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Multiple Functions Integrated inside a Single Molecule for Amplification of Photodynamic Therapy Activity.
- Source :
-
Molecular pharmaceutics [Mol Pharm] 2020 Jan 06; Vol. 17 (1), pp. 190-201. Date of Electronic Publication: 2019 Dec 17. - Publication Year :
- 2020
-
Abstract
- Nitric oxide (NO) can play both prosurvival and prodeath roles in photodynamic therapy (PDT). The generation efficiency of peroxynitrite anions (ONOO <superscript>-</superscript> ), by NO and superoxide anions (O <subscript>2</subscript> <superscript>•-</superscript> ), significantly influenced the outcome. Reports indicated that such efficiency is closely related to the distance between NO and O <subscript>2</subscript> <superscript>•-</superscript> . Thus, in this manuscript, l-arginine (Arg) ethyl ester-modified zinc phthalocyanine (Arg-ZnPc) was designed and synthesized as a photosensitizer (PS) and NO donor. Post light irradiation, the guanido of Arg-ZnPc can be effectively oxidized by the generated reactive oxygen species (ROS) in the PDT process to release NO. Such a strategy could ensure O <subscript>2</subscript> <superscript>•-</superscript> and NO generation in the same place at the same time to guarantee effective ONOO <superscript>-</superscript> formation. In addition, NO has other multiple synergistic cancer treatment functions, including tumor tissue vasodilatation for drug extravasation promotion, P-glycoprotein (P-gp) downregulation for drug efflux inhibition, and glutathione depletion for cancer cell endogenous antioxidant defense destruction. In vitro and in vivo results indicated that the effective ONOO <superscript>-</superscript> formation and multiple functions of Arg-ZnPc could synergistically enhance its PDT activity and ensure satisfactory cancer treatment outcome.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Animals
Apoptosis drug effects
Apoptosis radiation effects
Cell Line, Tumor
Cell Survival drug effects
Cell Survival radiation effects
Drug Synergism
Female
Fluorescence
Glutathione metabolism
Humans
Indoles chemical synthesis
Indoles radiation effects
Isoindoles
Mice
Neoplasms metabolism
Nitric Oxide chemistry
Organometallic Compounds chemical synthesis
Organometallic Compounds radiation effects
Peroxynitrous Acid chemistry
Reactive Oxygen Species chemistry
Superoxides chemistry
Tissue Distribution drug effects
Tissue Distribution radiation effects
Xenograft Model Antitumor Assays
Zinc Compounds
Indoles chemistry
Indoles pharmacology
Neoplasms drug therapy
Nitric Oxide pharmacology
Organometallic Compounds chemistry
Organometallic Compounds pharmacology
Photochemotherapy methods
Photosensitizing Agents pharmacology
Superoxides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1543-8392
- Volume :
- 17
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular pharmaceutics
- Publication Type :
- Academic Journal
- Accession number :
- 31804837
- Full Text :
- https://doi.org/10.1021/acs.molpharmaceut.9b00893