巨噬细胞封装的纳米颗粒白蛋白结合紫杉醇在低灌注癌症病变中的增强性能†,Nanoscale

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巨噬细胞封装的纳米颗粒白蛋白结合紫杉醇在低灌注癌症病变中的增强性能†
Nanoscale ( IF 5.8 ) Pub Date : 2016-01-19 00:00:00 , DOI: 10.1039/c5nr07796f
Fransisca Leonard ₁ , Louis T Curtis , Pooja Yesantharao , Tomonori Tanei , Jenolyn F Alexander , Min Wu , John Lowengrub , Xuewu Liu , Mauro Ferrari , Kenji Yokoi , Hermann B Frieboes , Biana Godin

Affiliation

肿瘤（例如源自乳腺和其他器官的肝转移瘤）的血管形成不足与化疗反应不佳和死亡率较高相关。不良预后与低分子量和高分子量药物向病灶内的转运受损以及高洗脱率有关。与紫杉醇和多西紫杉醇相比，纳米颗粒白蛋白结合紫杉醇 (nAb-PTX) 在临床试验中已证明具有优势。然而，其对乳腺癌肝转移的治疗效果却令人失望。由于巨噬细胞是肝脏肿瘤微环境中最丰富的细胞，我们设计了一个多级系统，利用巨噬细胞将药物递送到血管不足的转移性病灶中，并进行体外、体内和计算机评估。该系统将 nAb-PTX 封装到纳米孔生物相容性和可生物降解的多级载体 (MSV) 中，从而促进 nAb-PTX 在巨噬细胞中保留。我们开发了一种 3D体外模型来模拟临床观察到的被巨噬细胞包围的低灌注肿瘤病变。该模型能够评估 nAb-PTX 和 MSV-nab PTX 功效作为运输障碍的函数。在该系统中添加巨噬细胞可显着提高 MSV-nAb-PTX 功效，揭示巨噬细胞在药物转运中的作用。在体内模型中，与未受影响的肝脏相比，在小鼠中观察到巨噬细胞数量显着增加，证实了体外研究结果。此外，还建立了一个将药物释放和巨噬细胞保留联系起来的数学模型，以预测 MSV-nAb-PTX 在临床环境中的功效。基于通过肝脏肿瘤成像和活检检测到的巨噬细胞存在，所提出的实验/计算方法可以预测 MSV-nab PTX 治疗肝脏转移癌的性能。

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Enhanced performance of macrophage-encapsulated nanoparticle albumin-bound-paclitaxel in hypo-perfused cancer lesions†

Hypovascularization in tumors such as liver metastases originating from breast and other organs correlates with poor chemotherapeutic response and higher mortality. Poor prognosis is linked to impaired transport of both low- and high-molecular weight drugs into the lesions and to high washout rate. Nanoparticle albumin-bound-paclitaxel (nAb-PTX) has demonstrated benefits in clinical trials when compared to paclitaxel and docetaxel. However, its therapeutic efficacy for breast cancer liver metastasis is disappointing. As macrophages are the most abundant cells in the liver tumor microenvironment, we design a multistage system employing macrophages to deliver drugs into hypovascularized metastatic lesions, and perform in vitro, in vivo, and in silico evaluation. The system encapsulates nAb-PTX into nanoporous biocompatible and biodegradable multistage vectors (MSV), thus promoting nAb-PTX retention in macrophages. We develop a 3D in vitro model to simulate clinically observed hypo-perfused tumor lesions surrounded by macrophages. This model enables evaluation of nAb-PTX and MSV-nab PTX efficacy as a function of transport barriers. Addition of macrophages to this system significantly increases MSV-nAb-PTX efficacy, revealing the role of macrophages in drug transport. In the in vivo model, a significant increase in macrophage number, as compared to unaffected liver, is observed in mice, confirming the in vitro findings. Further, a mathematical model linking drug release and retention from macrophages is implemented to project MSV-nAb-PTX efficacy in a clinical setting. Based on macrophage presence detected via liver tumor imaging and biopsy, the proposed experimental/computational approach could enable prediction of MSV-nab PTX performance to treat metastatic cancer in the liver.

更新日期：2016-01-19

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