Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, 52242, USA.
Department of Pharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, Sohag University, Sohag, 82524, Egypt.
Drug Deliv Transl Res. 2022 Jul;12(7):1684-1696. doi: 10.1007/s13346-021-01065-7. Epub 2021 Oct 11.
Endometrial cancer is the most common gynecological cancer that affects the female reproductive organs. The standard therapy for EC for the past two decades has been chemotherapy and/or radiotherapy. PD98059 is a reversible MEK inhibitor that was found in these studies to increase the cytotoxicity of paclitaxel (PTX) against human endometrial cancer cells (Hec50co) in a synergistic and dose-dependent manner. Additionally, while PD98059 arrested Hec50co cells at the G/G phase, and PTX increased accumulation of cells at the G/M phase, the combination treatment increased accumulation at both the G/G and G/M phases at low PTX concentrations. We recently developed poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) modified with polyethylene glycol (PEG) and coated with polyamidoamine (PAMAM) (referred to here as PGM NPs) which have favorable biodistribution profiles in mice, compared to PD98059 solution. Here, in order to enhance tissue distribution of PD98059, PD98059-loaded PGM NPs were prepared and characterized. The average size, zeta potential, and % encapsulation efficiency (%EE) of these NPs was approximately 184 nm, + 18 mV, and 23%, respectively. The PD98059-loaded PGM NPs released ~ 25% of the total load within 3 days in vitro. In vivo murine studies revealed that the pharmacokinetics and biodistribution profile of intravenous (IV) injected PD98059 was improved when delivered as PD98059-loaded PGM NPs as opposed to soluble PD98059. Further investigation of the in vivo efficacy and safety of this formulation is expected to emphasize the potential of its clinical application in combination with commercial PTX formulations against different cancers.
子宫内膜癌是最常见的妇科癌症，影响女性生殖器官。在过去的二十年中，EC 的标准治疗方法是化疗和/或放疗。PD98059 是一种可逆的 MEK 抑制剂，在这些研究中发现它能以协同和剂量依赖的方式增加紫杉醇（PTX）对人子宫内膜癌细胞（Hec50co）的细胞毒性。此外，虽然 PD98059 将 Hec50co 细胞阻滞在 G/G 期，而 PTX 增加了 G/M 期细胞的积累，但联合治疗在低 PTX 浓度下同时增加了 G/G 和 G/M 期的积累。我们最近开发了聚（乳酸-共-乙醇酸）（PLGA）纳米粒子（NPs），并用聚乙二醇（PEG）进行修饰，并涂有聚酰胺胺（PAMAM）（这里称为 PGM NPs），与 PD98059 溶液相比，它们在小鼠体内具有良好的生物分布特征。在这里，为了增强 PD98059 的组织分布，制备并表征了载 PD98059 的 PGM NPs。这些 NPs 的平均粒径、Zeta 电位和包封效率（%EE）分别约为 184nm、+18mV 和 23%。在体外，PD98059 载药的 PGM NPs 在 3 天内释放了约 25%的总载药量。体内小鼠研究表明，当作为 PD98059 载药的 PGM NPs 而非可溶 PD98059 静脉（IV）注射时，PD98059 的药代动力学和生物分布特征得到改善。进一步研究这种制剂的体内疗效和安全性有望强调其与商业 PTX 制剂联合应用于不同癌症的临床应用潜力。
