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• W2993156910 abstract "Tumor-associated macrophages (TAMs) are often abundant in solid cancers, assuming an immunosuppressive (M2-like) phenotype which supports tumor growth and immune escape. Recent methods have focused on identification of means (e.g., drugs, nanomaterials) that polarize TAMs to a tumor suppressive (M1-like) phenotype; however, reducing the systemic side effects of these therapies and enabling their delivery to TAMs has remained a challenge. Methods: Here, we develop R848-Ad, an adamantane-modified derivative of the toll-like receptor (TLR) 7/8 agonist resiquimod (R848) through iterative drug screening against reporter cell lines. The adamantane undergoes guest-host interaction with cyclodextrin nanoparticles (CDNPs), enabling drug loading under aqueous conditions and TAM-targeted drug delivery. Therapeutic efficacy and systemic side effects were examined in a murine MC38 cancer model. Results: R848-Ad retained macrophage polarizing activity through agonization of TLR7/8, and the adamantane moiety improved drug affinity for the CDNP. In preclinical studies, nanoformulated R848-Ad resulted in a drastic reduction in measurable systemic effects (loss of body weight) relative to similarly formulated R848 alone while arresting tumor growth. Conclusions: The findings demonstrate the ability of strong nanoparticle-drug interactions to limit systemic toxicity of TLR agonists while simultaneously maintaining therapeutic efficacy." @default.
• W2993156910 created "2019-12-13" @default.
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• W2993156910 date "2019-01-01" @default.
• W2993156910 modified "2023-10-17" @default.
• W2993156910 title "Development of Adamantane-Conjugated TLR7/8 Agonists for Supramolecular Delivery and Cancer Immunotherapy" @default.
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• W2993156910 doi "https://doi.org/10.7150/thno.35434" @default.
• W2993156910 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6924259" @default.
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• W2993156910 hasPublicationYear "2019" @default.
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