Electrosprayed nanoparticles of poly(p-dioxanone-co-melphalan) macromolecular prodrugs for treatment of xenograft ovarian carcinoma

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. [Display omitted] •Melphalan is transformed into PDCM prodrug to protect it from hydrolysis.•PDCM is converted into ~300–350 nm by utilizing the comparatively straightforward electrospraying method .•Melphalan could be stably released from PDCM NPs extracellularly.•PDCM NPs could be phagocytosed by SKOV-3 cells via first-order kinetics.•Compared to free melphalan, PDCM NPs had better antitumor effects.