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Cytochrome P450 enzyme-mediated auto-enhanced photodynamic cancer therapy of co-nanoassembly between clopidogrel and photosensitizer.
Cytochrome P450 enzyme-mediated auto-enhanced photodynamic cancer therapy of co-nanoassembly between clopidogrel and photosensitizer.
- Source :
-
Theranostics [Theranostics] 2020 Apr 15; Vol. 10 (12), pp. 5550-5564. Date of Electronic Publication: 2020 Apr 15 (Print Publication: 2020). - Publication Year :
- 2020
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Abstract
- Reactive oxygen species (ROS)-based photodynamic therapy (PDT) has a widespread application in cancer therapy. Nevertheless, the efficiency of PDT is far from satisfactory. One major impediment is the overexpression of glutathione (GSH) in tumor cells, which could deplete the level of PDT-generated ROS. Herein, we develop a novel type of cytochrome P450 enzyme-mediated auto-enhanced photodynamic co-nanoassembly between clopidogrel (CPG) and photosensitizer pyropheophorbide a (PPa). Methods: In this work, we prepare the co-assembled nanoparticles of CPG and PPa (CPG/PPa NPs) by using one-step precipitation method. The assembly mechanism, drug release behavior, GSH consumption, ROS generation, cellular uptake, cytotoxicity of CPG/PPa NPs are investigated in vitro . The mice bearing 4T1 tumor are employed to evaluate in vivo biodistribution and anti-tumor effect of CPG/PPa NPs. Results: Such CPG/PPa NPs could disrupt the intracellular redox homeostasis, resulting from the elimination of GSH by CPG active metabolite mediated by cytochrome P450 enzyme (CYP2C19). The in vivo assays reveal that CPG/PPa NPs not only increase the drug accumulation in tumor sites but also significantly suppress tumor growth in BALB/c mice bearing 4T1 tumor. With CPG-mediated GSH consumption and PPa-triggered ROS generation, CPG/PPa NPs show the enhanced PDT treatment effect by breaking intracellular redox balance. Conclusion: Our findings provide a valuable knowledge for the rational design of the PDT-based combinational cancer therapy.<br />Competing Interests: Competing Interests: The authors have declared that no competing interest exists.<br /> (© The author(s).)
- Subjects :
- Animals
Cell Line, Tumor
Chlorophyll pharmacology
Disease Models, Animal
Glutathione metabolism
Mice
Mice, Inbred BALB C
Nanoparticles chemistry
Neoplasms metabolism
Photosensitizing Agents pharmacology
Purinergic P2Y Receptor Antagonists pharmacology
Reactive Oxygen Species metabolism
Chlorophyll analogs & derivatives
Clopidogrel pharmacology
Cytochrome P-450 Enzyme System metabolism
Nanoparticles administration & dosage
Neoplasms therapy
Photochemotherapy methods
Subjects
Details
- Language :
- English
- ISSN :
- 1838-7640
- Volume :
- 10
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Theranostics
- Publication Type :
- Academic Journal
- Accession number :
- 32373230
- Full Text :
- https://doi.org/10.7150/thno.42633