title: Dendrimer-Inspired Nanomaterials for the in Vivo Delivery of siRNA to Lung Vasculature.
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.
authors: †Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
authors: Omar F
authors: OF
authors: Khan
authors: †Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
authors: Edmond W
authors: EW
authors: Zaia
authors: †Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
authors: Siddharth
authors: S
authors: Jhunjhunwala
authors: †Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.|‡Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
authors: Wen
authors: W
authors: Xue
authors: †Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
authors: Wenxin
authors: W
authors: Cai
authors: †Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
authors: Dong Soo
authors: DS
authors: Yun
authors: ∥Alnylam Pharmaceuticals, Cambridge, Massachusetts 02142, United States.
authors: Carmen M
authors: CM
authors: Barnes
authors: †Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.|⊥Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
authors: James E
authors: JE
authors: Dahlman
authors: †Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.|§Department of Anesthesiology, Children's Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, United States.
authors: Yizhou
authors: Y
authors: Dong
authors: †Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
authors: Jeisa M
authors: JM
authors: Pelet
authors: †Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
authors: Matthew J
authors: MJ
authors: Webber
authors: †Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
authors: Jonathan K
authors: JK
authors: Tsosie
authors: †Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.|‡Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.|#Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
authors: Tyler E
authors: TE
authors: Jacks
authors: †Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.|⊥Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.|∇Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
authors: Robert
authors: R
authors: Langer
authors: †Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.|⊥Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.|∇Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
authors: Daniel G
authors: DG
authors: Anderson
mesh_terms: D000818:Animals; D050091:Dendrimers / Q000737:chemistry* / Q000627:therapeutic use; D042783:Endothelial Cells / Q000187:drug effects; D018014:Gene Transfer Techniques; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000473:pathology; D049329:Nanostructures / Q000737:chemistry* / Q000627:therapeutic use; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000235:genetics / Q000627:therapeutic use
chemical_list: D050091:Dendrimers; D034741:RNA, Small Interfering
keywords: in vivo; modified dendrimer nanoparticles; nanomaterial; siRNA; target lung endothelial cells