Polymer-Lipid Nanoparticles for Systemic Delivery of mRNA to the Lungs

James C Kaczmarek; Asha K Patel; Kevin J Kauffman; Owen S Fenton; Matthew J Webber; Michael W Heartlein; Frank DeRosa; Daniel G Anderson

doi:10.1002/anie.201608450

Polymer-Lipid Nanoparticles for Systemic Delivery of mRNA to the Lungs

Angew Chem Int Ed Engl. 2016 Oct 24;55(44):13808-13812. doi: 10.1002/anie.201608450. Epub 2016 Sep 30.

Authors

James C Kaczmarek^{1

2}, Asha K Patel^{1

3}, Kevin J Kauffman^{1

2}, Owen S Fenton^{1

4}, Matthew J Webber¹, Michael W Heartlein⁵, Frank DeRosa⁵, Daniel G Anderson^{6

7

8

9}

Affiliations

¹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, NG7 2RD, UK.
⁴ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Shire Pharmaceuticals, Lexington, MA, USA.
⁶ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
⁷ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
⁸ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
⁹ Harvard and MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.

Abstract

Therapeutic nucleic acids hold great promise for the treatment of disease but require vectors for safe and effective delivery. Synthetic nanoparticle vectors composed of poly(β-amino esters) (PBAEs) and nucleic acids have previously demonstrated potential utility for local delivery applications. To expand this potential utility to include systemic delivery of mRNA, hybrid polymer-lipid nanoformulations for systemic delivery to the lungs were developed. Through coformulation of PBAEs with lipid-polyethylene glycol (PEG), mRNA formulations were developed with increased serum stability and increased in vitro potency. The formulations were capable of functional delivery of mRNA to the lungs after intravenous administration in mice. To our knowledge, this is the first report of the systemic administration of mRNA for delivery to the lungs using degradable polymer-lipid nanoparticles.

Keywords: PBAEs; drug delivery; mRNA; nanoparticles; serum stability.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Intravenous
Animals
Lipids / chemistry*
Lung / chemistry*
Mice
Molecular Structure
Nanoparticles / chemistry*
Particle Size
Polymers / administration & dosage
Polymers / chemistry*
RNA, Messenger / administration & dosage
RNA, Messenger / chemical synthesis
RNA, Messenger / chemistry*
Surface Properties

Substances

Lipids
Polymers
RNA, Messenger
poly(beta-amino ester)

Grants and funding

P30 CA014051/CA/NCI NIH HHS/United States