PBPK modeling-based optimization of site-specific chemo-photodynamic therapy with far-red light-activatable paclitaxel prodrug.
Combination therapy
Drug delivery
Paclitaxel prodrug
Photodynamic therapy
Physiologically based pharmacokinetic model
Quantitative system pharmacology
Journal
Journal of controlled release : official journal of the Controlled Release Society
ISSN: 1873-4995
Titre abrégé: J Control Release
Pays: Netherlands
ID NLM: 8607908
Informations de publication
Date de publication:
28 08 2019
28 08 2019
Historique:
received:
08
05
2019
revised:
03
07
2019
accepted:
08
07
2019
pubmed:
13
7
2019
medline:
2
10
2020
entrez:
13
7
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31299262
pii: S0168-3659(19)30397-9
doi: 10.1016/j.jconrel.2019.07.010
pmc: PMC6710169
mid: NIHMS1535305
pii:
doi:
Substances chimiques
Antineoplastic Agents, Phytogenic
0
Prodrugs
0
Paclitaxel
P88XT4IS4D
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
86-97Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM113940
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.
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