Secretory phospholipase A2 responsive liposomes exhibit a potent anti-neoplastic effect in vitro, but induce unforeseen severe toxicity in vivo

Ragnhild Garborg Østrem, Ladan Parhamifar, Houman Pourhassan, Gael Clergeaud Veiga, Ole L. Nielsen, Andreas Kjær, Anders Elias Hansen, Thomas Lars Andresen

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    Abstract

    The clinical use of liposomal drug delivery vehicles is often hindered by insufficient drug release. Here we present the rational design of liposomes optimized for secretory phospholipase A2 (sPLA2) triggered drug release, and test their utility in vitro and in vivo. We hypothesized that by adjusting the level of cholesterol in anionic, unsaturated liposomes we could tune the enzyme specificity based on membrane fluidity, thus obtaining liposomes with an improved therapeutic outcome and reduced side effects. Cholesterol is generally important as a component in the membranes of liposome drug delivery systems due to its stabilizing effects in vivo. The incorporation of cholesterol in sPLA2 sensitive liposomes has not previously been possible due to reduced sPLA2 activity. However, in the present work we solved this challenge by optimizing membrane fluidity. In vitro release studies revealed enzyme specific drug release. Treatment of two different cancer cell lines with liposomal oxaliplatin revealed efficient growth inhibition compared to that of clinically used stealth liposomes. The in vivo therapeutic effect was evaluated in nude NMRI mice using the sPLA2 secreting mammary carcinoma cell line MT-3. Three days after first treatment all mice having received the novel sPLA2 sensitive liposome formulation were euthanized due to severe systemic toxicity. Thus the present study demonstrates that great caution should be implemented when utilizing sPLA2 sensitive liposomes and that the real utility can only be disclosed in vivo. The present studies have clinical implications, as sPLA2 sensitive formulations are currently undergoing clinical trials (LiPlaCis®).
    Original languageEnglish
    JournalJournal of Controlled Release
    Volume262
    Pages (from-to)212-221
    Number of pages10
    ISSN0168-3659
    DOIs
    Publication statusPublished - 2017

    Keywords

    • Cancer therapy
    • Drug delivery
    • Liposome
    • Oxaliplatin
    • Secretory phospholipase A(2)
    • Triggered release

    Cite this

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    title = "Secretory phospholipase A2 responsive liposomes exhibit a potent anti-neoplastic effect in vitro, but induce unforeseen severe toxicity in vivo",
    abstract = "The clinical use of liposomal drug delivery vehicles is often hindered by insufficient drug release. Here we present the rational design of liposomes optimized for secretory phospholipase A2 (sPLA2) triggered drug release, and test their utility in vitro and in vivo. We hypothesized that by adjusting the level of cholesterol in anionic, unsaturated liposomes we could tune the enzyme specificity based on membrane fluidity, thus obtaining liposomes with an improved therapeutic outcome and reduced side effects. Cholesterol is generally important as a component in the membranes of liposome drug delivery systems due to its stabilizing effects in vivo. The incorporation of cholesterol in sPLA2 sensitive liposomes has not previously been possible due to reduced sPLA2 activity. However, in the present work we solved this challenge by optimizing membrane fluidity. In vitro release studies revealed enzyme specific drug release. Treatment of two different cancer cell lines with liposomal oxaliplatin revealed efficient growth inhibition compared to that of clinically used stealth liposomes. The in vivo therapeutic effect was evaluated in nude NMRI mice using the sPLA2 secreting mammary carcinoma cell line MT-3. Three days after first treatment all mice having received the novel sPLA2 sensitive liposome formulation were euthanized due to severe systemic toxicity. Thus the present study demonstrates that great caution should be implemented when utilizing sPLA2 sensitive liposomes and that the real utility can only be disclosed in vivo. The present studies have clinical implications, as sPLA2 sensitive formulations are currently undergoing clinical trials (LiPlaCis{\circledR}).",
    keywords = "Cancer therapy, Drug delivery, Liposome, Oxaliplatin, Secretory phospholipase A(2), Triggered release",
    author = "{\O}strem, {Ragnhild Garborg} and Ladan Parhamifar and Houman Pourhassan and {Clergeaud Veiga}, Gael and Nielsen, {Ole L.} and Andreas Kj{\ae}r and Hansen, {Anders Elias} and Andresen, {Thomas Lars}",
    year = "2017",
    doi = "10.1016/j.jconrel.2017.07.031",
    language = "English",
    volume = "262",
    pages = "212--221",
    journal = "Journal of Controlled Release",
    issn = "0168-3659",
    publisher = "Elsevier",

    }

    Secretory phospholipase A2 responsive liposomes exhibit a potent anti-neoplastic effect in vitro, but induce unforeseen severe toxicity in vivo. / Østrem, Ragnhild Garborg; Parhamifar, Ladan; Pourhassan, Houman; Clergeaud Veiga, Gael; Nielsen, Ole L.; Kjær, Andreas ; Hansen, Anders Elias; Andresen, Thomas Lars.

