Effects of tumor microenvironment heterogeneity on nanoparticle disposition and efficacy in breast cancer tumor models.
Effects of tumor microenvironment heterogeneity on nanoparticle disposition and efficacy in breast cancer tumor models.
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DOI：
10.1158/1078-0432.ccr-14-0493
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发表时间：
2014-12-01
期刊：
影响因子：
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通讯作者：
Zamboni WC
中科院分区：
文献类型：
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作者：
Song G;Darr DB;Santos CM;Ross M;Valdivia A;Jordan JL;Midkiff BR;Cohen S;Nikolaishvili-Feinberg N;Miller CR;Tarrant TK;Rogers AB;Dudley AC;Perou CM;Zamboni WC
肿瘤细胞被复杂的微环境包围。我们研究的目的是评估肿瘤微环境的异质性在纳米颗粒（NP）递送和功效的可变性中的作用。评估了分别代表人类乳腺肿瘤亚型basal-like和claudin-low的C3(1)-T-抗原基因工程小鼠模型(C3-TAg)和T11/TP53Null原位同基因小鼠移植模型(T11)。对于药代动力学研究，以 6 mg/kg 静脉注射 (IV) x1 施用非脂质体阿霉素 (NL-doxo) 或聚乙二醇标记（聚乙二醇化）脂质体阿霉素 (PLD)。计算阿霉素的浓度与时间曲线下面积(AUC)。通过免疫组织化学评估巨噬细胞、胶原蛋白和脉管系统的数量。通过多重免疫化学测量趋化因子和细胞因子。在功效研究中，NL-doxo 或 PLD 以 6 mg/kg 静脉注射，每周 x6。对中间肿瘤反应和总生存率进行了分析。两种模型中 NL-doxo 和 PLD 封装并释放的阿霉素的血浆 AUC 相似。然而，C3-TAg 中 PLD 的肿瘤总 AUC 是 T11 的 2 倍（P<0.05）。与C3-TAg相比，T11肿瘤CC趋化因子配体（CCL）2和血管内皮生长因子（VEGF）-a的表达显着升高，血管数量增多，VEGF-c表达降低（P<0.05）。在两种模型中，PLD 均比 NL-doxo 更有效。乳腺癌的肿瘤微环境和/或肿瘤细胞特征影响 NP 肿瘤递送和疗效，但不影响小分子药物。我们的研究结果揭示了肿瘤微环境在 NP 递送和治疗结果变异性中的作用。
Tumor cells are surrounded by a complex microenvironment. The purpose of our study was to evaluate the role of heterogeneity of the tumor microenvironment in the variability of nanoparticle (NP) delivery and efficacy. C3(1)-T-Antigen genetically engineered mouse model (C3-TAg) and T11/TP53Null orthotopic syngeneic murine transplant model (T11) representing human breast tumor subtypes basal-like and claudin-low, respectively, were evaluated. For the pharmacokinetic studies, non-liposomal doxorubicin (NL-doxo) or polyethylene glycol tagged (PEGylated) liposomal doxorubicin (PLD) was administered at 6 mg/kg intravenously (IV) x1. Area-under-the concentration versus time curve (AUC) of doxorubicin was calculated. Macrophages, collagen, and the amount of vasculature were assessed by immunohistochemistry. Chemokines and cytokines were measured by multiplex immunochemistry. NL-doxo or PLD was administered at 6 mg/kg IV weekly x6 in efficacy studies. Analyses of intermediary tumor response and overall survival were performed. Plasma AUC of NL-doxo and PLD encapsulated and released doxorubicin were similar between two models. However, tumor sum total AUC of PLD was 2-fold greater in C3-TAg compared with T11 (P<0.05). T11 tumors showed significantly higher expression of CC chemokine ligand (CCL) 2 and vascular endothelial growth factor (VEGF)-a, greater vascular quantity, and decreased expression of VEGF-c compared to C3-TAg (P<0.05). PLD was more efficacious compared to NL-doxo in both models. The tumor microenvironment and/or tumor cell features of breast cancer affected NP tumor delivery and efficacy, but not the small molecule drug. Our findings reveal the role of the tumor microenvironment in variability of NP delivery and therapeutic outcomes.