Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr-/- Mice

Mikyung Yu, Jaume Amengual, Arjun Menon, Nazila Kamaly, Felix Zhou, Xiaoding Xu, Phei Er Saw, Seung-Joo Lee, Kevin Si, Carleena Angelica Ortega, Won Il Choi, In-Hyun Lee, Yazan Bdour, Jinjun Shi, Morteza Mahmoudi, Sangyong Jon, Edward A. Fisher, Omid C. Farokhzad

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    Abstract

    The pharmacological manipulation of liver X receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. This study presents the development and efficacy of nanoparticles (NPs) incorporating the synthetic LXR agonist GW3965 (GW) in targeting atherosclerotic lesions. Collagen IV (Col IV) targeting ligands are employed to functionalize the NPs to improve targeting to the atherosclerotic plaque, and formulation parameters such as the length of the polyethylene glycol (PEG) coating molecules are systematically optimized. In vitro studies indicate that the GW-encapsulated NPs upregulate the LXR target genes and downregulate proinflammatory mediator in macrophages. The Col IV-targeted NPs encapsulating GW (Col IV-GW-NPs) successfully reaches atherosclerotic lesions when administered for 5 weeks to mice with preexisting lesions, substantially reducing macrophage content (≈30%) compared to the PBS group, which is with greater efficacy versus nontargeting NPs encapsulating GW (GW-NPs) (≈18%). In addition, mice administered the Col IV-GW-NPs do not demonstrate increased hepatic lipid biosynthesis or hyperlipidemia during the treatment period, unlike mice injected with the free GW. These findings suggest a new form of LXR-based therapeutics capable of enhanced delivery of the LXR agonist to atherosclerotic lesions without altering hepatic lipid metabolism.
    Original languageEnglish
    Article number1700313
    JournalAdvanced Healthcare Materials
    Volume6
    Issue number20
    Number of pages14
    ISSN2192-2640
    DOIs
    Publication statusPublished - 2017

    Cite this

    Yu, Mikyung ; Amengual, Jaume ; Menon, Arjun ; Kamaly, Nazila ; Zhou, Felix ; Xu, Xiaoding ; Saw, Phei Er ; Lee, Seung-Joo ; Si, Kevin ; Ortega, Carleena Angelica ; Choi, Won Il ; Lee, In-Hyun ; Bdour, Yazan ; Shi, Jinjun ; Mahmoudi, Morteza ; Jon, Sangyong ; Fisher, Edward A. ; Farokhzad, Omid C. / Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr-/- Mice. In: Advanced Healthcare Materials. 2017 ; Vol. 6, No. 20.
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    title = "Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr-/- Mice",
    abstract = "The pharmacological manipulation of liver X receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. This study presents the development and efficacy of nanoparticles (NPs) incorporating the synthetic LXR agonist GW3965 (GW) in targeting atherosclerotic lesions. Collagen IV (Col IV) targeting ligands are employed to functionalize the NPs to improve targeting to the atherosclerotic plaque, and formulation parameters such as the length of the polyethylene glycol (PEG) coating molecules are systematically optimized. In vitro studies indicate that the GW-encapsulated NPs upregulate the LXR target genes and downregulate proinflammatory mediator in macrophages. The Col IV-targeted NPs encapsulating GW (Col IV-GW-NPs) successfully reaches atherosclerotic lesions when administered for 5 weeks to mice with preexisting lesions, substantially reducing macrophage content (≈30{\%}) compared to the PBS group, which is with greater efficacy versus nontargeting NPs encapsulating GW (GW-NPs) (≈18{\%}). In addition, mice administered the Col IV-GW-NPs do not demonstrate increased hepatic lipid biosynthesis or hyperlipidemia during the treatment period, unlike mice injected with the free GW. These findings suggest a new form of LXR-based therapeutics capable of enhanced delivery of the LXR agonist to atherosclerotic lesions without altering hepatic lipid metabolism.",
    author = "Mikyung Yu and Jaume Amengual and Arjun Menon and Nazila Kamaly and Felix Zhou and Xiaoding Xu and Saw, {Phei Er} and Seung-Joo Lee and Kevin Si and Ortega, {Carleena Angelica} and Choi, {Won Il} and In-Hyun Lee and Yazan Bdour and Jinjun Shi and Morteza Mahmoudi and Sangyong Jon and Fisher, {Edward A.} and Farokhzad, {Omid C.}",
    year = "2017",
    doi = "10.1002/adhm.201700313",
    language = "English",
    volume = "6",
    journal = "Advanced Healthcare Materials",
    issn = "2192-2640",
    publisher = "Wiley-VCH",
    number = "20",

