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Nano Lett. 2015 May 13;15(5):3008-16. doi: 10.1021/nl5048972. Epub 2015 Apr 2.

Dendrimer-Inspired Nanomaterials for the in Vivo Delivery of siRNA to Lung Vasculature.

Author information

1
†Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
2
‡Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
3
∥Alnylam Pharmaceuticals, Cambridge, Massachusetts 02142, United States.
4
⊥Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
5
§Department of Anesthesiology, Children's Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, United States.
6
#Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
7
∇Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.

Abstract

Targeted RNA delivery to lung endothelial cells has the potential to treat conditions that involve inflammation, such as chronic asthma and obstructive pulmonary disease. To this end, chemically modified dendrimer nanomaterials were synthesized and optimized for targeted small interfering RNA (siRNA) delivery to lung vasculature. Using a combinatorial approach, the free amines on multigenerational poly(amido amine) and poly(propylenimine) dendrimers were substituted with alkyl chains of increasing length. The top performing materials from in vivo screens were found to primarily target Tie2-expressing lung endothelial cells. At high doses, the dendrimer-lipid derivatives did not cause chronic increases in proinflammatory cytokines, and animals did not suffer weight loss due to toxicity. We believe these materials have potential as agents for the pulmonary delivery of RNA therapeutics.

KEYWORDS:

in vivo; modified dendrimer nanoparticles; nanomaterial; siRNA; target lung endothelial cells

PMID:
25789998
PMCID:
PMC4825876
DOI:
10.1021/nl5048972
[Indexed for MEDLINE]
Free PMC Article

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