸盐水凝胶已被构建用于特异性共递送NETs抑制剂(DNaseI)包封的PLGA纳米颗粒和非选择性β-肾上腺素能受体阻滞剂(普萘洛尔).这两个组件(即，纤维蛋白和藻酸盐）可以对两种触发因素（凝血酶和Ca2+，分别)在术后出血凝胶化，成型为具有高强度的互穿网络(IPN)。DNaseI和PR的持续释放可以破坏NETs并拮抗儿茶酚胺以降低微血管密度，阻断骨髓来源的抑制细胞，分泌各种促炎细胞因子，增强自然杀伤细胞功能并阻止细胞毒性T细胞耗尽。重新编程的TME显著抑制局部残留和远处肿瘤，诱导强烈的免疫记忆效应，从而抑制肺转移。因此，通过这种基于原位IPN的水凝胶药物储库实现的靶向降解NETs和阻断CANTs提供了一种针对SR诱导的癌症复发和转移的简单有效的方法。
