Centre for Advanced Macromolecular Design (CAMD), School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
Biomater Sci. 2019 Mar 26;7(4):1652-1660. doi: 10.1039/c8bm01326h.
Ovarian cancer is often diagnosed at a late stage, when disease has spread to extra-pelvic regions such as the omentum. There are limited treatment options available for women with extensive disease and tumours often relapse after current chemotherapy regimens. Therefore, novel drugs should be investigated for the treatment of ovarian cancer. A 3D organotypic model of ovarian cancer can provide a specific platform for the evaluation of nano-drugs. Using patient derived primary cells, the 3D model mimics the ovarian metastatic microenvironment allowing efficient and reproducible testing of many nanoparticles. Dichlororuthenium(ii) (p-cymene) (1,3,5-triaza-7-phosphaadamantane) (RAPTA-C) conjugated fructose-micelles have been used as the promising nano-drug for the treatment of metastatic cancer. Therefore we aimed to investigate the anti-metastatic properties of RAPTA-C conjugated micelles in ovarian cancer metastasis.
Ovarian cancer cell adhesion and invasion into a model of omentum were analyzed with and without RAPTA-C conjugated micelles in a range of conditions.
We observed that RAPTA-C showed low general toxicity to both primary healthy and cancer cell lines. RAPTA-C loaded micelles significantly enhance the internalization of ruthenium inside the cells compared to free drugs. RAPTA-C did not affect adhesion of OVCAR4 ovarian cancer cells; however, it significantly inhibited invasion of these cells within the omentum model, either in its free form or as cargos inside the micelles. However, when OVCAR4 were treated prior to implantation, invasion was not inhibited.
A 3D organotypic model provides a clinically relevant and simple method to evaluate the efficiency of nano-drug treatment of ovarian cancer. The ability to inhibit metastasis of RAPTA-C delivered in fructose coated nanoparticles was investigated for the first time via this model. These results provide a good basis to continue the development of this nano-drug in vivo.
卵巢癌通常在晚期诊断，此时疾病已扩散至盆外区域，如大网膜。对于广泛疾病的女性，治疗选择有限，且肿瘤经常在当前化疗方案后复发。因此，应研究新型药物来治疗卵巢癌。卵巢癌的 3D 器官型模型可为纳米药物的评估提供特定平台。使用患者来源的原代细胞，该 3D 模型模拟卵巢转移微环境，可高效且可重复地测试许多纳米颗粒。二氯合钌(ii)(对伞花烃)(1,3,5-三氮杂-7-磷杂金刚烷)(RAPTA-C)偶联果糖胶束已被用作转移性癌症治疗的有前途的纳米药物。因此，我们旨在研究 RAPTA-C 偶联胶束在卵巢癌转移中的抗转移特性。
在一系列条件下，分析了 RAPTA-C 偶联胶束存在和不存在的情况下，卵巢癌细胞在大网膜模型中的黏附和侵袭。
我们观察到 RAPTA-C 对原代健康细胞和癌细胞系的一般毒性较低。与游离药物相比，RAPTA-C 负载的胶束显著增加了细胞内钌的内化。RAPTA-C 不影响 OVCAR4 卵巢癌细胞的黏附；然而，它显著抑制了这些细胞在大网膜模型中的侵袭，无论是游离形式还是作为胶束内的载体。然而，当 OVCAR4 细胞在植入前进行处理时，侵袭则未被抑制。
3D 器官型模型为评估纳米药物治疗卵巢癌的效率提供了一种临床相关且简单的方法。首次通过该模型研究了在果糖涂层纳米颗粒中递送的 RAPTA-C 抑制转移的能力。这些结果为在体内继续开发这种纳米药物提供了良好的基础。
