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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | en_US |
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American Chemical Society (ACS)
2015
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| Online Access: | http://hdl.handle.net/1721.1/97217 https://orcid.org/0000-0002-2693-4982 |
| _version_ | 1826191063500455936 |
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| author | Suntharalingam, Kogularamanan Yoo, Hyunsuk Lin, Wei Brooks, Jamar G. Lippard, Stephen J. Zheng, Yaorong Johnstone, Timothy |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Suntharalingam, Kogularamanan Yoo, Hyunsuk Lin, Wei Brooks, Jamar G. Lippard, Stephen J. Zheng, Yaorong Johnstone, Timothy |
| author_sort | Suntharalingam, Kogularamanan |
| collection | MIT |
| 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(NH[subscript 3])[subscript 2]Cl[subscript 2](O[subscript 2]CCH[subscript 2]CH[subscript 2]COOH)(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. |
| first_indexed | 2024-09-23T08:49:35Z |
| format | Article |
| id | mit-1721.1/97217 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:49:35Z |
| publishDate | 2015 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/972172022-09-30T11:31:21Z Pt(IV) Prodrugs Designed to Bind Non-Covalently to Human Serum Albumin for Drug Delivery Suntharalingam, Kogularamanan Yoo, Hyunsuk Lin, Wei Brooks, Jamar G. Lippard, Stephen J. Zheng, Yaorong Johnstone, Timothy Massachusetts Institute of Technology. Department of Chemistry Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Zheng, Yaorong Suntharalingam, Kogularamanan Johnstone, Timothy Yoo, Hyunsuk Lin, Wei Brooks, Jamar G. Lippard, Stephen J. 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(NH[subscript 3])[subscript 2]Cl[subscript 2](O[subscript 2]CCH[subscript 2]CH[subscript 2]COOH)(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. National Cancer Institute (U.S.) (Grant CA34992) Kathy and Curt Marble Cancer Research Fund Misrock Foundation (Postdoctoral Fellowship) Samsung Scholarship Foundation MIT-Harvard Center of Cancer Nanotechnology Excellence (Grant 5 U54 CA151884) Massachusetts Institute of Technology. Undergraduate Research Opportunities Program 2015-06-08T16:05:56Z 2015-06-08T16:05:56Z 2014-06 2014-04 Article http://purl.org/eprint/type/JournalArticle 0002-7863 1520-5126 http://hdl.handle.net/1721.1/97217 Zheng, Yao-Rong, Kogularamanan Suntharalingam, Timothy C. Johnstone, Hyunsuk Yoo, Wei Lin, Jamar G. Brooks, and Stephen J. Lippard. “Pt(IV) Prodrugs Designed to Bind Non-Covalently to Human Serum Albumin for Drug Delivery.” Journal of the American Chemical Society 136, no. 24 (June 18, 2014): 8790–8798. https://orcid.org/0000-0002-2693-4982 en_US http://dx.doi.org/10.1021/ja5038269 Journal of the American Chemical Society Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) PMC |
| spellingShingle | Suntharalingam, Kogularamanan Yoo, Hyunsuk Lin, Wei Brooks, Jamar G. Lippard, Stephen J. Zheng, Yaorong Johnstone, Timothy Pt(IV) Prodrugs Designed to Bind Non-Covalently to Human Serum Albumin for Drug Delivery |
| title | Pt(IV) Prodrugs Designed to Bind Non-Covalently to Human Serum Albumin for Drug Delivery |
| title_full | Pt(IV) Prodrugs Designed to Bind Non-Covalently to Human Serum Albumin for Drug Delivery |
| title_fullStr | Pt(IV) Prodrugs Designed to Bind Non-Covalently to Human Serum Albumin for Drug Delivery |
| title_full_unstemmed | Pt(IV) Prodrugs Designed to Bind Non-Covalently to Human Serum Albumin for Drug Delivery |
| title_short | Pt(IV) Prodrugs Designed to Bind Non-Covalently to Human Serum Albumin for Drug Delivery |
| title_sort | pt iv prodrugs designed to bind non covalently to human serum albumin for drug delivery |
| url | http://hdl.handle.net/1721.1/97217 https://orcid.org/0000-0002-2693-4982 |
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