Abstract：
It is imperative to optimize chemotherapy for heightened anti-tumor therapeutic efficacy. Unrestrained tumor cell proliferation and sustained angiogenesis are pivotal for cancer progression. Plinabulin, a vascular disrupting agent, selectively destroys tumor blood vessels. Tirapazamine (TPZ), a hypoxia-activated prodrug, intensifies cytotoxicity in diminishing oxygen levels within tumor cells. Despite completing Phase III clinical trials, both agents exhibited modest treatment efficiency due to dose-limiting toxicity. In this study, we employed methoxy poly(ethylene glycol)-b-poly(D,L-lactide) (mPEG-b-PDLLA) to co-deliver Plinabulin and TPZ to the tumor site, concurrently disrupting blood vessels and eliminating tumor cells, addressing both symptoms and the root cause of tumor progression. Plinabulin was converted into a prodrug with esterase response (PSM), and TPZ was synthesized into a hexyl chain-containing derivative (TPZHex) for effective co-delivery. PSM and TPZHex were co-encapsulated with mPEG-b-PDLLA, forming nanodrugs (PT-NPs). At the tumor site, PT-NPs responded to esterase overexpression, releasing Plinabulin, disrupting blood vessels, and causing nutritional and oxygen deficiency. TPZHex was activated in response to increased hypoxia, killing tumor cells. In treating 4T1 tumors, PT-NPs demonstrated enhanced therapeutic efficacy, achieving a 92.9 % tumor suppression rate and a 20 % cure rate. This research presented an innovative strategy to enhance synergistic efficacy and reduce toxicity in combination chemotherapy.
摘要：
优化化疗以提高抗肿瘤治疗效果势在必行。不受约束的肿瘤细胞增殖和持续的血管生成是癌症进展的关键。普那布林,血管破坏剂,选择性地破坏肿瘤血管。Tirapazamine(TPZ),缺氧激活的前药，在减少肿瘤细胞内的氧水平时增强细胞毒性。尽管完成了III期临床试验,由于剂量限制性毒性,两种药物均表现出适度的治疗效率.在这项研究中,我们使用甲氧基聚（乙二醇）-b-聚（D，L-丙交酯）（mPEG-b-PDLLA）将普那布林和TPZ共同递送至肿瘤部位，同时破坏血管和消除肿瘤细胞，解决症状和肿瘤进展的根本原因。普那布林转化为具有酯酶反应（PSM）的前药，和TPZ被合成为含己基链的衍生物(TPZHex)用于有效的共递送。PSM和TPZHex与mPEG-b-PDLLA共封装，形成纳米药物（PT-NP）。在肿瘤部位，PT-NP对酯酶过表达有反应，释放普那布林，破坏血管,导致营养和缺氧。TPZHex响应于缺氧增加而被激活，杀死肿瘤细胞。在治疗4T1肿瘤时，PT-NP表现出增强的治疗效果，达到92.9%的抑瘤率和20%的治愈率。这项研究提出了一种创新的策略，以增强联合化疗的协同功效并减少毒性。
