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Enhancing Endosomal...
Enhancing Endosomal Escape for Intracellular Delivery of Macromolecular Biologic Therapeutics
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- Lönn, Peter (författare)
- Uppsala universitet,Molekylära verktyg,Science for Life Laboratory, SciLifeLab,Univ Calif San Diego, Dept Cellular & Mol Med, Sch Med, La Jolla, CA 92093 USA.
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- Kacsinta, Apollo D. (författare)
- Univ Calif San Diego, Dept Cellular & Mol Med, Sch Med, La Jolla, CA 92093 USA.
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- Cui, Xian-Shu (författare)
- Univ Calif San Diego, Dept Cellular & Mol Med, Sch Med, La Jolla, CA 92093 USA.
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- Hamil, Alexander S. (författare)
- Univ Calif San Diego, Dept Cellular & Mol Med, Sch Med, La Jolla, CA 92093 USA.
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- Kaulich, Manuel (författare)
- Univ Calif San Diego, Dept Cellular & Mol Med, Sch Med, La Jolla, CA 92093 USA.;Goethe Univ Frankfurt, Inst Biochem 2, Frankfurt, Germany.
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- Gogoi, Khirud (författare)
- Univ Calif San Diego, Dept Cellular & Mol Med, Sch Med, La Jolla, CA 92093 USA.;AM Chem, Oceanside, CA 92056 USA.
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- Dowdy, Steven F. (författare)
- Univ Calif San Diego, Dept Cellular & Mol Med, Sch Med, La Jolla, CA 92093 USA.
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(creator_code:org_t)
- 2016-09-08
- 2016
- Engelska.
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
- Relaterad länk:
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https://uu.diva-port... (primary) (Raw object)
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Bioactive macromolecular peptides and oligonucleotides have significant therapeutic potential. However, due to their size, they have no ability to enter the cytoplasm of cells. Peptide/Protein transduction domains (PTDs), also called cell-penetrating peptides (CPPs), can promote uptake of macromolecules via endocytosis. However, overcoming the rate-limiting step of endosomal escape into the cytoplasm remains a major challenge. Hydrophobic amino acid R groups are known to play a vital role in viral escape from endosomes. Here we utilize a real-time, quantitative live cell split-GFP fluorescence complementation phenotypic assay to systematically analyze and optimize a series of synthetic endosomal escape domains (EEDs). By conjugating EEDs to a TAT-PTD/CPP spilt-GFP peptide complementation assay, we were able to quantitatively measure endosomal escape into the cytoplasm of live cells via restoration of GFP fluorescence by intracellular molecular complementation. We found that EEDs containing two aromatic indole rings or one indole ring and two aromatic phenyl groups at a fixed distance of six polyethylene glycol (PEG) units from the TAT-PTD-cargo significantly enhanced cytoplasmic delivery in the absence of cytotoxicity. EEDs address the critical rate-limiting step of endosomal escape in delivery of macromolecular biologic peptide, protein and siRNA therapeutics into cells.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
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