Biotinylated Bilirubin Nanoparticles as a Tumor Microenvironment-Responsive Drug Delivery System for Targeted Cancer Therapy

Yonghyun Lee, Soyoung Lee, Sangyong Jon

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


The tumor microenvironment (TME) plays a crucial role in tumorigenesis and cancer cell metastasis. Accordingly, a drug-delivery system (DDS) that is capable of targeting tumor and releasing drugs in response to TME-associated stimuli should lead to potent antitumor efficacy. Here, a cancer targeting, reactive oxygen species (ROS)-responsive drug delivery vehicle as an example of a TME-targeting DDS is reported. Tumor targeting is achieved using biotin as a ligand for “biotin transporter”–overexpressing malignant tumors, and bilirubin-based nanoparticles (BRNPs) are used as a drug-delivery carrier that enables ROS-responsive drug release. Doxorubicin-loaded, biotinylated BRNPs (Dox@bt-BRNPs) with size of ≈100 nm are prepared by a one-step self-assembly process. Dox@bt-BRNPs exhibit accelerated Dox-release behavior in response to ROS and show specific binding as well as anticancer activity against biotin transporter–overexpressing HeLa cells in vitro. bt-BRNPs labeled with cypate, near-infrared dye, show much greater accumulation at tumor sites in HeLa tumor-bearing mice than BRNPs lacking the biotin ligand. Finally, intravenous injection of Dox@bt-BRNPs into HeLa tumor-bearing mice results in greater antitumor efficacy compared with free Dox, bt-BRNPs only, and Dox@BRNPs without causing any appreciable body weight loss. Collectively, these findings suggest that bt-BRNPs hold potential as a new TME-responsive DDS for effectively treating various tumors.

Original languageEnglish
Article number1800017
JournalAdvanced Science
Issue number6
StatePublished - Jun 2018

Bibliographical note

Funding Information:
This work was supported by the Global Research Laboratory (Grant No. NRF-2012K1A1A2045436) through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT (Information and Communication Technologies) and Future Planning.

Publisher Copyright:
© 2018 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim


  • bilirubin nanoparticles
  • biotin transporters
  • reactive oxygen species (ROS)
  • stimuli responsiveness
  • targeted cancer therapy
  • tumor microenvironments


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