SMARTc Unit, Laboratory of Pharmacokinetics and Toxicology UFR Pharmacy, Center for Research on Cancer of Marseille, Inserm UMR1068, CNRS UMR7258, Aix Marseille University, Marseille, France,
Pharmacy Department, APHM La Conception, Marseille, France.
Int J Nanomedicine. 2018 Oct 23;13:6677-6688. doi: 10.2147/IJN.S179290. eCollection 2018.
Nanoparticles are of rising interest in cancer research, but in vitro canonical cell monolayer models are not suitable to evaluate their efficacy when prototyping candidates. Here, we developed three-dimensional (3D) spheroid models to test the efficacy of trastuzumab-docetaxel immunoliposomes in breast cancer prior to further testing them in vivo.
Immunoliposomes were synthesized using the standard thin film method and maleimide linker. Two human breast cancer cell lines varying in Her2 expression were tested: Her2+ cells derived from metastatic site: mammary breast MDA-MB-453 and triple-negative MDA-MB-231 cells. 3D spheroids were developed and tested with fluorescence detection to evaluate viability. In vivo efficacy and biodistribution studies were performed on xenograft bearing nude mice using fluorescent and bioluminescent imaging.
In vitro, antiproliferative efficacy was dependent upon cell type, size of the spheroids, and treatment scheduling, resulting in subsequent changes between tested conditions and in vivo results. Immunoliposomes performed better than free docetaxel + free trastuzumab and ado-trastuzumab emtansine (T-DM1). On MDA-MB-453 and MDA-MB-231 cell growth was reduced by 76% and 25%, when compared to free docetaxel + free trastuzumab and by 85% and 70% when compared to T-DM1, respectively. In vivo studies showed tumor accumulation ranging from 3% up to 15% of the total administered dose in MDA-MB-453 and MDA-MB-231 bearing mice. When compared to free docetaxel + free trastuzumab, tumor growth was reduced by 89% (MDA-MB-453) and 25% (MDA-MB-231) and reduced by 66% (MDA-MB-453) and 29% (MDA-MB-231) when compared to T-DM1, an observation in line with data collected from 3D spheroids experiments.
We demonstrated the predictivity of 3D in vitro models when developing and testing nanoparticles in experimental oncology. In vitro and in vivo data showed efficient drug delivery with higher efficacy and prolonged survival with immunoliposomes when compared to current anti-Her2 breast cancer strategies.
纳米颗粒在癌症研究中越来越受到关注，但在体外经典细胞单层模型中，当对候选药物进行原型设计时，并不适合评估其疗效。在这里，我们开发了三维（3D）球体模型，以在体内进一步测试之前测试曲妥珠单抗-多西紫杉醇免疫脂质体在乳腺癌中的疗效。
免疫脂质体采用标准薄膜法和马来酰亚胺连接子合成。测试了两种 Her2 表达不同的人乳腺癌细胞系：源自转移部位的 Her2+细胞：乳腺 MDA-MB-453 和三阴性 MDA-MB-231 细胞。开发了 3D 球体，并通过荧光检测进行测试，以评估其活力。使用荧光和生物发光成像在携带异种移植物的裸鼠上进行体内疗效和生物分布研究。
体外实验中，抗增殖效果取决于细胞类型、球体大小和治疗方案，从而导致测试条件和体内结果之间的后续变化。免疫脂质体的效果优于游离多西紫杉醇+游离曲妥珠单抗和 ado-曲妥珠单抗emtansine（T-DM1）。与游离多西紫杉醇+游离曲妥珠单抗相比，MDA-MB-453 和 MDA-MB-231 细胞的生长分别降低了 76%和 25%，与 T-DM1 相比，分别降低了 85%和 70%。体内研究表明，在 MDA-MB-453 和 MDA-MB-231 荷瘤小鼠中，肿瘤累积量占总给药剂量的 3%至 15%不等。与游离多西紫杉醇+游离曲妥珠单抗相比，肿瘤生长分别降低了 89%（MDA-MB-453）和 25%（MDA-MB-231），与 T-DM1 相比，肿瘤生长分别降低了 66%（MDA-MB-453）和 29%（MDA-MB-231），这与 3D 球体实验收集的数据一致。
我们证明了 3D 体外模型在开发和测试实验肿瘤学中的纳米颗粒时的预测性。与当前的抗 Her2 乳腺癌策略相比，体内和体外数据显示免疫脂质体具有高效的药物传递作用，具有更高的疗效和更长的生存时间。
