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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.
This article was published in the following journal.
Name: Journal of controlled release : official journal of the Controlled Release Society
Chemo-photodynamic therapy is an attractive strategy against cancer. However, the combination of chemotherapeutic agent and photosensitizer is usually realized by physically embedding one or two agent...
The incorporation of chemo/photothermal/photodynamic therapy in subcellular organelles such as mitochondria has obtained extensive attention recently. Here, we designed a mitochondria-targeted hollow ...
Several physiologically-based pharmacokinetic (PBPK) models have been reported for intravenous (IV) and subcutaneous (SC) injections, but there has been a paucity of work for intramuscular (IM) inject...
Plasma concentrations of dabigatran (DAB), an active principle of prodrug dabigatran etexilate (DABE), are increased by renal impairment (RI) or co-administration of a P-glycoprotein (P-gp) inhibitor....
To investigate the efﬁcacy of antimicrobial photodynamic therapy (aPDT) adjunctive to conventional chemo-mechanical debridement of root canal system in patients with endodontic infections.
Developmental changes in physiology during childhood influence drug dosing. Failure to account for these changes leads to improper dosing, which is associated with decreased drug efficacy ...
The main goal of the OptimAT study main goal is to validate a PBPK model for 3 direct oral anticoagulants (rivaroxaban, apixaban, dabigatran) and 3 P2Y12 inhibitors (clopidogrel, ticagrelo...
Ticagrelor is a new generation antiplatelet agent with higher efficacy as compared to clopidogrel and prasugrel in treatment of patients with moderate and high ischemic risks. Ticagrelor i...
In patients with type III or IV cholangiocarcinoma, photodynamic therapy with biliary stent has been known for palliation of jaundice and improving survival. But most of therapeutic effect...
The present research will pilot-test a new state-of-the-art Internet-based intervention targeting adherence facilitation and optimization of medication use, and will be evaluated to assess...
Procedures by which protein structure and function are changed or created in vitro by altering existing or synthesizing new structural genes that direct the synthesis of proteins with sought-after properties. Such procedures may include the design of MOLECULAR MODELS of proteins using COMPUTER GRAPHICS or other molecular modeling techniques; site-specific mutagenesis (MUTAGENESIS, SITE-SPECIFIC) of existing genes; and DIRECTED MOLECULAR EVOLUTION techniques to create new genes.
The development and application of computational models of human pathophysiology that are individualized to patient-specific data.
The purified component of HEMATOPORPHYRIN DERIVATIVE, it consists of a mixture of oligomeric porphyrins. It is used in photodynamic therapy (HEMATOPORPHYRIN PHOTORADIATION); to treat malignant lesions with visible light and experimentally as an antiviral agent. It is the first drug to be approved in the use of PHOTODYNAMIC THERAPY in the United States.
Specific loci that show up during KARYOTYPING as a gap (an uncondensed stretch in closer views) on a CHROMATID arm after culturing cells under specific conditions. These sites are associated with an increase in CHROMOSOME FRAGILITY. They are classified as common or rare, and by the specific culture conditions under which they develop. Fragile site loci are named by the letters "FRA" followed by a designation for the specific chromosome, and a letter which refers to which fragile site of that chromosome (e.g. FRAXA refers to fragile site A on the X chromosome. It is a rare, folic acid-sensitive fragile site associated with FRAGILE X SYNDROME.)
The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis.
Bladder Cancer Brain Cancer Breast Cancer Cancer Cervical Cancer Colorectal Head & Neck Cancers Hodgkin Lymphoma Leukemia Lung Cancer Melanoma Myeloma Ovarian Cancer Pancreatic Cancer ...
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...
Clinical Approvals Clinical Trials Drug Approvals Drug Delivery Drug Discovery Generics Drugs Prescription Drugs In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are dis...