Abstract：
Transcatheter arterial chemoembolization (TACE) is the first-line therapy for hepatocellular carcinoma (HCC). However, the exacerbated hypoxia microenvironment induces tumor relapse and metastasis post-TACE. Here, temperature-sensitive block polymer complexed with polyphosphate-cisplatin (Pt-P@PND) was prepared for the enhancement of tumor artery embolization by coagulation activation. After supra-selective infusion into the tumor vessels, Pt-P@PND nanogels performed efficient embolization of tumor arteries by sol-gel transition at body temperature. Meanwhile, coagulation cascade was evoked to form blood clots in the peripheral arteries inaccessible to the nanogels by released PolyP. The blood clots-filled hydrogel networks composed of gel and clots showed a denser structure and higher modulus, thereby achieving long-term embolization of all levels of tumor arteries. Pt-P@PND nanogels efficiently inhibited tumor growth and reduced the expression of HIF-1α, VEGF, CD31, and MMP-9 on VX2 tumor-bearing rabbit model. The released Nitro-Pt stimulated the immunogenic cell death of tumor cells, thus enhancing the antitumor immune response to suppress tumor relapse and metastasis post-TACE. It is hoped that Pt-P@PND nanogels can be developed as a promising embolic agent with procoagulant activity for enhancing the antitumor immune response through a combination of embolism, coagulation, and chemotherapy. STATEMENT OF SIGNIFICANCE: Clinical embolic agents, such as Lipiodol and polyvinyl alcohol (PVA) microspheres, are limited by their rapid elimination or larger size, thus lead to incomplete embolization of trans-catheter arterial chemoembolization (TACE). Herein, temperature-sensitive Pt-P@PND nanogels were developed to achieve long-term embolization of all levels of tumor arteries by gel/clot generation. The released Nitro-Pt induced immunogenic cell death in tumor cells, which improved the antitumor immune microenvironment by the maturation of DCs and lymphocytic infiltration. Pt-P@PND nanogels successfully inhibited tumor growth and activated an antitumor immune response to curb the recurrence and metastasis of residual tumor cells both in VX2 tumor-bearing rabbit model and 4T1 tumor-bearing mouse model. These findings suggested that Pt-P@PND could be developed as an ideal embolic agent for clinical TACE treatment.
摘要：
经导管动脉化疗栓塞（TACE）是肝细胞癌（HCC）的一线治疗方法。然而,TACE后缺氧微环境加重可诱导肿瘤复发和转移。这里,制备了与聚磷酸盐-顺铂（Pt-P@PND）复合的温度敏感嵌段聚合物，用于通过凝血激活增强肿瘤动脉栓塞。在超选择性注入肿瘤血管后，Pt-P@PND纳米凝胶在体温下通过溶胶-凝胶转变有效地栓塞肿瘤动脉。同时,通过释放的PolyP在纳米凝胶无法进入的外周动脉中诱发凝血级联形成血凝块。由凝胶和凝块组成的充满血凝块的水凝胶网络显示出更致密的结构和更高的模量，从而实现各级肿瘤动脉的长期栓塞。Pt-P@PND纳米凝胶可有效抑制肿瘤生长，降低HIF-1α的表达，VEGF,CD31和MMP-9对VX2荷瘤兔模型的影响。释放的硝基-Pt刺激肿瘤细胞的免疫原性细胞死亡，从而增强抗肿瘤免疫应答以抑制TACE后肿瘤复发和转移。希望将Pt-P@PND纳米凝胶开发为具有促凝血活性的有前途的栓塞剂，通过联合栓塞增强抗肿瘤免疫反应，凝血,和化疗。重要声明：临床栓塞剂，如碘油和聚乙烯醇（PVA）微球，受限于它们的快速消除或更大的尺寸，因此导致经导管动脉化疗栓塞（TACE）的栓塞不完全。在这里，开发了对温度敏感的Pt-P@PND纳米凝胶，以通过凝胶/凝块生成实现所有水平肿瘤动脉的长期栓塞。释放的Pt在肿瘤细胞中诱导免疫原性细胞死亡，通过DCs的成熟和淋巴细胞浸润改善了抗肿瘤免疫微环境。在VX2荷瘤兔模型和4T1荷瘤小鼠模型中，Pt-P@PND纳米凝胶成功抑制了肿瘤生长并激活了抗肿瘤免疫反应，以抑制残留肿瘤细胞的复发和转移；这些发现表明，Pt-P@PND可以开发为临床TACE治疗的理想栓塞剂。
