Wrecking neutrophil extracellular traps and antagonizing cancer-associated neurotransmitters by interpenetrating network hydrogels prevent postsurgical cancer relapse and metastases

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 unselectiveβ-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.

主客体胶束水凝胶的制备及对神经生长因子的包载

通过可逆加成-断裂链转移聚合(RAFT)反应制备了一种亲水性两嵌段聚合物——聚乙二醇/聚N-异丙基丙烯酰胺(PEG-PNIPAM),利用α-环糊精(α-CD)与其中PEG链段的选择性包合形成了一种独特的主客体胶束,这种胶束由于具备中空结构,可对亲水性药物起到很好的负载作用。其对神经生长因子的包载率为经典普朗尼克F127胶束的2倍。进一步利用主客体胶束为大分子交联剂制备丙烯酰胺水凝胶,可赋予水凝胶优异的力学性能,拉伸伸长率为化学交联对照组5倍,并且强度高于对照组2倍以上。循环拉伸测试表明,该水凝胶具有良好的应力耗散机制。