Externally triggered smart drug delivery system encapsulating idarubicin shows superior kinetics and enhances tumoral drug uptake and response

Tao Lu*, Dieter Haemmerich, Hui Liu, Ann L.B. Seynhaeve, Gerard C. van Rhoon, Adriaan B. Houtsmuller, Timo L.M. ten Hagen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Scopus)
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Abstract

Rationale: Increasing the bioavailable drug level in a tumor is the key to enhance efficacy of chemotherapy. Thermosensitive smart drug delivery systems (SDDS) in combination with local hyperthermia facilitate high local drug levels, thus improving uptake in the tumor. However, inability to rapidly and efficiently absorb the locally released drug results in reduced efficacy, as well as undesired redistribution of the drug away from the tumor to the system. Methods: Based on this paradigm we propose a novel approach in which we replaced doxorubicin (DXR), one of the classic drugs for nanocarrier-based delivery, with idarubicin (IDA), a hydrophobic anthracycline used solely in the free form for treatment hematologic cancers. We established a series of in vitro and in vivo experiments to in depth study the kinetics of SDDS-based delivery, drug release, intratumor biodistribution and subsequent cell uptake. Results: We demonstrate that IDA is taken up over 10 times more rapidly by cancer cells than DXR in vitro. Similar trend is observed in in vivo online imaging and less drug redistribution is shown for IDA, together resulting in 4-times higher whole tumor drug uptake for IDA vs. DXR. Together his yielded an improved intratumoral drug distribution for IDA-SDDS, translating into superior tumor response compared to DXR-SDDS treatment at the same dose. Thus, IDA – a drug that is not used for treatment of solid cancers – shows superior therapeutic index and better outcome when administered in externally triggered SDDS. Conclusions: We show that a shift in selection of chemotherapeutics is urgently needed, away from the classic drugs towards selection based on properties of a chemotherapeutic in context of the nanoparticle and delivery mode, to maximize the therapeutic efficacy.

Original languageEnglish
Pages (from-to)5700-5712
Number of pages13
JournalTheranostics
Volume11
Issue number12
DOIs
Publication statusPublished - 2021

Bibliographical note

Funding Information:
We appreciate the funding support from Erasmus Medical Center. We thank colleagues of the Erasmus Medical Instrumentation Service for assistance with the development of the window model components. We also thank Dr. Gert-Jan Kremer for kindly offering the cell transfection agents.

Publisher Copyright:
© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

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