    }

    Yu, M, Amengual, J, Menon, A, Kamaly, N, Zhou, F, Xu, X, Saw, PE, Lee, S-J, Si, K, Ortega, CA, Choi, WI, Lee, I-H, Bdour, Y, Shi, J, Mahmoudi, M, Jon, S, Fisher, EA & Farokhzad, OC 2017, 'Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr-/- Mice', Advanced Healthcare Materials, vol. 6, no. 20, 1700313. https://doi.org/10.1002/adhm.201700313

    Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr-/- Mice. / Yu, Mikyung; Amengual, Jaume; Menon, Arjun; Kamaly, Nazila; Zhou, Felix; Xu, Xiaoding; Saw, Phei Er; Lee, Seung-Joo; Si, Kevin; Ortega, Carleena Angelica; Choi, Won Il; Lee, In-Hyun; Bdour, Yazan; Shi, Jinjun; Mahmoudi, Morteza; Jon, Sangyong; Fisher, Edward A.; Farokhzad, Omid C.

    In: Advanced Healthcare Materials, Vol. 6, No. 20, 1700313, 2017.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr-/- Mice

    AU - Yu, Mikyung

    AU - Amengual, Jaume

    AU - Menon, Arjun

    AU - Kamaly, Nazila

    AU - Zhou, Felix

    AU - Xu, Xiaoding

    AU - Saw, Phei Er

    AU - Lee, Seung-Joo

    AU - Si, Kevin

    AU - Ortega, Carleena Angelica

    AU - Choi, Won Il

    AU - Lee, In-Hyun

    AU - Bdour, Yazan

    AU - Shi, Jinjun

    AU - Mahmoudi, Morteza

    AU - Jon, Sangyong

    AU - Fisher, Edward A.

    AU - Farokhzad, Omid C.

    PY - 2017

    Y1 - 2017

    N2 - The pharmacological manipulation of liver X receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. This study presents the development and efficacy of nanoparticles (NPs) incorporating the synthetic LXR agonist GW3965 (GW) in targeting atherosclerotic lesions. Collagen IV (Col IV) targeting ligands are employed to functionalize the NPs to improve targeting to the atherosclerotic plaque, and formulation parameters such as the length of the polyethylene glycol (PEG) coating molecules are systematically optimized. In vitro studies indicate that the GW-encapsulated NPs upregulate the LXR target genes and downregulate proinflammatory mediator in macrophages. The Col IV-targeted NPs encapsulating GW (Col IV-GW-NPs) successfully reaches atherosclerotic lesions when administered for 5 weeks to mice with preexisting lesions, substantially reducing macrophage content (≈30%) compared to the PBS group, which is with greater efficacy versus nontargeting NPs encapsulating GW (GW-NPs) (≈18%). In addition, mice administered the Col IV-GW-NPs do not demonstrate increased hepatic lipid biosynthesis or hyperlipidemia during the treatment period, unlike mice injected with the free GW. These findings suggest a new form of LXR-based therapeutics capable of enhanced delivery of the LXR agonist to atherosclerotic lesions without altering hepatic lipid metabolism.

    AB - The pharmacological manipulation of liver X receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. This study presents the development and efficacy of nanoparticles (NPs) incorporating the synthetic LXR agonist GW3965 (GW) in targeting atherosclerotic lesions. Collagen IV (Col IV) targeting ligands are employed to functionalize the NPs to improve targeting to the atherosclerotic plaque, and formulation parameters such as the length of the polyethylene glycol (PEG) coating molecules are systematically optimized. In vitro studies indicate that the GW-encapsulated NPs upregulate the LXR target genes and downregulate proinflammatory mediator in macrophages. The Col IV-targeted NPs encapsulating GW (Col IV-GW-NPs) successfully reaches atherosclerotic lesions when administered for 5 weeks to mice with preexisting lesions, substantially reducing macrophage content (≈30%) compared to the PBS group, which is with greater efficacy versus nontargeting NPs encapsulating GW (GW-NPs) (≈18%). In addition, mice administered the Col IV-GW-NPs do not demonstrate increased hepatic lipid biosynthesis or hyperlipidemia during the treatment period, unlike mice injected with the free GW. These findings suggest a new form of LXR-based therapeutics capable of enhanced delivery of the LXR agonist to atherosclerotic lesions without altering hepatic lipid metabolism.

    U2 - 10.1002/adhm.201700313

    DO - 10.1002/adhm.201700313

    M3 - Journal article

    C2 - 28730752

    VL - 6

    JO - Advanced Healthcare Materials

    JF - Advanced Healthcare Materials

    SN - 2192-2640

    IS - 20

    M1 - 1700313

    ER -