Ionizable Amino-Polyesters Synthesized via Ring Opening Polymerization of Tertiary Amino-Alcohols for Tissue Selective mRNA Delivery
The utility of messenger RNA (mRNA) as a therapy is gaining a broad interest due to its potential for addressing a wide range of diseases, while effective delivery of mRNA molecules to various tissues still poses a challenge. This study reports on the design and characterization of new ionizable ami...
| Main Authors: | , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020
|
| Online Access: | https://hdl.handle.net/1721.1/125442 |
| _version_ | 1826196551925497856 |
|---|---|
| author | Kowalski, Piotr S Palmiero, Umberto Capasso Huang, Yuxuan Rudra, Arnab Langer, Robert S Anderson, Daniel Griffith |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering Kowalski, Piotr S Palmiero, Umberto Capasso Huang, Yuxuan Rudra, Arnab Langer, Robert S Anderson, Daniel Griffith |
| author_sort | Kowalski, Piotr S |
| collection | MIT |
| description | The utility of messenger RNA (mRNA) as a therapy is gaining a broad interest due to its potential for addressing a wide range of diseases, while effective delivery of mRNA molecules to various tissues still poses a challenge. This study reports on the design and characterization of new ionizable amino-polyesters (APEs), synthesized via ring opening polymerization (ROP) of lactones with tertiary amino-alcohols that enable tissue and cell type selective delivery of mRNA. With a diverse library of APEs formulated into lipid nanoparticles (LNP), structure-activity parameters crucial for efficient transfection are established and APE-LNPs are identified that can preferentially home to and elicit effective mRNA expression with low in vivo toxicity in lung endothelium, liver hepatocytes, and splenic antigen presenting cells, including APE-LNP demonstrating nearly tenfold more potent systemic mRNA delivery to the lungs than vivo-jetPEI. Adopting tertiary amino-alcohols to initiate ROP of lactones allows to control polymer molecular weight and obtain amino-polyesters with narrow molecular weight distribution, exhibiting batch-to-batch consistency. All of which highlight the potential for clinical translation of APEs for systemic mRNA delivery and demonstrate the importance of employing controlled polymerization in the design of new polymeric nanomaterials to improve in vivo nucleic acid delivery. |
| first_indexed | 2024-09-23T10:29:16Z |
| format | Article |
| id | mit-1721.1/125442 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:29:16Z |
| publishDate | 2020 |
| publisher | Wiley |
| record_format | dspace |
| spelling | mit-1721.1/1254422022-09-27T09:46:36Z Ionizable Amino-Polyesters Synthesized via Ring Opening Polymerization of Tertiary Amino-Alcohols for Tissue Selective mRNA Delivery Kowalski, Piotr S Palmiero, Umberto Capasso Huang, Yuxuan Rudra, Arnab Langer, Robert S Anderson, Daniel Griffith Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Department of Chemistry Massachusetts Institute of Technology. Department of Materials Science and Engineering Massachusetts Institute of Technology. Institute for Medical Engineering & Science Koch Institute for Integrative Cancer Research at MIT The utility of messenger RNA (mRNA) as a therapy is gaining a broad interest due to its potential for addressing a wide range of diseases, while effective delivery of mRNA molecules to various tissues still poses a challenge. This study reports on the design and characterization of new ionizable amino-polyesters (APEs), synthesized via ring opening polymerization (ROP) of lactones with tertiary amino-alcohols that enable tissue and cell type selective delivery of mRNA. With a diverse library of APEs formulated into lipid nanoparticles (LNP), structure-activity parameters crucial for efficient transfection are established and APE-LNPs are identified that can preferentially home to and elicit effective mRNA expression with low in vivo toxicity in lung endothelium, liver hepatocytes, and splenic antigen presenting cells, including APE-LNP demonstrating nearly tenfold more potent systemic mRNA delivery to the lungs than vivo-jetPEI. Adopting tertiary amino-alcohols to initiate ROP of lactones allows to control polymer molecular weight and obtain amino-polyesters with narrow molecular weight distribution, exhibiting batch-to-batch consistency. All of which highlight the potential for clinical translation of APEs for systemic mRNA delivery and demonstrate the importance of employing controlled polymerization in the design of new polymeric nanomaterials to improve in vivo nucleic acid delivery. Juvenile Diabetes Research Foundation ( Postdoctoral Fellowship Grant 3-PDF-2017–383-A-N) United States. Defense Advanced Research Projects Agency (Grant W32P4Q-13–1-0011) 2020-05-26T13:29:28Z 2020-05-26T13:29:28Z 2020-01 2020-01-21T15:43:44Z Article http://purl.org/eprint/type/JournalArticle 1521-4095 0935-9648 https://hdl.handle.net/1721.1/125442 Kowalski, Piotr S. et al. “Ionizable Amino-Polyesters Synthesized via Ring Opening Polymerization of Tertiary Amino-Alcohols for Tissue Selective mRNA Delivery.” Advanced materials (2020): e1801151 © 2020 The Author(s) en https://dx.doi.org/10.1002/ADMA.201801151 Advanced materials Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Wiley PMC |
| spellingShingle | Kowalski, Piotr S Palmiero, Umberto Capasso Huang, Yuxuan Rudra, Arnab Langer, Robert S Anderson, Daniel Griffith Ionizable Amino-Polyesters Synthesized via Ring Opening Polymerization of Tertiary Amino-Alcohols for Tissue Selective mRNA Delivery |
| title | Ionizable Amino-Polyesters Synthesized via Ring Opening Polymerization of Tertiary Amino-Alcohols for Tissue Selective mRNA Delivery |
| title_full | Ionizable Amino-Polyesters Synthesized via Ring Opening Polymerization of Tertiary Amino-Alcohols for Tissue Selective mRNA Delivery |
| title_fullStr | Ionizable Amino-Polyesters Synthesized via Ring Opening Polymerization of Tertiary Amino-Alcohols for Tissue Selective mRNA Delivery |
| title_full_unstemmed | Ionizable Amino-Polyesters Synthesized via Ring Opening Polymerization of Tertiary Amino-Alcohols for Tissue Selective mRNA Delivery |
| title_short | Ionizable Amino-Polyesters Synthesized via Ring Opening Polymerization of Tertiary Amino-Alcohols for Tissue Selective mRNA Delivery |
| title_sort | ionizable amino polyesters synthesized via ring opening polymerization of tertiary amino alcohols for tissue selective mrna delivery |
| url | https://hdl.handle.net/1721.1/125442 |
| work_keys_str_mv | AT kowalskipiotrs ionizableaminopolyesterssynthesizedviaringopeningpolymerizationoftertiaryaminoalcoholsfortissueselectivemrnadelivery AT palmieroumbertocapasso ionizableaminopolyesterssynthesizedviaringopeningpolymerizationoftertiaryaminoalcoholsfortissueselectivemrnadelivery AT huangyuxuan ionizableaminopolyesterssynthesizedviaringopeningpolymerizationoftertiaryaminoalcoholsfortissueselectivemrnadelivery AT rudraarnab ionizableaminopolyesterssynthesizedviaringopeningpolymerizationoftertiaryaminoalcoholsfortissueselectivemrnadelivery AT langerroberts ionizableaminopolyesterssynthesizedviaringopeningpolymerizationoftertiaryaminoalcoholsfortissueselectivemrnadelivery AT andersondanielgriffith ionizableaminopolyesterssynthesizedviaringopeningpolymerizationoftertiaryaminoalcoholsfortissueselectivemrnadelivery |