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Published, Version of Record (VoR)CC BY-NC V4.0, Open
Journal article
Development of Adamantane-Conjugated TLR7/8 Agonists for Supramolecular Delivery and Cancer Immunotherapy
Theranostics, v 9(26), pp 8426-8436
2019
PMID: 31879528
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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.
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.
The findings demonstrate the ability of strong nanoparticle-drug interactions to limit systemic toxicity of TLR agonists while simultaneously maintaining therapeutic efficacy.
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Details
- Title
- Development of Adamantane-Conjugated TLR7/8 Agonists for Supramolecular Delivery and Cancer Immunotherapy
- Creators
- Christopher B Rodell - Center for Systems BiologyMaaz S Ahmed - Center for Systems BiologyChristopher S Garris - Harvard UniversityMikael J Pittet - Center for Systems BiologyRalph Weissleder - Department of Systems Biology Harvard Medical School Boston MA 02115 USA
- Publication Details
- Theranostics, v 9(26), pp 8426-8436
- Grant note
- U01 CA206997 / NCI NIH HHS R33 CA202064 / NCI NIH HHS R01 CA204019 / NCI NIH HHS T32 CA079443 / NCI NIH HHS R01 CA206890 / NCI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:001008095500001
- Scopus ID
- 2-s2.0-85077293277
- Other Identifier
- 991019176798004721
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- Web of Science research areas
- Medicine, Research & Experimental