Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 29, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2113180119
Keywords
NSCLC; KRAS; antisense oligonucleotide; molecular brush; gene regulation
Categories
Funding
- National Cancer Institute [R01CA251730]
- National Institute of General Medical Sciences [R01GM121612]
- NSF (DMR Grant) [2004947]
- Cancer Center Support from the National Cancer Institute [P30CA14051]
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The bottlebrush polyethylene glycol (PEG)-conjugated antisense oligonucleotides (ASOs) can effectively reduce KRAS and inhibit tumor growth, surpassing the performance of current ASO paradigms, and relaxing the requirement on ASO chemistry.
The mutant form of the guanosine triphosphatase (GTPase) KRAS is a key driver in human tumors but remains a challenging therapeutic target, making KRASMUT 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 associated with DNA-protein interactions and substantially enhance the pharmacological properties of the ASO, such as plasma pharmacokinetics and tumor uptake. Systemic delivery to mice bearing human non-small-cell lung carcinoma xenografts results in a significant reduction in both KRAS levels and tumor growth, and the antitumor performance well exceeds that of current popular ASO paradigms, such as chemically modified oligonucleotides and PEGylation using linear or slightly branched PEG. Importantly, these conjugates relax the requirement on the ASO chemistry, allowing unmodified, natural phosphodiester ASOs to achieve efficacy comparable to that of chemically modified ones. Both the bottlebrush polymer and its ASO conjugates appear to be safe and well tolerated in mice. Together, these data indicate that the molecular brush-ASO conjugate is a promising therapeutic platform for the treatment of KRAS-driven human cancers and warrant further preclinical and clinical development.
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