Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity
Nanoscale drug delivery vehicles have been harnessed extensively as carriers for cancer chemotherapeutics. However, traditional pharmaceutical approaches for nanoformulation have been a challenge with molecules that exhibit incompatible physicochemical properties, such as platinum-based chemotherape...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2013
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| Online Access: | http://hdl.handle.net/1721.1/76785 https://orcid.org/0000-0002-5436-389X |
| _version_ | 1811088641901985792 |
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| author | Sengupta, Poulomi Basu, Sudipta Soni, Shivani Pandey, Ambarish Roy, Bhaskar Oh, Michael S. Chin, Kenneth T. Paraskar, Abhimanyu S. Sarangi, Sasmit Connor, Yamicia D. Sabbisetti, Venkata Kopparam, Jawahar Kulkarni, Ashish Muto, Katherine Amarasiriwardena, Chitra Jayawardene, Innocent Lupoli, Nicola Dinulescu, Daniela M. Bonventre, Joseph V. Mashelkar, Raghunath Anant Sengupta, Shiladitya |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology Sengupta, Poulomi Basu, Sudipta Soni, Shivani Pandey, Ambarish Roy, Bhaskar Oh, Michael S. Chin, Kenneth T. Paraskar, Abhimanyu S. Sarangi, Sasmit Connor, Yamicia D. Sabbisetti, Venkata Kopparam, Jawahar Kulkarni, Ashish Muto, Katherine Amarasiriwardena, Chitra Jayawardene, Innocent Lupoli, Nicola Dinulescu, Daniela M. Bonventre, Joseph V. Mashelkar, Raghunath Anant Sengupta, Shiladitya |
| author_sort | Sengupta, Poulomi |
| collection | MIT |
| description | Nanoscale drug delivery vehicles have been harnessed extensively as carriers for cancer chemotherapeutics. However, traditional pharmaceutical approaches for nanoformulation have been a challenge with molecules that exhibit incompatible physicochemical properties, such as platinum-based chemotherapeutics. Here we propose a paradigm based on rational design of active molecules that facilitate supramolecular assembly in the nanoscale dimension. Using cisplatin as a template, we describe the synthesis of a unique platinum (II) tethered to a cholesterol backbone via a unique monocarboxylato and O→Pt coordination environment that facilitates nanoparticle assembly with a fixed ratio of phosphatidylcholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000]. The nanoparticles formed exhibit lower IC50 values compared with carboplatin or cisplatin in vitro, and are active in cisplatin-resistant conditions. Additionally, the nanoparticles exhibit significantly enhanced in vivo antitumor efficacy in murine 4T1 breast cancer and in K-RasLSL/+/Ptenfl/fl ovarian cancer models with decreased systemic- and nephro-toxicity. Our results indicate that integrating rational drug design and supramolecular nanochemistry can emerge as a powerful strategy for drug development. Furthermore, given that platinum-based chemotherapeutics form the frontline therapy for a broad range of cancers, the increased efficacy and toxicity profile indicate the constructed nanostructure could translate into a next-generation platinum-based agent in the clinics. |
| first_indexed | 2024-09-23T14:05:13Z |
| format | Article |
| id | mit-1721.1/76785 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:05:13Z |
| publishDate | 2013 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/767852022-10-01T19:05:43Z Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity Sengupta, Poulomi Basu, Sudipta Soni, Shivani Pandey, Ambarish Roy, Bhaskar Oh, Michael S. Chin, Kenneth T. Paraskar, Abhimanyu S. Sarangi, Sasmit Connor, Yamicia D. Sabbisetti, Venkata Kopparam, Jawahar Kulkarni, Ashish Muto, Katherine Amarasiriwardena, Chitra Jayawardene, Innocent Lupoli, Nicola Dinulescu, Daniela M. Bonventre, Joseph V. Mashelkar, Raghunath Anant Sengupta, Shiladitya Harvard University--MIT Division of Health Sciences and Technology Connor, Yamicia D. Sengupta, Shiladitya Nanoscale drug delivery vehicles have been harnessed extensively as carriers for cancer chemotherapeutics. However, traditional pharmaceutical approaches for nanoformulation have been a challenge with molecules that exhibit incompatible physicochemical properties, such as platinum-based chemotherapeutics. Here we propose a paradigm based on rational design of active molecules that facilitate supramolecular assembly in the nanoscale dimension. Using cisplatin as a template, we describe the synthesis of a unique platinum (II) tethered to a cholesterol backbone via a unique monocarboxylato and O→Pt coordination environment that facilitates nanoparticle assembly with a fixed ratio of phosphatidylcholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000]. The nanoparticles formed exhibit lower IC50 values compared with carboplatin or cisplatin in vitro, and are active in cisplatin-resistant conditions. Additionally, the nanoparticles exhibit significantly enhanced in vivo antitumor efficacy in murine 4T1 breast cancer and in K-RasLSL/+/Ptenfl/fl ovarian cancer models with decreased systemic- and nephro-toxicity. Our results indicate that integrating rational drug design and supramolecular nanochemistry can emerge as a powerful strategy for drug development. Furthermore, given that platinum-based chemotherapeutics form the frontline therapy for a broad range of cancers, the increased efficacy and toxicity profile indicate the constructed nanostructure could translate into a next-generation platinum-based agent in the clinics. United States. Dept. of Defense (Breast Cancer Research Program Era of Hope Scholar Award W81XWH-07-1- 0482) United States. Dept. of Defense (Collaborative Innovator Grant) National Institutes of Health (U.S.) (Grant R01 CA135242-01A2) Medical Foundation, inc. (Charles A. King Trust Postdoctoral Research Fellowship Program) United States. Dept. of Defense (Breast Cancer Research Program Postdoctoral Fellowship Award) Dana-Farber/Harvard Cancer Center (Ovarian Cancer SPORE award) Canary Foundation Mary Kay Foundation V Foundation for Cancer Research 2013-02-12T21:22:58Z 2013-02-12T21:22:58Z 2012-07 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/76785 Sengupta, P. et al. “Cholesterol-tethered Platinum II-based Supramolecular Nanoparticle Increases Antitumor Efficacy and Reduces Nephrotoxicity.” Proceedings of the National Academy of Sciences 109.28 (2012): 11294–11299. Web. https://orcid.org/0000-0002-5436-389X en_US http://dx.doi.org/10.1073/pnas.1203129109 Proceedings of the National Academy of Sciences of the United States of America 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 National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Sengupta, Poulomi Basu, Sudipta Soni, Shivani Pandey, Ambarish Roy, Bhaskar Oh, Michael S. Chin, Kenneth T. Paraskar, Abhimanyu S. Sarangi, Sasmit Connor, Yamicia D. Sabbisetti, Venkata Kopparam, Jawahar Kulkarni, Ashish Muto, Katherine Amarasiriwardena, Chitra Jayawardene, Innocent Lupoli, Nicola Dinulescu, Daniela M. Bonventre, Joseph V. Mashelkar, Raghunath Anant Sengupta, Shiladitya Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity |
| title | Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity |
| title_full | Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity |
| title_fullStr | Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity |
| title_full_unstemmed | Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity |
| title_short | Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity |
| title_sort | cholesterol tethered platinum ii based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity |
| url | http://hdl.handle.net/1721.1/76785 https://orcid.org/0000-0002-5436-389X |
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