TNBCs present an interesting treatment paradox in that they are highly aggressive tumors that tend to be relatively chemosensitive. However, as they do no express estrogen, progesterone or epidermal growth factor type 2 receptors (ER, PR and Her2/Erbb2 respectively) patients with these cancers do not benefit from the typical hormonal modulations used to treat breast cancers. While TNBCs fail to express a variety of hormonal receptors, they typically overexpress the type 1 epidermal growth factor type 1 receptors (EGFR/Erbb1) and therefore could potentially benefit from EGFR targeted therapies. Here we seek to improve the imaging and treatment of triple negative breast cancers (TNBCs) with the utilization of NDs as delivery vehicles targeted to the epidermal growth factor receptor (EGFR). Nanodiamonds (NDs) have emerged as attractive nano-vehicles for both imaging and therapy due to their innate biocompatibility, scalable synthetic methods and unique carbon surface that facilitates bio agent attachment. Furthermore, ND attachment has been shown to enhance imaging efficiency, sustain drug release, boost therapeutic efficacy, overcome cellular resistance and improve drug safety profiles in both cell based and animal models. This project will build upon the already promising ND-based delivery system with the addition a targeting method, in this case the FDA-approved therapeutic antibody to EGFR, Cetuximab (CXB). Antibody-based targeting of ND-conjugates for imaging should allow for detailed tumor imaging, thereby improving diagnostic imaging, detection of metastases, tumor margin assessment and monitoring of therapy progression. Furthermore, antibody-based targeting of therapeutic NDs will allow for broader application of ND conjugates. NDs have been shown to be highly effective at delivering chemotherapeutic agents by passive targeting to tumors that experience the enhanced permeability and retention effect (EPR). As not all tumors experience EPR, active targeting mechanisms such as antibody attachment could enable the application of ND-conjugates in a wider variety of disease states. Additionally, if the targeting antibody is also therapeutic, as is the case here, targeted particle delivery will also serve as combination therapy.

Public Health Relevance

Triple negative breast cancers (TNBCs) are notoriously aggressive cancers that do not respond to the typical hormone targeted breast cancer therapies because they do not express the requisite receptors. However, since TNBCs typically overexpress the epidermal growth factor receptor (EGFR) they stand too significantly benefit from EGFR targeted therapies. Our goal is to develop EGFR-targeted nanodiamonds to improve the imaging and treatment of TNBCs in addition to enhancing the utility of nanodiamonds as a biological agent delivery platform.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F09-A (09))
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Damico, Mark W
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Northwestern University at Chicago
Schools of Engineering
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Moore, Laura; Yang, Junyu; Lan, Thanh T Ha et al. (2016) Biocompatibility Assessment of Detonation Nanodiamond in Non-Human Primates and Rats Using Histological, Hematologic, and Urine Analysis. ACS Nano 10:7385-400
Moore, Laura; Grobárová, Valéria; Shen, Helen et al. (2014) Comprehensive interrogation of the cellular response to fluorescent, detonation and functionalized nanodiamonds. Nanoscale 6:11712-21
Kim, Ho-Joong; Zhang, Kangyi; Moore, Laura et al. (2014) Diamond nanogel-embedded contact lenses mediate lysozyme-dependent therapeutic release. ACS Nano 8:2998-3005
Moore, L; Gatica, M; Kim, H et al. (2013) Multi-protein delivery by nanodiamonds promotes bone formation. J Dent Res 92:976-81
Moore, Laura K; Chow, Edward K; Osawa, Eiji et al. (2013) Diamond-lipid hybrids enhance chemotherapeutic tolerance and mediate tumor regression. Adv Mater 25:3532-41