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Abstract：
Imperceptible examination and unideal treatment effect are still intractable difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). At present, despite 5-fluorouracil (5-FU), as a clinical first-line FOLFIRINOX chemo-drug, has achieved significant therapeutic effects. Nevertheless, these unavoidable factors such as low solubility, lack of biological specificity and easy to induce immunosuppressive surroundings formation, severely limit their treatment in PDAC. As an important source of energy for many tumor cells, tryptophan (Trp), is easily degraded to kynurenine (Kyn) by indolamine 2,3- dioxygenase 1 (IDO1), which activates the axis of Kyn-AHR to form special suppressive immune microenvironment that promotes tumor growth and metastasis. However, our research findings that 5-FU can induce effectively immunogenic cell death (ICD) to further treat tumor by activating immune systems, while the secretion of interferon-γ (IFN-γ) re-induce the Kyn-AHR axis activation, leading to poor treatment efficiency. Therefore, a metal matrix protease-2 (MMP-2) and endogenous GSH dual-responsive liposomal-based nanovesicle, co-loading with 5-FU (anti-cancer drug) and NLG919 (IDO1 inhibitor), was constructed (named as ENP919@5-FU). The multifunctional ENP919@5-FU can effectively reshape the tumor immunosuppression microenvironment to enhance the effect of chemoimmunotherapy, thereby effectively inhibiting cancer growth. Mechanistically, PDAC with high expression of MMP-2 will propel the as-prepared nanovesicle to dwell in tumor region via shedding PEG on the nanovesicle surface, effectively enhancing tumor uptake. Subsequently, the S-S bond containing nanovesicle was cut via high endogenous GSH, leading to the continued release of 5-FU and NLG919, thereby enabling circulating chemoimmunotherapy to effectively cause tumor ablation. Moreover, the combination of ENP919@5-FU and PD-L1 antibody (αPD-L1) showed a synergistic anti-tumor effect on the PDAC model with abdominal cavity metastasis. Collectively, ENP919@5-FU nanovesicle, as a PDAC treatment strategy, showed excellent antitumor efficacy by remodeling tumor microenvironment to circulate tumor chemoimmunotherapy amplification, which has promising potential in a precision medicine approach.
摘要：
对胰腺导管腺癌(PDAC)的临床治疗仍然存在难以察觉的检查和治疗效果不佳的问题。目前,尽管5-氟尿嘧啶（5-FU），作为临床一线FOLFIRINOX化疗药物，取得了显著的治疗效果。然而，这些不可避免的因素，如低溶解度，缺乏生物特异性，容易诱导免疫抑制环境的形成，严重限制了他们在PDAC的治疗。作为许多肿瘤细胞的重要能量来源，色氨酸(Trp),容易被吲哚胺2,3-双加氧酶1（IDO1）降解为犬尿氨酸（Kyn），激活Kyn-AHR轴以形成促进肿瘤生长和转移的特殊抑制性免疫微环境。然而,我们的研究发现，5-FU可以诱导有效的免疫原性细胞死亡（ICD），通过激活免疫系统进一步治疗肿瘤，而干扰素-γ（IFN-γ）的分泌重新诱导Kyn-AHR轴的激活，导致治疗效率低下。因此,金属基质蛋白酶-2（MMP-2）和内源性GSH双响应脂质体基纳米囊泡，与5-FU（抗癌药物）和NLG919（IDO1抑制剂）共负载，已建成（命名为ENP919@5-FU）。多功能ENP919@5-FU可有效重塑肿瘤免疫抑制微环境，增强化疗疗效，从而有效抑制癌症生长。机械上,高表达MMP-2的PDAC将通过在纳米囊泡表面上脱落PEG推动制备的纳米囊泡停留在肿瘤区域，有效增强肿瘤的摄取。随后，通过高内源性GSH切割含有S-S键的纳米囊泡，导致5-FU和NLG919的持续释放，从而使循环化学免疫疗法能够有效地引起肿瘤消融。此外，ENP919@5-FU联合PD-L1抗体(αPD-L1)对腹腔转移的PDAC模型具有协同抗肿瘤作用。总的来说，ENP919@5-FU纳米囊泡，作为PDAC治疗策略，通过重塑肿瘤微环境循环肿瘤化学免疫疗法扩增显示出优异的抗肿瘤疗效，在精准医学方法中具有很好的潜力。
