Department of Chemical and Biomolecular Engineering, North Carolina State University , Raleigh, North Carolina 27695, United States.
Nano Lett. 2017 May 10;17(5):2879-2886. doi: 10.1021/acs.nanolett.7b00021. Epub 2017 Apr 11.
As the enhanced permeation and retention (EPR) effect continues to be a controversial topic in nanomedicine, we sought to examine EPR as a function of nanoparticle size, tumor model, and tumor location, while also evaluating tumors for EPR mediating factors such as microvessel density, vascular permeability, lymphatics, stromal content, and tumor-associated immune cells. Tumor accumulation was evaluated for 55 × 60, 80 × 180, and 80 × 320 nm PRINT particles in four subcutaneous flank tumor models (SKOV3 human ovarian, 344SQ murine nonsmall cell lung, A549 human nonsmall cell lung, and A431 human epidermoid cancer). Each tumor model revealed specific particle accumulation trends with evident particle size dependence. Immuno-histochemistry staining revealed differences in tumor microvessel densities that correlated with overall tumor accumulation. Immunofluorescence images displayed size-mediated tumor penetration with signal from the larger particles concentrated close to the blood vessels, while signal from the smaller particle was observed throughout the tissue. Differences were also observed for the 55 × 60 nm particle tumor penetration across flank tumor models as a function of stromal content. The 55 × 60 nm particles were further evaluated in three orthotopic, metastatic tumor models (344SQ, A549, and SKOV3), revealing preferential accumulation in primary tumors and metastases over healthy tissue. Moreover, we observed higher tumor accumulation in the orthotopic lung cancer models than in the flank lung cancer models, whereas tumor accumulation was constant for both orthotopic and flank ovarian cancer models, further demonstrating the variability in the EPR effect as a function of tumor model and location.
作为增强型渗透和保留（EPR）效应在纳米医学中仍然是一个有争议的话题，我们试图研究 EPR 作为纳米颗粒大小、肿瘤模型和肿瘤位置的函数，同时还评估了肿瘤中的 EPR 介导因子，如微血管密度、血管通透性、淋巴管、基质含量和肿瘤相关免疫细胞。在四个皮下 flank 肿瘤模型（SKOV3 人卵巢、344SQ 鼠非小细胞肺癌、A549 人非小细胞肺癌和 A431 人表皮样癌）中评估了 55×60、80×180 和 80×320nm PRINT 颗粒的肿瘤积累。每个肿瘤模型都揭示了特定的颗粒积累趋势，具有明显的颗粒尺寸依赖性。免疫组织化学染色显示了肿瘤微血管密度的差异，这些差异与总体肿瘤积累相关。免疫荧光图像显示了大小介导的肿瘤穿透，较大颗粒的信号集中在血管附近，而较小颗粒的信号则分布在整个组织中。在 flank 肿瘤模型中，55×60nm 颗粒的肿瘤穿透也因基质含量的不同而有所不同。55×60nm 颗粒在三个原位、转移性肿瘤模型（344SQ、A549 和 SKOV3）中进一步进行了评估，结果显示在原发性肿瘤和转移瘤中优先积累，而在健康组织中则较少积累。此外，我们观察到在原位肺癌模型中的肿瘤积累高于 flank 肺癌模型，而在原位和 flank 卵巢癌模型中，肿瘤积累是恒定的，这进一步证明了 EPR 效应作为肿瘤模型和位置的函数存在可变性。
