Utilizing in vitro drug release assays to predict in vivo drug retention in micelles

Aida Varela-Moreira, Heleen van Leur, Danielle Krijgsman, Veronika Ecker, Martina Braun, Maike Buchner, Marcel H.A.M. Fens*, Wim E. Hennink, Raymond M. Schiffelers

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


In the present work, we aim at developing an in vitro release assay to predict circulation times of hydrophobic drugs loaded into polymeric micelles (PM), upon intravenous (i.v.) administration. PM based on poly (ethylene glycol)-b-poly (N-2-benzoyloxypropyl methacrylamide) (mPEG-b-p(HPMA-Bz)) block copolymer were loaded with a panel of hydrophobic anti-cancer drugs and characterized for size, loading efficiency and release profile in different release media. Circulation times in mice of two selected drugs loaded in PM were evaluated and compared to the in vitro release profile. Release of drugs from PM was evaluated over 7 days in PBS containing Triton X-100 and in PBS containing albumin at physiological concentration (40 g/L). The results were utilized to identify crucial molecular features of the studied hydrophobic drugs leading to better micellar retention. For the best and the worst retained drugs in the in vitro assays (ABT-737 and BCI, respectively), the circulation of free and entrapped drugs into PM was examined after i.v. administration in mice. We found in vivo drug retention at 24 h post-injection similar to the retention found in the in vitro assays. This demonstrates that in vitro release assay in buffers supplemented with albumin, and to a lesser degree Triton X-100, can be employed to predict the in vivo circulation kinetics of drugs loaded in PM. Utilizing media containing acceptor molecules for hydrophobic compounds, provide a first screen to understand the stability of drug-loaded PM in the circulation and, therefore, can contribute to the reduction of animals used for circulation kinetics studies.

Original languageEnglish
Article number121638
Pages (from-to)1-10
JournalInternational Journal of Pharmaceutics
Publication statusPublished - 25 Apr 2022


  • 3R principle
  • Circulation kinetics
  • Drug delivery
  • Hydrophobic drugs
  • In vitro - in vivo correlation
  • Polymeric micelles


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