Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Department of Molecular Cell Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
J Control Release. 2019 Jan 10;293:183-192. doi: 10.1016/j.jconrel.2018.11.029. Epub 2018 Dec 4.
The effect of poly(2-ethyl-butyl cyanoacrylate) nanoparticles containing the cytotoxic drug cabazitaxel was studied in three breast cancer cell lines and one basal-like patient-derived xenograft model grown in the mammary fat pad of immunodeficient mice. Nanoparticle-encapsulated cabazitaxel had a much better efficacy than similar concentrations of free drug in the basal-like patient-derived xenograft and resulted in complete remission of 6 out of 8 tumors, whereas free drug gave complete remission only with 2 out of 9 tumors. To investigate the different efficacies obtained with nanoparticle-encapsulated versus free cabazitaxel, mass spectrometry quantification of cabazitaxel was performed in mice plasma and selected tissue samples. Nanoparticle-encapsulated drug had a longer circulation time in blood. There was approximately a three times higher drug concentration in tumor tissue 24 h after injection, and two times higher 96 h after injection of nanoparticles with drug compared to the free drug. The tissue biodistribution obtained after 24 h using mass spectrometry analyses correlates well with biodistribution data obtained using IVIS® Spectrum in vivo imaging of nanoparticles labeled with the fluorescent substance NR668, indicating that these data also are representative for the nanoparticle distribution. Furthermore, immunohistochemistry was used to estimate infiltration of macrophages into the tumor tissue following injection of nanoparticle-encapsulated and free cabazitaxel. The higher infiltration of anti-tumorigenic versus pro-tumorigenic macrophages in tumors treated with the nanoparticles might also contribute to the improved effect obtained with the nanoparticle-encapsulated drug. Tumor infiltration of pro-tumorigenic macrophages was four times lower when using nanoparticles containing cabazitaxel than when using particles without drug, and we speculate that the very good therapeutic efficacy obtained with our cabazitaxel-containing particles may be due to their ability to reduce the level of pro-tumorigenic macrophages in the tumor. In summary, encapsulation of cabazitaxel in poly(2-ethyl-butyl cyanoacrylate) nanoparticles seems promising for treatment of breast cancer.
聚（2-乙基丁基氰基丙烯酸酯）纳米颗粒载细胞毒药物卡巴他赛的作用在三种乳腺癌细胞系和一种基底样患者来源的异种移植模型中进行了研究，该模型在免疫缺陷小鼠的乳腺脂肪垫中生长。纳米颗粒包裹的卡巴他赛比游离药物具有更好的疗效，在基底样患者来源的异种移植中，8 个肿瘤中有 6 个完全缓解，而游离药物只有 9 个肿瘤中有 2 个完全缓解。为了研究纳米颗粒包裹的卡巴他赛与游离卡巴他赛的不同疗效，对小鼠血浆和选定的组织样本中的卡巴他赛进行了质谱定量分析。纳米颗粒包裹的药物在血液中的循环时间更长。注射后 24 小时，肿瘤组织中的药物浓度约高 3 倍，注射纳米颗粒载药后 96 小时，药物浓度高 2 倍。用质谱分析获得的 24 小时组织分布与用 IVIS® Spectrum 体内成像获得的纳米颗粒标记荧光物质 NR668 的分布数据非常吻合，表明这些数据也代表了纳米颗粒的分布。此外，免疫组织化学用于估计注射纳米颗粒包裹的和游离的卡巴他赛后肿瘤组织中巨噬细胞的浸润。在用纳米颗粒处理的肿瘤中，抗肿瘤浸润性巨噬细胞的浸润程度高于促肿瘤性巨噬细胞，这也可能有助于提高纳米颗粒包裹药物的疗效。用含有卡巴他赛的纳米颗粒时，肿瘤中促肿瘤性巨噬细胞的浸润程度比用不含药物的颗粒低 4 倍，我们推测，我们的含有卡巴他赛的颗粒具有非常好的治疗效果，可能是因为它们能够降低肿瘤中促肿瘤性巨噬细胞的水平。总之，聚（2-乙基丁基氰基丙烯酸酯）纳米颗粒包载卡巴他赛有望用于治疗乳腺癌。
