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ACS Chem Biol. 2019 Apr 19;14(4):751-757. doi: 10.1021/acschembio.9b00032. Epub 2019 Mar 12.

Colloidal Drug Aggregate Stability in High Serum Conditions and Pharmacokinetic Consequence.

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Department of Chemical Engineering and Applied Chemistry , University of Toronto , 200 College Street , Toronto , Ontario M5S 3E5 , Canada.
Institute of Biomaterials and Biomedical Engineering, University of Toronto , 164 College Street , Toronto , Ontario M5S 3G9 , Canada.
Drug Discovery Program , Ontario Institute for Cancer Research , 661 University Avenue, Suite 510 , Toronto , Ontario M5G 0A3 , Canada.
Department of Chemistry and Biochemistry , University of Colorado , Boulder , Colorado 80309-0215 , United States.
School of Pharmacy , Regis University , 3333 Regis Boulevard , Denver , Colorado 80221-1099 , United States.
Department of Pharmaceutical Chemistry and Quantitative Biology Institute , University of California, San Francisco , 1700 Fourth Street, Mail Box 2550 , San Francisco , California 94143 , United States.
Department of Chemistry , University of Toronto , 80 St. George Street , Toronto , Ontario M5S 3H6 , Canada.


Colloidal drug aggregates have been a nuisance in drug screening, yet, because they inherently comprise drug-rich particles, they may be useful in vivo if issues of stability can be addressed. As the first step toward answering this question, we optimized colloidal drug aggregate formulations using a fluorescence-based assay to study fulvestrant colloidal formation and stability in high (90%) serum conditions in vitro. We show, for the first time, that the critical aggregation concentration of fulvestrant depends on media composition and increases with serum concentration. Excipients, such as polysorbate 80, stabilize fulvestrant colloids in 90% serum in vitro for over 48 h. Using fulvestrant and an investigational pro-drug, pentyloxycarbonyl-( p-aminobenzyl) doxazolidinylcarbamate (PPD), as proof-of-concept colloidal formulations, we demonstrate that the in vivo plasma half-life for stabilized colloids is greater than their respective monomeric forms. These studies demonstrate the potential of turning the nuisance of colloidal drug aggregation into an opportunity for drug-rich formulations.

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