Tumor-Priming Smoothened Inhibitor Enhances Deposition and Efficacy of Cytotoxic Nanoparticles in a Pancreatic Cancer Model.
Tumor-Priming Smoothened Inhibitor Enhances Deposition and Efficacy of Cytotoxic Nanoparticles in a Pancreatic Cancer Model.
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DOI：
10.1158/1535-7163.mct-15-0602
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发表时间：
2016-01
影响因子：
5.7
通讯作者：
Straubinger RM
中科院分区：
文献类型：
--
作者：
Roy Chaudhuri T;Straubinger NL;Pitoniak RF;Hylander BL;Repasky EA;Ma WW;Straubinger RM
大多数胰腺癌（PaCA）患者存在不可切除的疾病，化疗获益甚微。肿瘤灌注和血管通透性差限制了药物沉积。先前的工作表明，刺猬信号传导平滑抑制剂（sHHI）促进自发性PaCA小鼠模型中的新血管形成，并增强肿瘤对低分子量化合物的渗透性。在这里，我们测试了这样的假设，即sHHI可以增强肿瘤沉积和由80- 100 nm含有阿霉素的空间稳定脂质体（SSL）（SSL-DXR）组成的含药物纳米颗粒的功效。将携带低传代患者来源的PaCA异种移植物（PDX）的SCID小鼠用40 mg/kg/天NVP-LDE 225（erismodegib）经口预处理10天，然后静脉内注射SSL-DXR。微血管密度，渗透性，灌注和形态学进行了比较，与未经处理的对照组，SSL沉积和治疗效果。单独的sHHI对肿瘤生长的影响最小，但显著增加了纳米颗粒向肿瘤的腺癌细胞富集区域的外渗。免疫染色显示，sHHI处理降低了CD 31+血管内皮结构的周细胞覆盖率（α-SMA+），增加了内皮贫乏（CD 31 −）基底膜结构（胶原IV+）的丰度，表明未成熟微血管增加。在sHHI预处理后给予SSL-DXR（15 mg/kg）阻止了肿瘤体积进展并降低了肿瘤灌注/渗透性，表明了初始血管修剪反应。与对照组相比，一个周期的10天sHHI预处理，然后6 mg/kg SSL-DXR加倍中位肿瘤进展时间。三个周期的sHHI和SSL-DXR治疗，10天的周期之间的药物假期，几乎三倍的中位数肿瘤进展时间。基于这些数据，与纳米颗粒药物载体一起进行的短期sHHI治疗构成了增强胰腺癌治疗功效的潜在策略。
Most pancreatic adenocarcinoma (PaCA) patients present with unresectable disease and benefit little from chemotherapy. Poor tumor perfusion and vascular permeability limit drug deposition. Previous work showed that smoothened inhibitors of hedgehog signaling (sHHI) promote neovascularization in spontaneous mouse models of PaCA and enhance tumor permeability to low-molecular weight compounds. Here we tested the hypothesis that sHHI can enhance tumor deposition and efficacy of drug-containing nanoparticles consisting of 80–100nm sterically-stabilized liposomes (SSL) containing doxorubicin (SSL-DXR). SCID mice bearing low-passage patient-derived PaCA xenografts (PDX) were pretreated po for 10 days with 40 mg/kg/day NVP-LDE225 (erismodegib), followed by i.v. SSL-DXR. Microvessel density, permeability, perfusion, and morphology were compared with untreated controls, as was SSL deposition and therapeutic efficacy. The sHHI alone affected tumor growth minimally, but markedly increased extravasation of nanoparticles into adenocarcinoma cell-enriched regions of the tumor. Immunostaining showed that sHHI treatment decreased pericyte coverage (α-SMA+) of CD31+ vascular endothelium structures, and increased the abundance of endothelium-poor (CD31−) basement membrane structures (collagen IV+), suggesting increased immature microvessels. SSL-DXR (15 mg/kg) administered after sHHI pretreatment arrested tumor volume progression and decreased tumor perfusion/permeability, suggesting an initial vascular pruning response. Compared to controls, one cycle of 10d sHHI pretreatment followed by 6 mg/kg SSL-DXR doubled median tumor progression time. Three cycles of treatment with sHHI and SSL-DXR, with a 10d between-cycle drug holiday, nearly tripled median tumor progression time. Based upon these data, short-term sHHI treatment sequenced with nanoparticulate drug carriers constitutes a potential strategy to enhance efficacy of pancreatic cancer therapy.