Conventional chemotherapies in cancer medicine typically act indiscriminately, killing both healthy and diseased cells, and thus result in numerous side effects. Nanoshell-assisted photothermal therapy (NAPT) enables more site-specific treatment of cancerous tissue because the heating effect is only achieved where near-infrared (NIR) light and nanoshells are combined locally. We are currently exploring methods to enhance the specificity of NAPT through multimodal imaging as well as biological approaches with the incorporation of proteins and peptides. For instance, after surface conjugation to gadolinium, nanoshells exhibit contrast enhancement across a range of diagnostic modalities, including magnetic resonance (MR) and a variety of optical imaging methods. By affording positive contrast at both the anatomic and microscopic levels, gadolinium-nanoshell conjugates offer the ability to identify cancerous lesions for appropriate NIR laser application. Additionally, with nanoparticle surface conjuation to specific proteins and peptides that bind overexpressed surface markers on cancer cells, particle homing to diseased tissue could be facilitated. For example, ephrinA1-conjugated nanoshells target a variety of cancer cell types with increased expression of the EphA2 tyrosine kinase receptor. These methods have demonstrated success in vitro with prostate cancer cells, and in vivo validation is underway.
Dark field micrographs of PC3, PCS 440, and HDF cells (shown in blue-gray) after incubation with gold-silica nanoshells (shown in gold).
(Top row) EphrinA1 nanoshells demonstrated greatest degree of cell binding to PC3 cells, which overexpress the EphA2 receptor, as compared to the other cell types. (Bottom row) PEG only coated nanoshells resisted cell binding and showed low levels of labeling among all cell types.
My research project focuses on the creation of a novel delivery platform for cancer therapeutics. I aim to create an injectable delivery system which controls drug release to occur only at the site of malignant tissue. This system consists of two novel material components: a thermally responsive poly[n-isopropylacrylamide-co- acrylamide] (NIPAAm-co-AAm) hydrogel material acts to encapsulate the drug, leading to increased serum stability and decreased exposure to off-site tissues. In addition, embedded gold-silica nanoshells act as a triggering mechanism to release the therapeutic payload only at the site of malignant tissue.
Drug release from a poly(NIPAAm-co-AAm)-gold nanoshell composite
gel over 60 seconds. A blue drug is released from the gel upon exposure to an NIR laser.
- Dual-Energy Micro-CT Functional Imaging of Primary Lung Cancer in Mice Using Gold and Iodine Nanoparticle Contrast Agents: A Validation Study. PLoS ONE. 9(2), e88129. (2014).
- Hydrogel-nanoparticle composites for optically modulated cancer therapeutic delivery. Journal of Controlled Release. 178, 63 - 68 (2014).
- Gadolinium-Conjugated Gold Nanoshells for Multimodal Diagnostic Imaging and Photothermal Cancer Therapy. Small. (2013).
- Coughlin, A.J.; and West, J.L. (2012) Targeting Gold Nanoparticles for Cancer Diagnostics and Therapeutics. (Hepel, M., Zhong, C., Eds). Functional Nanoparticles for Bioanalysis, Nanomedicine and Bioelectronic Devices; 2, 37-54.
- Day, E. S., Zhang L., Thompson P. A., Zawaski J. A., Kaffes C. C., Gaber W. M., et al. (2012). Vascular-targeted photothermal therapy of an orthotopic murine glioma model. Nanomedicine. 7(8), 1133 - 1148.