Tansi Felista L, Fröbel Filipp, Maduabuchi Wisdom O, Steiniger Frank, Westermann Martin, Quaas Rainer, Teichgräber Ulf K, Hilger Ingrid
Department of Experimental Radiology, Institute of Diagnostic and Interventional Radiology, Jena University Hospital-Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany.
Center for Electron Microscopy, Jena University Hospital-Friedrich Schiller University Jena, Ziegelmuehlenweg 1, 07743 Jena, Germany.
Nanomaterials (Basel). 2021 Feb 9;11(2):438. doi: 10.3390/nano11020438.
Magnetic hyperthermia can cause localized thermal eradication of several solid cancers. However, a localized and homogenous deposition of high concentrations of magnetic nanomaterials into the tumor stroma and tumor cells is mostly required. Poorly responsive cancers such as the pancreatic adenocarcinomas are hallmarked by a rigid stroma and poor perfusion to therapeutics and nanomaterials. Hence, approaches that enhance the infiltration of magnetic nanofluids into the tumor stroma convey potentials to improve thermal tumor therapy. We studied the influence of the matrix-modulating enzymes hyaluronidase and collagenase on the uptake of magnetic nanoparticles by pancreatic cancer cells and 3D spheroids thereof, and the overall impact on magnetic heating and cell death. Furthermore, we validated the effect of hyaluronidase on magnetic hyperthermia treatment of heterotopic pancreatic cancer models in mice. Treatment of cultured cells with the enzymes caused higher uptake of magnetic nanoparticles (MNP) as compared to nontreated cells. For example, hyaluronidase caused a 28% increase in iron deposits per cell. Consequently, the thermal doses (cumulative equivalent minutes at 43 °C, CEM43) increased by 15-23% as compared to heat dose achieved for cells treated with magnetic hyperthermia without using enzymes. Likewise, heat-induced cell death increased. In in vivo studies, hyaluronidase-enhanced infiltration and distribution of the nanoparticles in the tumors resulted in moderate heating levels (CEM43 of 128 min as compared to 479 min) and a slower, but persistent decrease in tumor volumes over time after treatment, as compared to comparable treatment without hyaluronidase. The results indicate that hyaluronidase, in particular, improves the infiltration of magnetic nanoparticles into pancreatic cancer models, impacts their thermal treatment and cell depletion, and hence, will contribute immensely in the fight against pancreatic and many other adenocarcinomas.
磁热疗可实现多种实体癌的局部热消融。然而，大多需要将高浓度磁性纳米材料局部且均匀地沉积到肿瘤基质和肿瘤细胞中。像胰腺腺癌这类反应欠佳的癌症，其特征在于基质坚硬，对治疗药物和纳米材料的灌注较差。因此，增强磁性纳米流体渗入肿瘤基质的方法具有改善热肿瘤治疗的潜力。我们研究了基质调节酶透明质酸酶和胶原酶对胰腺癌细胞及其三维球体摄取磁性纳米颗粒的影响，以及对磁热疗和细胞死亡的总体影响。此外，我们验证了透明质酸酶对小鼠异位胰腺癌模型磁热疗治疗效果的影响。与未处理的细胞相比，用这些酶处理培养的细胞会导致磁性纳米颗粒（MNP）摄取量更高。例如，透明质酸酶使每个细胞的铁沉积量增加了28%。因此，与未使用酶进行磁热疗处理的细胞相比，热剂量（43℃下的累积等效分钟数，CEM43）增加了15 - 23%。同样，热诱导的细胞死亡也增加了。在体内研究中，透明质酸酶增强了纳米颗粒在肿瘤中的浸润和分布，与未使用透明质酸酶的类似治疗相比，导致中等加热水平（CEM43为128分钟，而未使用酶时为479分钟），并且治疗后肿瘤体积随时间呈缓慢但持续的减小。结果表明，特别是透明质酸酶可改善磁性纳米颗粒对胰腺癌模型的浸润，影响其热疗和细胞清除，因此将在对抗胰腺癌和许多其他腺癌方面发挥巨大作用。
