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

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

doi:10.1109/IEMBS.2006.259861

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

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

Research output: Chapter in Book/Report/Conference proceeding › Conference contribution

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.

Original language	English (US)
Title of host publication	28th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS'06
Pages	4350-4353
Number of pages	4
DOIs	https://doi.org/10.1109/IEMBS.2006.259861
State	Published - Dec 1 2006
Event	28th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS'06 - New York, NY, United States Duration: Aug 30 2006 → Sep 3 2006

Other

Other	28th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS'06
Country/Territory	United States
City	New York, NY
Period	8/30/06 → 9/3/06

ASJC Scopus subject areas

Signal Processing
Biomedical Engineering
Computer Vision and Pattern Recognition
Health Informatics

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10.1109/IEMBS.2006.259861

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Younghoon, K., Tewari, M., Pajeroski, D. J., Sen, S., Jason, W., Sirsi, S., Lutz, G., & Discher, D. E. (2006). Efficient nuclear delivery and nuclear body localization of antisense oligo-nucleotides using degradable polymersomes. In 28th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS'06 (pp. 4350-4353). Article 4030280 https://doi.org/10.1109/IEMBS.2006.259861

Efficient nuclear delivery and nuclear body localization of antisense oligo-nucleotides using degradable polymersomes. / Younghoon, Kim; Tewari, Manu; Pajeroski, David J. et al.
28th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS'06. 2006. p. 4350-4353 4030280.

Research output: Chapter in Book/Report/Conference proceeding › Conference contribution

Younghoon, K, Tewari, M, Pajeroski, DJ, Sen, S, Jason, W, Sirsi, S, Lutz, G & Discher, DE 2006, Efficient nuclear delivery and nuclear body localization of antisense oligo-nucleotides using degradable polymersomes. in 28th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS'06., 4030280, pp. 4350-4353, 28th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS'06, New York, NY, United States, 8/30/06. https://doi.org/10.1109/IEMBS.2006.259861

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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.",

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AU - Sirsi, Shashank

AU - Lutz, Gordon

AU - Discher, Dennis E.

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

Abstract

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