Efficient nuclear delivery and nuclear body localization of antisense oligo-nucleotides using degradable polymersomes.

Younghoon Kim, Manu Tewari, David J. Pajeroski, Shamik Sen, Williams Jason, Shashank Sirsi, Gordon Lutz, Dennis E. Discher

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Delivery of antisense oligonucleotides, AON, presents many of the same challenges as delivery of any nucleic acid: charge, stability, cell uptake, endolysosomal escape, and entry into the nucleus. Here we demonstrate efficient delivery of AON after loading into biodegradable polymer vesicles or 'polymersomes'. We focus on AON delivery to muscle cells in vitro and in vivo because of the emergence of AON in therapeutic strategies directed at muscular dystrophies. To first clarify uptake kinetics without the complications of typical multi-layered myotube cultures, we use micro-patterned C2C12 cells and show efficient uptake of AON-polymersomes. The biodegradable polymersomes break down and foster AON escape with the binding of fluorescent-AON into the nuclear bodies. Intramuscular injections of the polymersome-AON into the hind limbs of mdx-dystrophic mice show more efficient nuclear uptake than AON alone and also lead to dystrophin expression in the mdx mice. In sum, these neutral, degradable carriers of AON show promise in vivo.

Fingerprint

Inbred mdx Mouse
Biodegradable polymers
Oligonucleotides
Nucleic acids
Nucleotides
Muscle
Cells
Dystrophin
Kinetics
Muscular Dystrophies
Antisense Oligonucleotides
Intramuscular Injections
Skeletal Muscle Fibers
Muscle Cells
Nucleic Acids
Polymers
Extremities
Therapeutics
In Vitro Techniques

ASJC Scopus subject areas

  • Signal Processing
  • Biomedical Engineering
  • Computer Vision and Pattern Recognition
  • Health Informatics

Cite this

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title = "Efficient nuclear delivery and nuclear body localization of antisense oligo-nucleotides using degradable polymersomes.",
abstract = "Delivery of antisense oligonucleotides, AON, presents many of the same challenges as delivery of any nucleic acid: charge, stability, cell uptake, endolysosomal escape, and entry into the nucleus. Here we demonstrate efficient delivery of AON after loading into biodegradable polymer vesicles or 'polymersomes'. We focus on AON delivery to muscle cells in vitro and in vivo because of the emergence of AON in therapeutic strategies directed at muscular dystrophies. To first clarify uptake kinetics without the complications of typical multi-layered myotube cultures, we use micro-patterned C2C12 cells and show efficient uptake of AON-polymersomes. The biodegradable polymersomes break down and foster AON escape with the binding of fluorescent-AON into the nuclear bodies. Intramuscular injections of the polymersome-AON into the hind limbs of mdx-dystrophic mice show more efficient nuclear uptake than AON alone and also lead to dystrophin expression in the mdx mice. In sum, these neutral, degradable carriers of AON show promise in vivo.",
author = "Younghoon Kim and Manu Tewari and Pajeroski, {David J.} and Shamik Sen and Williams Jason and Shashank Sirsi and Gordon Lutz and Discher, {Dennis E.}",
year = "2006",
month = "12",
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language = "English (US)",
pages = "4350--4353",
journal = "Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference",
issn = "1557-170X",
publisher = "Institute of Electrical and Electronics Engineers Inc.",

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T1 - Efficient nuclear delivery and nuclear body localization of antisense oligo-nucleotides using degradable polymersomes.

AU - Kim, Younghoon

AU - Tewari, Manu

AU - Pajeroski, David J.

AU - Sen, Shamik

AU - Jason, Williams

AU - Sirsi, Shashank

AU - Lutz, Gordon

AU - Discher, Dennis E.

PY - 2006/12/1

Y1 - 2006/12/1

N2 - Delivery of antisense oligonucleotides, AON, presents many of the same challenges as delivery of any nucleic acid: charge, stability, cell uptake, endolysosomal escape, and entry into the nucleus. Here we demonstrate efficient delivery of AON after loading into biodegradable polymer vesicles or 'polymersomes'. We focus on AON delivery to muscle cells in vitro and in vivo because of the emergence of AON in therapeutic strategies directed at muscular dystrophies. To first clarify uptake kinetics without the complications of typical multi-layered myotube cultures, we use micro-patterned C2C12 cells and show efficient uptake of AON-polymersomes. The biodegradable polymersomes break down and foster AON escape with the binding of fluorescent-AON into the nuclear bodies. Intramuscular injections of the polymersome-AON into the hind limbs of mdx-dystrophic mice show more efficient nuclear uptake than AON alone and also lead to dystrophin expression in the mdx mice. In sum, these neutral, degradable carriers of AON show promise in vivo.

AB - Delivery of antisense oligonucleotides, AON, presents many of the same challenges as delivery of any nucleic acid: charge, stability, cell uptake, endolysosomal escape, and entry into the nucleus. Here we demonstrate efficient delivery of AON after loading into biodegradable polymer vesicles or 'polymersomes'. We focus on AON delivery to muscle cells in vitro and in vivo because of the emergence of AON in therapeutic strategies directed at muscular dystrophies. To first clarify uptake kinetics without the complications of typical multi-layered myotube cultures, we use micro-patterned C2C12 cells and show efficient uptake of AON-polymersomes. The biodegradable polymersomes break down and foster AON escape with the binding of fluorescent-AON into the nuclear bodies. Intramuscular injections of the polymersome-AON into the hind limbs of mdx-dystrophic mice show more efficient nuclear uptake than AON alone and also lead to dystrophin expression in the mdx mice. In sum, these neutral, degradable carriers of AON show promise in vivo.

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JO - Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference

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