Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City 73117, OK, USA.
Clinical Pharmacology Program, National Cancer Institute, NIH, Bethesda 20892, MD, USA.
J Control Release. 2019 Aug 28;308:86-97. doi: 10.1016/j.jconrel.2019.07.010. Epub 2019 Jul 9.
Photodynamic therapy (PDT) is a clinically approved therapeutic modality to treat certain types of cancers. However, incomplete ablation of tumor is a challenge. Visible and near IR-activatable prodrug, exhibiting the combined effects of PDT and local chemotherapy, showed better efficacy than PDT alone, without systemic side effects. Site-specifically released chemotherapeutic drugs killed cancer cells surviving from rapid PDT damage via bystander effects. Recently, we developed such a paclitaxel (PTX) prodrug that targets folate receptors. The goals of this study were to determine the optimal treatment conditions, based on modeling, for maximum antitumor efficacy in terms of drug-light interval (DLI), and to investigate the impact of rapid PDT effects on the pharmacokinetic (PK) profiles of the released PTX. PK profiles of the prodrug were determined in key organs and a quantitative systems pharmacology (QSP) model was established to simulate PK profiles of the prodrug and the released PTX. Three illumination time points (DLI = 0.5, 9, or 48 h) were selected for the treatment based on the plasma/tumor ratio of the prodrug to achieve V-PDT (vascular targeted-PDT, 0.5 h), C-PDT (cellular targeted-PDT, 48 h), or both V- and C-PDT (9 h). The anti-tumor efficacy of the PTX prodrug was greatly influenced by the DLI. The 9 h DLI group, when both tumor and plasma concentrations of the prodrug were sufficient, showed the best antitumor effect. The clearance of the released PTX from tumor seemed to be largely impacted by blood circulation. Here, QSP modeling was an invaluable tool for rational optimization of the treatment conditions and for a deeper mechanistic understanding of the positive physiological effect of the combination therapy.
光动力疗法（PDT）是一种临床认可的治疗某些类型癌症的方法。然而，肿瘤的不完全消融是一个挑战。可见和近红外光激活的前药，同时具有 PDT 和局部化疗的联合作用，显示出比单独 PDT 更好的疗效，而没有全身副作用。通过旁观者效应，从快速 PDT 损伤中存活的肿瘤细胞被特异性释放的化疗药物杀死。最近，我们开发了一种靶向叶酸受体的紫杉醇（PTX）前药。本研究的目的是基于模型确定最佳治疗条件，以在药物光照间隔（DLI）方面获得最大的抗肿瘤疗效，并研究快速 PDT 效应对释放的 PTX 的药代动力学（PK）曲线的影响。在关键器官中确定了前药的 PK 曲线，并建立了定量系统药理学（QSP）模型来模拟前药和释放的 PTX 的 PK 曲线。基于前药在血浆/肿瘤中的比值选择了三个光照时间点（DLI=0.5、9 或 48 h）进行治疗，以实现血管靶向-PDT（V-PDT，0.5 h）、细胞靶向-PDT（C-PDT，48 h）或 V-和 C-PDT（9 h）。PTX 前药的抗肿瘤疗效受 DLI 的影响很大。9 h DLI 组在肿瘤和前药血浆浓度都足够时，显示出最好的抗肿瘤效果。从肿瘤中释放的 PTX 的清除似乎受到血液循环的很大影响。在这里，QSP 建模是优化治疗条件和深入了解联合治疗的积极生理效应的机制的宝贵工具。
