2. Academic Validation
  3. Synthetic Ionizable Colloidal Drug Aggregates Enable Endosomal Disruption

Synthetic Ionizable Colloidal Drug Aggregates Enable Endosomal Disruption

  • Adv Sci (Weinh). 2023 Mar 11;e2300311. doi: 10.1002/advs.202300311.
Eric N Donders 1 2 3,  Kai V Slaughter 2 3,  Christian Dank 4,  Ahil N Ganesh 1 2 3,  Brian K Shoichet 5,  Mark Lautens 4,  Molly S Shoichet 1 2 3
Affiliations

Affiliations

  • 1 Department of Chemical Engineering & Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON, M5S 3E5, Canada.
  • 2 Institute of Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON, M5S 3G9, Canada.
  • 3 Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON, M5S3E1, Canada.
  • 4 Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, M5S 3H6, Canada.
  • 5 Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 Fourth Street, Mail Box 2550, San Francisco, CA, 94143, USA.
PMID: 36905240 DOI: 10.1002/advs.202300311
Abstract

Colloidal drug aggregates enable the design of drug-rich nanoparticles; however, the efficacy of stabilized colloidal drug aggregates is limited by entrapment in the endo-lysosomal pathway. Although ionizable drugs are used to elicit lysosomal escape, this approach is hindered by toxicity associated with phospholipidosis. It is hypothesized that tuning the pKa of the drug would enable endosomal disruption while avoiding phospholipidosis and minimizing toxicity. To test this idea, 12 analogs of the nonionizable colloidal drug fulvestrant are synthesized with ionizable groups to enable pH-dependent endosomal disruption while maintaining bioactivity. Lipid-stabilized fulvestrant analog colloids are endocytosed by Cancer cells, and the pKa of these ionizable colloids influenced the mechanism of endosomal and lysosomal disruption. Four fulvestrant analogs-those with pKa values between 5.1 and 5.7-disrupted endo-lysosomes without measurable phospholipidosis. Thus, by manipulating the pKa of colloid-forming drugs, a tunable and generalizable strategy for endosomal disruption is established.

Keywords

colloidal drug aggregates; drug delivery; endosomal disruption; fulvestrant; nanoparticles.

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