Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Li M

PROVIDER: S-EPMC6710169 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Li Mengjie M Nguyen Luong L Subramaniyan Bharathiraja B Bio Moses M Peer Cody J CJ Kindrick Jessica J Figg William D WD Woo Sukyung S You Youngjae Y

Journal of controlled release : official journal of the Controlled Release Society 20190709

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 paclitaxe ...[more]

PMID: 31299262

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Project description:We recently demonstrated the far-red light-activatable prodrug of paclitaxel (PTX), Pc-(L-PTX)2. Upon illumination with a 690 nm laser, Pc-(L-PTX)2 showed combinational cell killing from rapid photodynamic therapy damage by singlet oxygen, followed by sustained chemotherapy effects from locally released PTX. However, its high lipophilicity (log D7.4 > 3.1) caused aggregation in aqueous solutions and has nonselectivity toward cancer cells. To solve these important problems, we prepared folic acid (FA)-conjugated and photoactivatable prodrugs of PTX with a polyethylene glycol (PEG) spacer of various chain lengths: FA-PEG n -Pc-L-PTX [n = 0 (0k, 5), ?23 (1k, 7a), ?45 (2k, 7b), ?80 (3.5k, 7c), or ?114 (5k, 7d)]. The PEGylated prodrugs 7a-d had a much improved hydrophilicity compared with the non-PEGylated prodrug, Pc-(L-PTX)2. As the PEG length increased, the hydrophilicity of the prodrug increased (log D7.4 values: 1.28, 0.09, -0.24, and -0.59 for 1k, 2k, 3.5k, and 5k PEG prodrugs, respectively). Fluorescence spectral data suggested that the PEGylated prodrugs had good solubility in the culture medium at lower concentrations (<1-2 ?M), but showed fluorescence quenching due to limited solubility at higher concentrations (>2 ?M). Dynamic light scattering indicated that all of the prodrugs formed nanosized particles in both phosphate-buffered saline and culture medium at a concentration of 5 ?M. The PEG length affected both nonspecific and folate receptor (FR)-mediated uptake of the prodrugs. The enhanced cellular uptake was observed for the prodrugs with medium-sized PEGs (1k, 2k, or 3.5k) in FR-positive SKOV-3 cells, but not for the prodrugs with no PEG or with the longest PEG (5k), which suggests the optimal range of PEG length around 1k-3.5k for effective uptake of our prodrug system. Consistent with the cellular uptake pattern, medium-sized PEGylated prodrugs showed more potent phototoxic activity (IC50s, ?130 nM) than prodrugs with no PEG or the longest PEG (IC50, ?400 nM). In conclusion, we have developed far-red light-activatable prodrugs with improved water solubility and FR-targeting properties compared with the nontargeted prodrug.

Dataset Information

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

Publications

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

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