Synthetic Ionizable Colloidal Drug Aggregates Enable Endosomal Disruption

Author:

Donders Eric N.123ORCID,Slaughter Kai V.23ORCID,Dank Christian4ORCID,Ganesh Ahil N.123,Shoichet Brian K.5ORCID,Lautens Mark4ORCID,Shoichet Molly S.123ORCID

Affiliation:

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

Abstract

AbstractColloidal 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.

Funder

Natural Sciences and Engineering Research Council of Canada

Austrian Science Fund

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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