| Intracellular delivery of the reactive oxygen species generating agent D-penicillamine upon conjugation to poly-L-glutamic acid. | |
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MedLine Citation:
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PMID: 20349949 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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D-penicillamine is an aminothiol that is cytotoxic to cancer cells and generates dose dependent reactive oxygen species (ROS) via copper catalyzed oxidation. However, the delivery of D-pen to cancer cells remains a challenge due to its high hydrophilicity, highly reactive thiol group and impermeability to the cell membrane. To overcome this challenge, we investigated a novel poly-L-glutamic acid (PGA) conjugate of D-pen (PGA-D-pen) where D-pen was conjugated to PGA modified with 2-(2-pyridyldithio)-ethylamine (PDE) via disulfide bonds. Confocal microscopy and cell uptake studies showed that the fluorescently labeled PGA-D-pen was taken up by human leukemia cells (HL-60) in a time dependent manner. Treatment of HL-60, murine leukemia cells (P388) and human breast cancer cells (MDA-MB-468) with PGA-D-pen resulted in dose dependent cytotoxicity and elevation of intracellular ROS levels. PGA-D-pen induced apoptosis in HL-60 cells which was verified by Annexin V binding. The in vivo evaluation of the conjugate in the P388 murine leukemia model (intraperitoneal) resulted in significant enhancement in the survival of CD2F1 mice over vehicle control. |
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Authors:
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Saurabh Wadhwa; Russell J Mumper |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Molecular pharmaceutics Volume: 7 ISSN: 1543-8392 ISO Abbreviation: Mol. Pharm. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-06-07 Completed Date: 2010-09-07 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101197791 Medline TA: Mol Pharm Country: United States |
Other Details:
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Languages: eng Pagination: 854-62 Citation Subset: IM |
Affiliation:
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Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina 27599-7362, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects Cell Line, Tumor Chelating Agents / administration & dosage, chemistry, pharmacology Chromatography, High Pressure Liquid HL-60 Cells Humans Mice Microscopy, Confocal Molecular Structure Neoplasms / drug therapy Penicillamine / administration & dosage*, chemistry*, pharmacology Polyglutamic Acid / chemistry* Reactive Oxygen Species / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Chelating Agents; 0/Reactive Oxygen Species; 25513-46-6/Polyglutamic Acid; 52-67-5/Penicillamine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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