Colloidal Drug Aggregate Stability in High Serum Conditions and Pharmacokinetic Consequence

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

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics*
  • Carbamates / blood
  • Carbamates / chemistry*
  • Carbamates / pharmacokinetics*
  • Colloids
  • Doxorubicin / analogs & derivatives*
  • Doxorubicin / blood
  • Doxorubicin / chemistry
  • Doxorubicin / pharmacokinetics
  • Drug Stability
  • Excipients
  • Female
  • Fulvestrant / chemistry
  • Humans
  • MCF-7 Cells
  • Mice
  • Neoplasm Transplantation
  • Oxazoles / blood
  • Oxazoles / chemistry*
  • Oxazoles / pharmacokinetics*
  • Polysorbates / chemistry
  • Prodrugs / chemistry*
  • Prodrugs / pharmacokinetics*
  • Proof of Concept Study
  • Serum

Substances

  • Antineoplastic Agents
  • Carbamates
  • Colloids
  • Excipients
  • Oxazoles
  • Polysorbates
  • Prodrugs
  • doxazolidine
  • Fulvestrant
  • Doxorubicin