Theranostic Imaging May Vaccinate against the Therapeutic Benefit of Long Circulating PEGylated Liposomes and Change Cargo Pharmacokinetics

Betina Børresen, Jonas R. Henriksen, Gael Clergeaud, Jennifer S. Jørgensen, Fredrik Melander, Dennis R. Elema, Janos Szebeni, Svend Aage Engelholm, Annemarie T. Kristensen, Andreas Kjær, Thomas L. Andresen, Anders E. Hansen*

*Corresponding author for this work

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    The enhanced permeability and retention (EPR) effect increases tumor accumulation of liposomal chemotherapy and should, in theory, increase anticancer effects and lower toxicity. Unfortunately, liposomal chemotherapy has generally not met the expected potential, perhaps because the EPR effect is not ubiquitous. PET imaging using radiolabeled liposomes can identify cancers positive for the EPR effect. In the current study, we show in clinical canine cancer patients that repeated imaging with radiolabeled liposomes (64Cu-liposome) induces the accelerated blood clearance (ABC) phenomenon. This was observed even with very long intervals between PEGylated liposome injections, which contradict previous reporting in experimental animal models. The induction of ABC may be devastating for the theranostic use of liposomal imaging, as this could vaccinate patients against therapeutic efficacy. To investigate and solve this important problem, an additional study part was designed in which rats were subjected to repeated liposomal administrations, including stealth 64Cu-liposome PET imaging and Caelyx chemotherapy. Most importantly, it was found that, by increasing the lipid dose at the first injection or by supplying a small predose before the second 64Cu-liposome injection, ABC could be prevented. Importantly, signs of liposome tracer breakdown with subsequent renal excretion were observed. These findings highlight the importance of the ABC phenomenon for liposomal predictive imaging in a clinically relevant setting and show that carefully planned application is central to avoid potential detrimental effects on patient benefit.

    Original languageEnglish
    JournalACS Nano
    Volume12
    Issue number11
    Pages (from-to)11386-11398
    ISSN1936-0851
    DOIs
    Publication statusPublished - 2018

    Keywords

    • ABC-effect
    • Anti-PEG
    • EPR-effect
    • Liposome
    • Nanomedicine
    • Theranostic

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