In addition, antibodies directed against immune checkpoints expressed by myeloid cells (e.g., TIM-3) or self-recognition pathways (e.g., CD47/SIRPɑ axis) have been used to perpetuate anti-tumor TAM activity. These drugs include small molecule inhibitors of tyrosine kinases, histone deacetylases (HDACs), indoleamine 2,3-dioxygenase (IDO), and colony stimulating factor 1 receptor (CSF1R), amongst others.
A number of pharmacological activators of TAM activity are under active investigation. However, macrophage phenotypes are plastic, motivating the development of means to polarize these cells to an anti-tumorigenic and immunosupportive (“M1-like”) phenotype, bolstering their tumoricidal capacity. TAMs thereby contribute to a tumor immune microenvironment (TIME) that supports accelerated tumor growth and resistance to therapy. TAMs can also negatively impact the efficacy of anticancer drugs, including checkpoint blockade immunotherapies their abundance in tumors is therefore associated with altered patient survival. These cells commonly assume a pro-angiogenic and immunosuppressive (“M2-like”) phenotype in vivo, supporting continued tumor growth. These cells include tumor-associated macrophages (TAMs), which accumulate at high density in a broad range of tumors. Myeloid cells have attracted attention as therapeutic targets in cancer. Keywords: nanoparticle, cyclodextrin, drug screening, drug delivery, immunotherapy, macrophage Introduction 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.Ĭonclusions: The findings demonstrate the ability of strong nanoparticle-drug interactions to limit systemic toxicity of TLR agonists while simultaneously maintaining therapeutic efficacy. Results: R848-Ad retained macrophage polarizing activity through agonization of TLR7/8, and the adamantane moiety improved drug affinity for the CDNP. Therapeutic efficacy and systemic side effects were examined in a murine MC38 cancer model. The adamantane undergoes guest-host interaction with cyclodextrin nanoparticles (CDNPs), enabling drug loading under aqueous conditions and TAM-targeted drug delivery. 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. 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. Tumor-associated macrophages (TAMs) are often abundant in solid cancers, assuming an immunosuppressive (M2-like) phenotype which supports tumor growth and immune escape. Select the file that you have just downloaded and select import option Reference Manager (RIS).
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Development of Adamantane-Conjugated TLR7/8 Agonists for Supramolecular Delivery and Cancer Immunotherapy. Rodell CB, Ahmed MS, Garris CS, Pittet MJ, Weissleder R.
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