    In: Journal of Controlled Release, Vol. 262, 2017, p. 212-221.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Secretory phospholipase A2 responsive liposomes exhibit a potent anti-neoplastic effect in vitro, but induce unforeseen severe toxicity in vivo

    AU - Østrem, Ragnhild Garborg

    AU - Parhamifar, Ladan

    AU - Pourhassan, Houman

    AU - Clergeaud Veiga, Gael

    AU - Nielsen, Ole L.

    AU - Kjær, Andreas

    AU - Hansen, Anders Elias

    AU - Andresen, Thomas Lars

    PY - 2017

    Y1 - 2017

    N2 - The clinical use of liposomal drug delivery vehicles is often hindered by insufficient drug release. Here we present the rational design of liposomes optimized for secretory phospholipase A2 (sPLA2) triggered drug release, and test their utility in vitro and in vivo. We hypothesized that by adjusting the level of cholesterol in anionic, unsaturated liposomes we could tune the enzyme specificity based on membrane fluidity, thus obtaining liposomes with an improved therapeutic outcome and reduced side effects. Cholesterol is generally important as a component in the membranes of liposome drug delivery systems due to its stabilizing effects in vivo. The incorporation of cholesterol in sPLA2 sensitive liposomes has not previously been possible due to reduced sPLA2 activity. However, in the present work we solved this challenge by optimizing membrane fluidity. In vitro release studies revealed enzyme specific drug release. Treatment of two different cancer cell lines with liposomal oxaliplatin revealed efficient growth inhibition compared to that of clinically used stealth liposomes. The in vivo therapeutic effect was evaluated in nude NMRI mice using the sPLA2 secreting mammary carcinoma cell line MT-3. Three days after first treatment all mice having received the novel sPLA2 sensitive liposome formulation were euthanized due to severe systemic toxicity. Thus the present study demonstrates that great caution should be implemented when utilizing sPLA2 sensitive liposomes and that the real utility can only be disclosed in vivo. The present studies have clinical implications, as sPLA2 sensitive formulations are currently undergoing clinical trials (LiPlaCis®).

    AB - The clinical use of liposomal drug delivery vehicles is often hindered by insufficient drug release. Here we present the rational design of liposomes optimized for secretory phospholipase A2 (sPLA2) triggered drug release, and test their utility in vitro and in vivo. We hypothesized that by adjusting the level of cholesterol in anionic, unsaturated liposomes we could tune the enzyme specificity based on membrane fluidity, thus obtaining liposomes with an improved therapeutic outcome and reduced side effects. Cholesterol is generally important as a component in the membranes of liposome drug delivery systems due to its stabilizing effects in vivo. The incorporation of cholesterol in sPLA2 sensitive liposomes has not previously been possible due to reduced sPLA2 activity. However, in the present work we solved this challenge by optimizing membrane fluidity. In vitro release studies revealed enzyme specific drug release. Treatment of two different cancer cell lines with liposomal oxaliplatin revealed efficient growth inhibition compared to that of clinically used stealth liposomes. The in vivo therapeutic effect was evaluated in nude NMRI mice using the sPLA2 secreting mammary carcinoma cell line MT-3. Three days after first treatment all mice having received the novel sPLA2 sensitive liposome formulation were euthanized due to severe systemic toxicity. Thus the present study demonstrates that great caution should be implemented when utilizing sPLA2 sensitive liposomes and that the real utility can only be disclosed in vivo. The present studies have clinical implications, as sPLA2 sensitive formulations are currently undergoing clinical trials (LiPlaCis®).

    KW - Cancer therapy

    KW - Drug delivery

    KW - Liposome

    KW - Oxaliplatin

    KW - Secretory phospholipase A(2)

    KW - Triggered release

    U2 - 10.1016/j.jconrel.2017.07.031

    DO - 10.1016/j.jconrel.2017.07.031

    M3 - Journal article

    VL - 262

    SP - 212

    EP - 221

    JO - Journal of Controlled Release

    JF - Journal of Controlled Release

    SN - 0168-3659

    ER -