Department of Gynecology and Obstetrics, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.
School of Pharmacy, North Sichuan Medical College, Nanchong, China.
Mater Sci Eng C Mater Biol Appl. 2020 Jun;111:110759. doi: 10.1016/j.msec.2020.110759. Epub 2020 Feb 19.
Ovarian cancer is considered to be the most fatal reproductive cancers. Melphalan is used to treat ovarian cancer as an intraperitoneal chemotherapy agent. However, elucidating its pharmacokinetic behavior and preparing it for administration are challenging since it undergoes spontaneous hydrolysis. In this study, melphalan is transformed into a macromolecular prodrug by copolymerizing with p-dioxanone. The hydrophobicity of copolymer chains protects melphalan from hydrolysis. Poly(p-dioxanone-co-melphalan; PDCM) is electrosprayed and converted into nanoparticles (PDCM NPs) with diameters of ~300-350 nm to facilitate its intracellular delivery. UPLC-MS and HPLC are applied to verify and monitor the release of melphalan from PDCM NPs. PDCM NPs could suppress the proliferation of SKOV-3 cells. The IC50 of 4.3% melphalan-containing PDCM-3 NP was 70 mg/L, 72 h post administration. These suppression characteristics not only affected by the degradation and then the extracellular release of melphalan from PDCM NPs, but also the uptake via phagocytosis phenomenon in SKOV-3 cells. As revealed by flow cytometry, phagocytosis is a first-order process. Once phagocytosed, PDCM NPs are digested by lysosomes, causing a rapid release of melphalan into the cytoplasm, which ultimately causes suppression of SKOV-3 cell proliferation. Finally, the in vivo antitumor effects of PDCM NPs are verified in xenograft ovarian carcinoma. After a 20-day treatment, the tumor growth rate of the PDCM-3 NP group was (266 ± 178%) which was lower than those in the free melphalan group (367 ± 150%) and control group (648 ± 149%). Besides, significant tissue necrosis and growth suppression were observed in animals administered injections of PDCM NPs. Furthermore, the in vivo tracing results of Nile red-labeled PDCM NPs demonstrated that PDCM-3 NPs might be phagocytosed by macrophages and then taken to adjacent lymph nodes, which is a way of prevention or early treatment of lymphatic metastasis of tumors.
卵巢癌被认为是最致命的生殖系统癌症。美法仑被用作治疗卵巢癌的腹腔内化疗药物。然而，由于其自发水解，阐明其药代动力学行为并将其准备用于给药具有挑战性。在这项研究中，美法仑通过与对二氧环己酮共聚转化为高分子前药。共聚物链的疏水性保护美法仑免受水解。将聚（对二氧环己酮-共-美法仑；PDCM）电喷雾转化为直径约 300-350nm 的纳米颗粒（PDCM NPs），以促进其细胞内递送。UPLC-MS 和 HPLC 用于验证和监测 PDCM NPs 中美法仑的释放。PDCM NPs 可以抑制 SKOV-3 细胞的增殖。给药后 72 小时，含 4.3%美法仑的 PDCM-3 NP 的 IC50 为 70mg/L。这些抑制特性不仅受到 PDCM NPs 中美法仑的降解及其随后的细胞外释放的影响，还受到 SKOV-3 细胞吞噬现象摄取的影响。如流式细胞术所示，吞噬作用是一个一级过程。一旦被吞噬，PDCM NPs 就会被溶酶体消化，导致美法仑迅速释放到细胞质中，最终导致 SKOV-3 细胞增殖受到抑制。最后，在卵巢癌异种移植模型中验证了 PDCM NPs 的体内抗肿瘤作用。经过 20 天的治疗，PDCM-3 NP 组的肿瘤生长率（266±178%）低于游离美法仑组（367±150%）和对照组（648±149%）。此外，在给予 PDCM NPs 注射的动物中观察到明显的组织坏死和生长抑制。此外，尼罗红标记的 PDCM NPs 的体内示踪结果表明，PDCM-3 NPs 可能被巨噬细胞吞噬，然后被带到相邻的淋巴结，这是预防或早期治疗肿瘤淋巴转移的一种方法。
