Folate decorated polymeric micelles for targeted delivery of the kinase inhibitor dactolisib to cancer cells

Haili Shi, Mies J. van Steenbergen, Bo Lou, Yanna Liu, Wim E. Hennink, Robbert J. Kok*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


One of the main challenges in clinical translation of polymeric micelles is retention of the drug in the nanocarrier system upon its systemic administration. Core crosslinking and coupling of the drug to the micellar backbone are common strategies to overcome these issues. In the present study, polymeric micelles were prepared for tumor cell targeting of the kinase inhibitor dactolisib which inhibits both the mammalian Target of Rapamycin (mTOR) kinase and phosphatidylinositol-3-kinase (PI3K). We employed platinum(II)-based linker chemistry to couple dactolisib to the core of poly(ethylene glycol)-b-poly(acrylic acid) (PEG-b-PAA) polymeric micelles. The formed dactolisib-PEG-PAA unimers are amphiphilic and self-assemble in an aqueous milieu into core–shell polymeric micelles. Folate was conjugated onto the surface of the micelles to yield folate-decorated polymeric micelles which can target folate receptor over-expressing tumor cells. Fluorescently labeled polymeric micelles were prepared using a lissamine-platinum complex linked in a similar manner as dactolisib. Dactolisib polymeric micelles showed good colloidal stability in water and released the coupled drug in buffers containing chloride or glutathione. Folate decorated micelles were avidly internalized by folate-receptor-positive KB cells and displayed targeted cellular cytotoxicity at 50–75 nM IC50. In conclusion, we have prepared a novel type of folate-receptor targeted polymeric micelles in which platinum(II) linker chemistry modulates drug retention and sustained release of the coupled inhibitor dactolisib.

Original languageEnglish
Article number119305
Number of pages16
JournalInternational Journal of Pharmaceutics
Publication statusPublished - 30 May 2020


  • Cancer
  • Coordination chemistry
  • Dactolisib
  • Folate
  • Polymeric micelles
  • Signal transduction inhibitor
  • Targeted drug delivery


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