2022
DOI: 10.1073/pnas.2113180119
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Targeting oncogenic KRAS with molecular brush-conjugated antisense oligonucleotides

Abstract: The mutant form of the guanosine triphosphatase (GTPase) KRAS is a key driver in human tumors but remains a challenging therapeutic target, making KRAS MUT cancers a highly unmet clinical need. Here, we report a class of bottlebrush polyethylene glycol (PEG)–conjugated antisense oligonucleotides (ASOs) for potent in vivo KRAS depletion. Owing to their highly branched architecture, these molecular nanoconstructs suppress nearly all side effects a… Show more

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Cited by 20 publications
(25 citation statements)
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“…Termed pacDNA (polymer‐assisted compaction of DNA), these nanoscopic bioconjugates produce a novel biodistribution profile, elevate blood circulation times, and augment tissue retention (up to 15 weeks post intravenous injection). These improvements result in massively boosted antisense activities in vivo, with 1–2 orders of magnitude reduction in dosage requirement in certain cancer xenograft models [11] . However, our initial pacDNA system may not be ideal for aptamers due to their tendency to undergo endocytosis, which we speculate stems from the hydrophobic polynorbornene (PN) backbone of the bottlebrush polymer [12] .…”
Section: Introductionmentioning
confidence: 99%
“…Termed pacDNA (polymer‐assisted compaction of DNA), these nanoscopic bioconjugates produce a novel biodistribution profile, elevate blood circulation times, and augment tissue retention (up to 15 weeks post intravenous injection). These improvements result in massively boosted antisense activities in vivo, with 1–2 orders of magnitude reduction in dosage requirement in certain cancer xenograft models [11] . However, our initial pacDNA system may not be ideal for aptamers due to their tendency to undergo endocytosis, which we speculate stems from the hydrophobic polynorbornene (PN) backbone of the bottlebrush polymer [12] .…”
Section: Introductionmentioning
confidence: 99%
“…27 In addition, the treatment was free of common deleterious effects such as acute toxicity, inflammation, coagulopathy, and anti-PEG immunity. 27 When tested in vitro, the pacDNA exhibits moderate cellular uptake and can regulate mRNA expression with reasonable efficiency if equipped with an appropriate ASO or siRNA. However, to date, the mechanism for the cellular uptake of the pacDNA and how it regulates protein expression at the molecular level is not well understood.…”
mentioning
confidence: 99%
“…13 In addition, the treatment was free of common deleterious effects such as acute toxicity, inflammation, coagulopathy, and anti-PEG immunity. 13…”
mentioning
confidence: 99%
“…12 In one example where we compared pacDNA with AZD4785, a clinical ASO targeting wild-type KRAS mRNA, pacDNA achieved more pronounced tumor suppression levels than AZD4785 at a fraction (2.5%) of the dosage and with greatly reduced dosing frequency in non-small cell lung carcinoma (NSCLC) mouse models. 13 In addition, the treatment was free of common deleterious effects such as acute toxicity, inflammation, coagulopathy, and anti-PEG immunity. 13 When tested in vitro, the pacDNA exhibits moderate cellular uptake and can regulate mRNA expression with reasonable efficiency if equipped with an appropriate ASO or siRNA.…”
mentioning
confidence: 99%
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