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 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.

Gas flooding is a promising way to enhance oil recovery in unconventional oil reservoirs, but accurate identification of the distributions of movable and residual oil during gas flooding is difficult. In this study, the movable and residual oil distributions of tight conglomerate oil reservoirs during gas flooding are monitored with low-field nuclear magnetic resonance (NMR). The NMR T 2 spectra are converted into pore throat size distributions using a nonlinear conversion method in conjunction with high-pressure mercury intrusion, and then the lower limit of the pore throat size of movable oil under different pressure differences is determined. In addition, a mathematical model is proposed to predict the lower limit of the pore throat size of movable oil during gas flooding based on the capillary tube model and the fractal characteristics of pore structures in conglomerates. The research studies show that the model prediction results are very close to the results measured from experiments. The lower limit of the pore throat size of movable oil decreases with the increasing pressure difference of gas injection and decreasing core permeability. This study will be beneficial for characterizing residual oil distribution after gas flooding in unconventional oil reservoirs.

No abstract

Abstract