PBPK modeling-based optimization of site-specific chemo-photodynamic therapy with far-red light-activatable paclitaxel prodrug

JOURNAL OF CONTROLLED RELEASE

卷:308

Article

Li, Mengjie¹  Nguyen, Luong¹  Subramaniyan, Bharathiraja¹  Bio, Moses¹  Peer, Cody J.²  Kindrick, Jessica²  Figg, William D.²  Woo, Sukyung¹  You, Youngjae¹ 

[1] Univ Oklahoma, Coll Pharm, Dept Pharmaceut Sci, Hlth Sci Ctr, 1110 N Stonewall Ave CPB 317, Oklahoma City, OK 73117 USA

[2] NCI, Clin Pharmacol Program, NIH, Bethesda, MD 20892 USA

关键词: Paclitaxel prodrug;    Photodynamic therapy;    Combination therapy;    Quantitative system pharmacology;    Physiologically based pharmacokinetic model;    Drug delivery;   

DOI  :  10.1016/j.jconrel.2019.07.010

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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