Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
Acta Biomater. 2020 Apr 1;106:289-300. doi: 10.1016/j.actbio.2020.01.039. Epub 2020 Jan 28.
Poor tumor penetration and highly immunosuppressive tumor microenvironment are two major factors that limit the therapeutic efficacy for the treatment of pancreatic ductal adenocarcinoma (PDA). In this work, a redox-responsive gemcitabine (GEM)-conjugated polymer, PGEM, was employed as a tumor penetrating nanocarrier to co-load an immunomodulating agent (NLG919, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) and a chemotherapeutic drug (paclitaxel (PTX)) for immunochemo combination therapy. The NLG919/PTX co-loaded micelles showed very small size of 15 nm. In vivo tumor imaging study indicated that PGEM was much more effective than the relatively large-sized POEG-co-PVD nanoparticles (160 nm) in deep tumor penetration and could reach the core of the pancreatic tumor. PTX formulated in the PGEM carrier showed improved tumor inhibition effect compared with PGEM alone. Incorporation of NLG919 in the formulation led to a more immunoactive tumor microenvironment with significantly decreased percentage of Treg cells, and increased percentages of CD4 IFNγ T and CD8 IFNγ T cells. PGEM micelles co-loaded with PTX and NLG919 showed the best anti-tumor activity in pancreatic (PANC02) as well as two other tumor models compared to PGEM micelles loaded with PTX or NLG919 alone, suggesting that codelivery of NLG919 and PTX via PGEM may represent an effective strategy for immunochemotherapy of PDA as well as other types of cancers. STATEMENT OF SIGNIFICANCE: In order to effectively accumulate and penetrate the PDA that is poorly vascularized and enriched with dense fibrotic stroma, the size of nanomedicine has to be well controlled. Here, we reported an immunochemotherapy regimen based on co-delivery of GEM, PTX and IDO1 inhibitor NLG919 through an ultra-small sized GEM-based nanocarrier (PGEM). We demonstrated that the PGEM carrier was effective in accumulating and penetrating into PDA tumors. Besides, PGEM co-loaded with PTX and NLG9 induced an improved anti-tumor immune response and was highly efficacious in inhibiting tumor growth as well as in prolonging the survival rate in PANC02 xenograft model. Our work represents a potential strategy for enhancing PDA tumor penetration and immunochemotherapy.
乏氧和高度免疫抑制的肿瘤微环境是限制胰腺导管腺癌 (PDA) 治疗效果的两个主要因素。在这项工作中，我们使用了一种氧化还原响应的吉西他滨 (GEM) 偶联聚合物 PGEM，作为一种肿瘤穿透纳米载体来共载一种免疫调节剂 (NLG919，吲哚胺 2,3-双加氧酶 1 (IDO1) 的抑制剂) 和一种化疗药物 (紫杉醇 (PTX))，用于免疫化疗联合治疗。共载有 NLG919/PTX 的胶束粒径非常小，约为 15nm。体内肿瘤成像研究表明，PGEM 比相对较大尺寸的 POEG-co-PVD 纳米颗粒 (~160nm) 更有效地穿透肿瘤深部，并能到达胰腺肿瘤的核心部位。与 PGEM 单独给药相比，PGEM 中包载的 PTX 显示出更好的肿瘤抑制效果。制剂中加入 NLG919 可使肿瘤微环境更具免疫活性，Treg 细胞的百分比显著降低，CD4 IFNγ T 和 CD8 IFNγ T 细胞的百分比增加。与单独载有 PTX 或 NLG919 的 PGEM 胶束相比，共载有 PTX 和 NLG919 的 PGEM 胶束在胰腺 (PANC02) 以及另外两种肿瘤模型中表现出更好的抗肿瘤活性，这表明通过 PGEM 共递药可能是治疗 PDA 以及其他类型癌症的有效免疫化疗策略。
为了有效地积累和穿透血管化不良且富含致密纤维基质的 PDA，纳米药物的大小必须得到很好的控制。在这里，我们通过一种基于 GEM 的超小型纳米载体 (PGEM) 报告了一种基于 GEM、PTX 和 IDO1 抑制剂 NLG919 的共递药免疫化疗方案。我们证明了 PGEM 载体在积聚和穿透 PDA 肿瘤方面是有效的。此外，共载有 PTX 和 NLG9 的 PGEM 诱导了改善的抗肿瘤免疫反应，并在 PANC02 异种移植模型中高度有效地抑制肿瘤生长和延长存活率。我们的工作代表了增强 PDA 肿瘤穿透性和免疫化疗的一种潜在策略。
