Liposomal doxorubicin extravasation controlled by phenotype-specific transport properties of tumor microenvironment and vascular barrier

Kenji Yokoi, Diana Chan, Milos Kojic, Miljan Milosevic, David Engler, Rise Matsunami, Tomonori Tanei, Yuki Saito, Mauro Ferrari, Arturas Ziemys

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Although nanotherapeutics can be advantageous over free chemotherapy, the benefits of drug vectors can vary from patient to patient based on differences in tumor microenvironments. Although systemic pharmacokinetics (PK) of drugs is considered as the major determinant of its efficacy in clinics, recent clinical and basic research indicates that tumor-based PK can provide better representation of therapeutic efficacy. Here, we have studied the role of the tumor extravascular tissue in the extravasation kinetics of doxorubicin (DOX), delivered by pegylated liposomes (PLD), to murine lung (3LL) and breast (4T1) tumors. We found that phenotypically different 3LL and 4T1 tumors shared the similar systemic PK, but DOX extravasation in the tumor extravascular tissue was substantially different. Liquid chromatography-mass spectrometry (LC-MS) measurements showed that DOX fluorescence imaged by fluorescence microscopy could be used as a marker to study tumor microenvironment PK, providing an excellent match to DOX kinetics in tumor tissues. Our results also suggest that therapeutic responses can be closely related to the interplay of concentration levels and exposure times in extravascular tissue of tumors. Finally, the computational model of capillary drug transport showed that internalization of drug vectors was critical and could lead to 2-3 orders of magnitude more efficient drug delivery into the extravascular tissue, compared to non-internalized localization of drug vectors, and explaining the differences in therapeutic efficacy between the 3LL and 4T1 tumors. These results show that drug transport and partitioning characteristics can be phenotype- and microenvironment-dependent and are highly important in drug delivery and therapeutic efficacy.

Original languageEnglish (US)
Pages (from-to)293-299
Number of pages7
JournalJournal of Controlled Release
Volume217
DOIs
StatePublished - Nov 10 2015

Keywords

  • Computational diffusion model
  • Doxorubicin
  • Drug vector
  • Kinetics
  • Liposome
  • Nanotherapeutics

ASJC Scopus subject areas

  • Pharmaceutical Science

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