Ionizable Drugs Enable Intracellular Delivery of Co-Formulated siRNA

Kai V Slaughter; Eric N Donders; Michael S Jones; Sami G Sabbah; Mitchell J Elliott; Brian K Shoichet; David W Cescon; Molly S Shoichet

doi:10.1002/adma.202403701

Ionizable Drugs Enable Intracellular Delivery of Co-Formulated siRNA

Adv Mater. 2024 Aug 15:e2403701. doi: 10.1002/adma.202403701. Online ahead of print.

Authors

Kai V Slaughter^{1

2}, Eric N Donders^{1

2

3}, Michael S Jones^{1

2}, Sami G Sabbah^{1

2}, Mitchell J Elliott⁴, Brian K Shoichet⁵, David W Cescon⁴, Molly S Shoichet^{1

2

3}

Affiliations

¹ Institute of Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON, M5S 3G9, Canada.
² Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON, M5S 3E1, Canada.
³ Department of Chemical Engineering & Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON, M5S 3E5, Canada.
⁴ Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON, M5G 2C1, Canada.
⁵ Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 Fourth Street, Mail Box 2550, San Francisco, CA, 94143, USA.

PMID: 39148215
DOI: 10.1002/adma.202403701

Abstract

Targeting complementary pathways in diseases such as cancer can be achieved with co-delivery of small interfering ribonucleic acid (siRNA) and small molecule drugs; however, current formulation strategies are typically limited to one, but not both. Here, ionizable small molecule drugs and siRNA are co-formulated in drug-rich nanoparticles. Ionizable analogs of the selective estrogen receptor degrader fulvestrant self-assemble into colloidal drug aggregates and cause endosomal disruption, allowing co-delivery of siRNA against a non-druggable target. siRNA is encapsulated in lipid-stabilized, drug-rich colloidal nanoparticles where the ionizable lipid used in conventional lipid nanoparticles is replaced with an ionizable fulvestrant analog. The selection of an appropriate phospholipid and formulation buffer enables endocytosis and potent reporter gene knockdown in cancer cells. Importantly, siRNA targeting cyclin E1 is effectively delivered to drug-resistant breast cancer cells, demonstrating the utility of this approach. This strategy opens the possibility of using ionizable drugs to co-deliver RNA and ultimately improve therapeutic outcomes.

Keywords: colloidal drug aggregates; fulvestrant; gene therapy; nanomedicine; nanoparticles.