Ionizable Amino‐Polyesters Synthesized via Ring Opening Polymerization of Tertiary Amino‐Alcohols for Tissue Selective mRNA Delivery. Issue 34 (5th July 2018)

• Record Type: Journal Article
• Authors: Kowalski, Piotr S.; Capasso Palmiero, Umberto; Huang, Yuxuan; Rudra, Arnab; Langer, Robert; Anderson, Daniel G.
• Is Part Of: Advanced materials. Volume 30:Issue 34(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-07-05
• Subjects: biomaterials -- messenger RNA -- nucleic acid delivery -- polyesters -- polymeric nanoparticles; Materials -- Periodicals; Chemical vapor deposition -- Periodicals; 620.11
• DOI: 10.1002/adma.201801151
• Languages: English
• ISSNs: 0935-9648

Abstract

Abstract: 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. Abstract : Most polymeric carriers have been developed for short RNAs, while effective delivery of significantly larger mRNA molecules to various tissues poses an additional challenge. This study reports on the design and characterization of new ionizable amino‐polyesters, synthesized via ring opening polymerization of lactones with tertiary amino‐alcohols, that enable tissue and cell type selective delivery of mRNA.