INTRODUCTION Panobinostat is a histone deacetylase inhibitor (HDACi) that is a clinical candidate for treatment of pediatric medulloblastoma and diffuse intrinsic pontine glioma. Panobinostat is poorly water-soluble and experiences a number of barriers to effective delivery. Here, we developed a novel drug delivery system consisting of β-cyclodextrin-poly(β-amino ester). These cyclodextrin-networks (CDNs) self-assemble into nanoparticles encapsulating a high quantity of HDACi for slow release. We sought to test the hypothesis that panobinostat-loaded CDNs would demonstrate a differentiated pharmacokinetic profile compared to free panobinostat in mice after direct administration to cerebrospinal fluid. METHODS CDNs were synthesized via Michael addition and engineered to encapsulate a library of HDACi drugs. Nanoparticles were characterized for size, surface charge, loading, controlled release, and stability. CDNs or fluorescent surrogate nanoparticles were administered to the cisterna magna of mice. Tissues were collected for LC-MS/MS (pharmacokinetics [PK]: 1, 4, 8, 24, and 48 hrs) or microscopy (localization: 2, 6, 24, and 48 hrs, 1 and 3 wks). RESULTS Intravital and confocal microscopy demonstrate that nanoparticles distribute rapidly in subarachnoid space and can localize with metastases, persisting for > 3 weeks. Nanoparticle panobinostat is released over weeks and is better tolerated than free drug. CDN-panobinostat delivery tended to be higher in the cerebellum and lower in the spinal cord at both early and late time points compared to freely administered drug. CONCLUSIONS We present a nanoparticle platform for HDACi delivery with a differentiated PK profile in the CSF compared to free drug. Additional PK and therapeutic studies are ongoing.
Antibody-dependent cell-mediated cytotoxicity (ADCC) is a key mechanism of action for some therapeutic antibodies. ADCC involves killing of an antibody-coated target cell by an effector cell through the release of cytotoxic or cell death-inducing molecules. ADCC is triggered through interaction of Fcγ receptors present on the effector cell surface with the Fc region of the target-bound antibody. Natural killer (NK) cells are one of the primary effector cells that mediate ADCC. There is significant interest in designing therapeutic agents that can enhance ADCC because this can result in improved clinical responses with approved antibodies. We have developed a suite of highly substituted imidazoquinolines, which activate TLR 7 and/or 8 and induce significantly higher levels of cytokines compared to the FDA-approved TLR7 agonist imiquimod. In the current study, we evaluated our series of TLR7-specific, 8-specific and 7/8 dual selective agonists for their ability to improve ADCC with Cetuximab. We investigated NK cell activation in the presence of these compounds, as well as NK cell mediated ADCC against an EGFR expressing lung cancer cell line, A549. In addition, we also measured cytokine induction in human peripheral blood mononuclear cells in response to these compounds. Our studies show dual TLR 7/8 and 8-specific agonists induce robust pro-inflammatory cytokine secretion and activate NK cells. however, mixed agonists also induce greater immunosuppressive cytokines compared to TLR8-specific agonists. Further, these agonists also significantly enhanced Cetuximab mediated ADCC in vitro. In vivo studies examining the anticancer efficacy of the combination of selected TLR7/8 agonists and Cetuximab are ongoing. Citation Format: Vidhi Khanna, Hyunjoon Kim, Wenqui Zhang, Peter Larson, David Ferguson, Jayanth Panyam. Novel small molecule TLR7/8 agonists for enhancing NK cell-mediated ADCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4129.
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