我国胰腺神经内分泌肿瘤（pNET）发病率在所有NET中居首位，且预后最差，药物治疗手段匮乏，其中奥曲肽（Oct）生物治疗是首选，但中位有效时间不足1年。pNET富血供，瘤体大且易产生缺氧环境。我们前期研究发现黄芩素（BE）可协同Oct降低缺氧条件下血管内皮生长因子（VEGF）的表达来减少pNET血管新生，Oct:BE为1:4时效价最高；随后构建控释型Oct/BE双前药纳米胶束，在肿瘤细胞内部低pH值和高浓度谷胱甘肽刺激下释放药物：该胶束中Oct既主动靶向pNET细胞表面高表达的生长抑素受体，又可抑制VEGF分泌；BE可降低缺氧诱导因子1α表达来增强Oct的作用，抑制PI3K/Akt信号，减少血管新生，抑制肿瘤增殖。本课题拟阐明Oct/BE纳米胶束体系主动靶向并抑制pNET细胞增殖的作用及其基于缺氧条件下VEGF/PI3K/Akt介导血管新生的分子机制，为pNET纳米生物治疗提供依据。

Pancreatic neuroendocrine tumors (pNET) accounts for the highest proportion of all NET in China with the worst prognosis and limited drug treatment of which biotherapy with octreotide (Oct) is the first choice. However, the median effective time of Oct is less than 1 year. pNET is rich in blood supply with relatively larger tumor volume and anoxic environment. Our previous research found that baicalein (BE) could cooperate with Oct to decrease the expression of vascular endothelial growth factor (VEGF) and reduce the formation of pNET neovascularization, thereby exerting tumor-inhibiting effect with the best effect when the ratio of Oct and BE is 1: 4. We constructed a control-released Oct and BE dual prodrug nanomicelles which could release BE and Oct under the stimulation of glutathione at high concentration and lower pH. Oct targeted high level somatostatin receptors on pNET tumor cells as well as decreased the secretion of VEGF; BE enhanced the effect of Oct by reducing the expression of hypoxia-inducible factor 1α to inhibit PI3K/Akt signal, the following neovascularization and tumor proliferation.This topic intends to clarify the role of Oct/BE nanomicelle system in targeting and inhibiting the proliferation of pNET and the molecular mechanism based on VEGF/PI3K/Akt-mediated neovascularization under hypoxia to provide a theoretical basis for its precise delivery of nano-biotherapy.