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Pt(IV) prodrugs designed to bind non-covalently to human serum albumin for drug delivery.

Albumin is the most abundant protein in human serum and drugs that are administered intravenously inevitably interact with it. We present here a series of platinum(IV) prodrugs designed specifically to enhance interaction with human serum albumin (HSA) for drug delivery. This goal is achieved by asy... Full description

Journal Title: Journal of the American Chemical Society June 18, 2014, Vol.136(24), pp.8790-8798
Main Author: Zheng, Yao-Rong
Other Authors: Suntharalingam, Kogularamanan , Johnstone, Timothy C , Yoo, Hyunsuk , Lin, Wei , Brooks, Jamar G , Lippard, Stephen J
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1520-5126 ; DOI: 1520-5126 ; DOI: 10.1021/ja5038269
Link: http://search.proquest.com/docview/1537593832/?pq-origsite=primo
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title: Pt(IV) prodrugs designed to bind non-covalently to human serum albumin for drug delivery.
format: Article
creator:
  • Zheng, Yao-Rong
  • Suntharalingam, Kogularamanan
  • Johnstone, Timothy C
  • Yoo, Hyunsuk
  • Lin, Wei
  • Brooks, Jamar G
  • Lippard, Stephen J
subjects:
  • Antineoplastic Agents–Chemical Synthesis
  • Cell Cycle–Chemistry
  • Cell Line, Tumor–Pharmacology
  • Cell Proliferation–Drug Effects
  • Cell Survival–Drug Effects
  • Dose-Response Relationship, Drug–Drug Effects
  • Drug Delivery Systems–Chemical Synthesis
  • Drug Design–Chemistry
  • Drug Screening Assays, Antitumor–Pharmacology
  • Humans–Chemical Synthesis
  • Models, Molecular–Chemistry
  • Molecular Conformation–Pharmacology
  • Organoplatinum Compounds–Chemistry
  • Prodrugs–Chemistry
  • Serum Albumin–Chemistry
  • Structure-Activity Relationship–Chemistry
  • Antineoplastic Agents
  • Organoplatinum Compounds
  • Prodrugs
  • Serum Albumin
ispartof: Journal of the American Chemical Society, June 18, 2014, Vol.136(24), pp.8790-8798
description: Albumin is the most abundant protein in human serum and drugs that are administered intravenously inevitably interact with it. We present here a series of platinum(IV) prodrugs designed specifically to enhance interaction with human serum albumin (HSA) for drug delivery. This goal is achieved by asymmetrically functionalizing the axial ligands of the prodrug so as to mimic the overall features of a fatty acid. Systematic variation of the length of the aliphatic tail tunes the cellular uptake and, consequently, the cytotoxicity of cis,cis,trans-[Pt(NH3)2Cl2(O2CCH2CH2COOH)(OCONHR)], 4, where R is a linear alkyl group. Investigation of an analogue bearing a fluorophore conjugated to the succinate ligand confirmed that these compounds are reduced by biological reductants with loss of the axial ligands. Intracellular release of cisplatin from 4 was further confirmed by observing the characteristic effects of cisplatin on the cell cycle and morphology following treatment with the prodrug. The most potent member of series 4, for which R is a hexadecyl chain, interacts with HSA in a 1:1 stoichiometry to form the platinum-protein complex 7. The interaction is non-covalent and extraction with octanol completely removes the prodrug from an aqueous solution of HSA. Construct 7 is robust and can be isolated following fast protein liquid chromatography. The nature of the tight interaction was investigated computationally, and these studies suggest that the prodrug is buried below the surface of the protein. Consequently, complexation to HSA is able to reduce the rate of reduction of the prodrug by ascorbate. The lead compound from series 4 also exhibited significant stability in whole human blood, attributed to its interaction with HSA. This favorable redox profile, in conjunction with the established nonimmunogenicity, biocompatibility, and enhanced tumor accumulation of HSA, produces a system that holds significant therapeutic potential.
language: eng
source:
identifier: E-ISSN: 1520-5126 ; DOI: 1520-5126 ; DOI: 10.1021/ja5038269
fulltext: no_fulltext
issn:
  • 15205126
  • 1520-5126
url: Link


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titlePt(IV) prodrugs designed to bind non-covalently to human serum albumin for drug delivery.
creatorZheng, Yao-Rong ; Suntharalingam, Kogularamanan ; Johnstone, Timothy C ; Yoo, Hyunsuk ; Lin, Wei ; Brooks, Jamar G ; Lippard, Stephen J
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subjectAntineoplastic Agents–Chemical Synthesis ; Cell Cycle–Chemistry ; Cell Line, Tumor–Pharmacology ; Cell Proliferation–Drug Effects ; Cell Survival–Drug Effects ; Dose-Response Relationship, Drug–Drug Effects ; Drug Delivery Systems–Chemical Synthesis ; Drug Design–Chemistry ; Drug Screening Assays, Antitumor–Pharmacology ; Humans–Chemical Synthesis ; Models, Molecular–Chemistry ; Molecular Conformation–Pharmacology ; Organoplatinum Compounds–Chemistry ; Prodrugs–Chemistry ; Serum Albumin–Chemistry ; Structure-Activity Relationship–Chemistry ; Antineoplastic Agents ; Organoplatinum Compounds ; Prodrugs ; Serum Albumin
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descriptionAlbumin is the most abundant protein in human serum and drugs that are administered intravenously inevitably interact with it. We present here a series of platinum(IV) prodrugs designed specifically to enhance interaction with human serum albumin (HSA) for drug delivery. This goal is achieved by asymmetrically functionalizing the axial ligands of the prodrug so as to mimic the overall features of a fatty acid. Systematic variation of the length of the aliphatic tail tunes the cellular uptake and, consequently, the cytotoxicity of cis,cis,trans-[Pt(NH3)2Cl2(O2CCH2CH2COOH)(OCONHR)], 4, where R is a linear alkyl group. Investigation of an analogue bearing a fluorophore conjugated to the succinate ligand confirmed that these compounds are reduced by biological reductants with loss of the axial ligands. Intracellular release of cisplatin from 4 was further confirmed by observing the characteristic effects of cisplatin on the cell cycle and morphology following treatment with the prodrug. The most potent member of series 4, for which R is a hexadecyl chain, interacts with HSA in a 1:1 stoichiometry to form the platinum-protein complex 7. The interaction is non-covalent and extraction with octanol completely removes the prodrug from an aqueous solution of HSA. Construct 7 is robust and can be isolated following fast protein liquid chromatography. The nature of the tight interaction was investigated computationally, and these studies suggest that the prodrug is buried below the surface of the protein. Consequently, complexation to HSA is able to reduce the rate of reduction of the prodrug by ascorbate. The lead compound from series 4 also exhibited significant stability in whole human blood, attributed to its interaction with HSA. This favorable redox profile, in conjunction with the established nonimmunogenicity, biocompatibility, and enhanced tumor accumulation of HSA, produces a system that holds significant therapeutic potential.
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titlePt(IV) prodrugs designed to bind non-covalently to human serum albumin for drug delivery.
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