Evolution of Toll-like receptor 7/8 agonist therapeutics and their delivery approaches: From antiviral formulations to vaccine adjuvants
Imidazoquinoline derivatives (IMDs) and related compounds function as synthetic agonists of Toll-like receptors 7 and 8 (TLR7/8) and one is FDA approved for topical antiviral and skin cancer treatments. Nevertheless, these innate immune system-activating drugs have potentially much broader therapeut...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Elsevier BV
2021
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| Online Access: | https://hdl.handle.net/1721.1/135625 |
| _version_ | 1826193901734592512 |
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| author | Bhagchandani, Sachin Johnson, Jeremiah A Irvine, Darrell J |
| author_facet | Bhagchandani, Sachin Johnson, Jeremiah A Irvine, Darrell J |
| author_sort | Bhagchandani, Sachin |
| collection | MIT |
| description | Imidazoquinoline derivatives (IMDs) and related compounds function as synthetic agonists of Toll-like receptors 7 and 8 (TLR7/8) and one is FDA approved for topical antiviral and skin cancer treatments. Nevertheless, these innate immune system-activating drugs have potentially much broader therapeutic utility; they have been pursued as antitumor immunomodulatory agents and more recently as candidate vaccine adjuvants for cancer and infectious disease. The broad expression profiles of TLR7/8, poor pharmacokinetic properties of IMDs, and toxicities associated with systemic administration, however, are formidable barriers to successful clinical translation. Herein, we review IMD formulations that have advanced to the clinic and discuss issues related to biodistribution and toxicity that have hampered the further development of these compounds. Recent strategies aimed at enhancing safety and efficacy, particularly through the use of bioconjugates and nanoparticle formulations that alter pharmacokinetics, biodistribution, and cellular targeting, are described. Finally, key aspects of the biology of TLR7 signaling, such as TLR7 tolerance, that may need to be considered in the development of new IMD therapeutics are discussed. |
| first_indexed | 2024-09-23T09:47:06Z |
| format | Article |
| id | mit-1721.1/135625 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:47:06Z |
| publishDate | 2021 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1356252021-10-28T04:40:25Z Evolution of Toll-like receptor 7/8 agonist therapeutics and their delivery approaches: From antiviral formulations to vaccine adjuvants Bhagchandani, Sachin Johnson, Jeremiah A Irvine, Darrell J Imidazoquinoline derivatives (IMDs) and related compounds function as synthetic agonists of Toll-like receptors 7 and 8 (TLR7/8) and one is FDA approved for topical antiviral and skin cancer treatments. Nevertheless, these innate immune system-activating drugs have potentially much broader therapeutic utility; they have been pursued as antitumor immunomodulatory agents and more recently as candidate vaccine adjuvants for cancer and infectious disease. The broad expression profiles of TLR7/8, poor pharmacokinetic properties of IMDs, and toxicities associated with systemic administration, however, are formidable barriers to successful clinical translation. Herein, we review IMD formulations that have advanced to the clinic and discuss issues related to biodistribution and toxicity that have hampered the further development of these compounds. Recent strategies aimed at enhancing safety and efficacy, particularly through the use of bioconjugates and nanoparticle formulations that alter pharmacokinetics, biodistribution, and cellular targeting, are described. Finally, key aspects of the biology of TLR7 signaling, such as TLR7 tolerance, that may need to be considered in the development of new IMD therapeutics are discussed. 2021-10-27T20:24:19Z 2021-10-27T20:24:19Z 2021 2021-09-03T17:37:40Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/135625 en 10.1016/j.addr.2021.05.013 Advanced Drug Delivery Reviews Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV Elsevier |
| spellingShingle | Bhagchandani, Sachin Johnson, Jeremiah A Irvine, Darrell J Evolution of Toll-like receptor 7/8 agonist therapeutics and their delivery approaches: From antiviral formulations to vaccine adjuvants |
| title | Evolution of Toll-like receptor 7/8 agonist therapeutics and their delivery approaches: From antiviral formulations to vaccine adjuvants |
| title_full | Evolution of Toll-like receptor 7/8 agonist therapeutics and their delivery approaches: From antiviral formulations to vaccine adjuvants |
| title_fullStr | Evolution of Toll-like receptor 7/8 agonist therapeutics and their delivery approaches: From antiviral formulations to vaccine adjuvants |
| title_full_unstemmed | Evolution of Toll-like receptor 7/8 agonist therapeutics and their delivery approaches: From antiviral formulations to vaccine adjuvants |
| title_short | Evolution of Toll-like receptor 7/8 agonist therapeutics and their delivery approaches: From antiviral formulations to vaccine adjuvants |
| title_sort | evolution of toll like receptor 7 8 agonist therapeutics and their delivery approaches from antiviral formulations to vaccine adjuvants |
| url | https://hdl.handle.net/1721.1/135625 |
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