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Synthetic small interfering RNAs conjugated to trivalent N -acetylgalactosamine (GalNAc) are clinically validated drugs for treatment of liver diseases. Incorporation of phosphorothioate linkages and ribose modifications are necessary for stability, potency, and duration of pharmacology. Although multiple alternative siRNA designs such as Dicer-substrate RNA, shRNA, and circular RNA have been evaluated in vitro and in preclinical studies with some success, clinical applications of these designs are limited as it is difficult to incorporate chemical modifications in these designs. An alternative siRNA design that can incorporate chemical modifications through straightforward synthesis without compromising potency will significantly advance the field. Here, we report a facile synthesis of GalNAc ligand-containing single-stranded loop hairpin RNAs (loopmeRNAs) with clinically relevant chemical modifications. We evaluated the efficiency of novel loopmeRNA designs in vivo and correlated their structure-activity relationship with the support of in vitro metabolism data. Sequences and chemical modifications in the loop region of the loopmeRNA design were optimized for maximal potency. Our studies demonstrate that loopmeRNAs can efficiently silence expression of target genes with comparable efficacy to conventional double-stranded siRNAs but reduced environmental and regulatory burdens.

Objectives: The aim of this study was to investigate the pharmacokinetics (PK) of poorly soluble compounds when administered intramuscularly (i.m.) as crystalline particles of different sizes., Methods: Three uncharged compounds (griseofulvin, AZ'72, and AZ'07) with varying aqueous solubility were dosed to mice at 10 and 50 mg/kg as nano- and microparticle formulations. The PK of the compounds was evaluated., Key Findings: The smaller particles of the drugs resulted in higher maximum plasma concentration (Cmax) and area under the plasma concentration-time profile (AUC) at 50 mg/kg. There was a dose-proportional increase in AUC but less than dose dose-proportional increase in Cmax. The evaluation at 10 mg/kg was more complex as increased exposure for nanoparticles was only observed for griseofulvin which has the highest solubility. In addition, there was an increase in half-life with an increase in dose., Conclusions: This study highlights that general expectations based on in vitro dissolution (i.e. that smaller particles dissolve faster than larger particles when surrounded by liquid) do not always translate to in vivo and demonstrates the importance of understanding the physicochemical properties of the drug, the characteristics of the formulations and the microphysiology at the delivery site., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)