2015 Nanobiotechnology Seminar Series
Seminar & Discussion 5:30 - 6:30 pm
Reception 6:30 - 6:50 pm
January 8, 2015
Department of Biomedical Operations
Separation/Isolation of rare cells, including circulating tumor cells, in patient blood: It is not the same as spiking cancer cells into normal blood!
In this presentation, I wish to describe our journey from taking more fundamental studies of magnetic cell separation to our extensive involvement in the isolation and characterization of targeted cells, including cancer, and cancer associated cells, from the blood of cancer patients. We are not only interested in the strictly defined circulating tumor cells, CTC, but we are also venturing into characterizing the plethora of other unusual cells in the blood of these cancer patients. Given the highly interdisciplinary nature of this work, in this presentation I wish to attempt to present aspects of this work which will appeal to traditional engineering researchers through to clinical researchers interested in developing diagnostics not just for diagnosis and prognosis of cancer but also the effectiveness of experimental drugs/treatments. Specifically, I wish to highlight our work with squamous cell carcinoma of the head and neck and breast cancer, including a clinical trial sponsored by the National Cancer Institute. I also wish to also present some of our more recent work which, surprisingly, indicates that under highly specific conditions, we are able to sort rare cells using a high end flow cytometer.
April 9, 2015
Deptartments of Bioengineering, Chemistry and Pathology
University of North Carolina
Integrated Fluidic System for Analysis of Circulating Tumor Cells: Searching for Drug-induced DNA Damage using Nanosensors
here has been progress made in early detection of breast cancers and better classification of breast malignancies. But, improved therapies that yield more cures and better overall survival are still needed; women with breast cancer still have a poor prognosis with a 5-year survival rate of 22% (Stage IV) and 72% (Stage III). Doxorubicin, cisplatin, paclitaxel, and tamoxifen are examples of drugs used for treating breast cancer with selection of therapy typically based on the classification and staging of the patient’s cancer. While treatment regimens assigned to some patients may be optimal using the current classification model, others within certain breast cancer sub-types fail therapy. New assays must be developed to determine how a patient’s physiology affects drug efficacy.
In this presentation, an integrated fluidic system for the isolation and processing of circulating tumor cells (CTCs) will be discussed. The system quantifies response to therapy using three pieces of information secured from the CTCs; (1) CTC number; (2) CTC viability; and (3) the frequency of DNA damage (abasic (AP) sites) in genomic DNA (gDNA) harvested from the CTCs. The fluidic system consists of task-specific modules integrated to a fluidic motherboard. Micro-scale modules are used for CTC selection, CTC enumeration and viability determinations, lysing CTCs, and purifying gDNA. The module to read AP sites is a nanosensor made via embossing in plastics and contains a nanochannel with dimensions less than the persistence length of double-stranded DNA (~50 nm). Labeling AP sites with fluorescent dyes and stretching the gDNA in the nanochannel allows for direct readout of the AP sites, even from a few CTCs.
May 5, 2015
Spencer T. Olin Professor of Engineering
Dept. of MSE,
Cornell Dots as a New Class of Fluorescent Nanoparticles to Improve Visualization in Cancer Surgery and Treatments
Despite significant promise of nanomaterials in medicine, few colloidal materials make the transition into the realm of human clinical applications. In this presentation a novel class of multifunctional fluorescent silica-based core-shell nanoparticles will be introduced referred to as “Cornell dots” or simply “C dots”. These particles have sizes below 10 nm, which is below the threshold for renal clearance, leading to favorable biodistributions and pharmacokinetics. These smaller than 10 nm sized PEGylated labels for nanomedicine are the first dual-modality (optical/PET) hybrid nanoparticles of their class and properties receiving investigational new drug (IND) FDA approval for first in-human clinical trials in the US. In this presentation, results on C dot synthesis, characterization, and optical properties will be reported with focus on materials properties that facilitate transition into clinical applications. After discussion of first animal studies, first results will be reported on clinical trials with human melanoma patients assessing particle safety. Subsequently, work towards employing these probes in sentinel lymph node (SLN) mapping will be described in which a specific camera system enables surgeons to visualize nodes during surgery. These efforts recently lead to a second FDA IND approval for a new human clinical trial in SLN mapping, using the hand-held camera system, which is now open for patient recruitment. After discussion of these diagnostic applications the talk will finally describe studies toward theranostic (therapeutic plus diagnostic) applications. This includes baseline studies of how the particles up- or down-regulate cellular metabolic pathways as a result of receptor-mediated uptake as well as the development of first Cornell dots bearing small molecule therapeutics for specific drug delivery.
- E. Phillips, O. Penate-Medina, P. B. Zanzonico, R. D. Carvajal, P. Mohan, Y. Ye, J. Humm, M. Gönen, H. Kaliagian, H. Schöder, H. W. Strauss, S. M. Larson, U. Wiesner, M. S. Bradbury, Clinical translation of an ultrasmall inorganic optical-PET imaging nanoparticle probe, Sci. Transl. Med. 6 (2014), 260ra149.
- T. Suteewong, H. Sai, R. Hovden, D. Muller, M. Bradbury, S. M. Gruner, U. Wiesner, Multicompartment mesoporous silica nanoparticles with branched shapes: An epitaxial growth mechanism, Science 340 (2013), 337-341.
- M. Benezra, O. Penate-Medina, P. B. Zanzonico, D. Schaer, H. Ow, A. Burns, E. DeStanchina, V. Longo, E. Herz, S. Iyer, J. Wolchok, S. M. Larson, U. Wiesner, M S. Bradbury, Multimodal silica nanoparticles are effective cancer-targeted probes in a model for human melanoma, J. Clin. Invest. 121 (2011), 2768–2780.
May 14, 2015
Assistant Professor Department of Chemical Engineering, University of Michigan
Integrated Micro Nanotechnologies for the Isolation, Ex-vivo Expansion and Single Cell Analysis of CTCs
Circulating tumor cells (CTCs) are shed from the primary tumor into the peripheral blood. CTCs are emerging as important biomarkers with high clinical relevance. Enumeration of CTCs may have several clinical uses, including determination of prognosis in patients with established malignancy, or even detection of previously undiagnosed cancer. However, due to the limitation of sensitivity and specificity of current technologies for CTC isolation, the full potential of CTCs has yet to be realized. Furthermore, emerging research show that a small number of cells have stem cell-like nature in various cancers and those are called cancer stem cells (CSC) which may arise from differentiated cancer cells through EMT and have the potential to self-renew and are pluripotent. Emerging microfluidic technologies are promising for isolating both CTCs and CSCs with a high yield and specificity. We present novel integrated nano microfluidic technologies that enable both functional and genomic assays beyond enumeration. Using these strategies, blood collected from cancer patients was analyzed for CTCs and CSCs. Isolated CTCs were expanded by in-situ capture and culture methodology using a multicellular, three dimensional co-culture model. Furthermore, we examined the heterogeneity of circulating cells by single cell analysis. The gene expression signatures of isolated CTCs determined using a highly sensitive microfluidic-based 96-plex RT-qPCR method revealed both MET and EMT phenotypes in CTCs. The ability to reliably detect and quantify CSCs from patients with both early and advanced stages of cancer will constitute a major step forward in monitoring the disease. We demonstrate that the quantification of CSCs can be used to predict pathologic stage, onset of metastasis, and response to therapy.
Sponsored by: Center for Cancer Nanotechnology Excellence and Translation - NIH/NCI U54 (MIPS);
Host: Director, Sanjiv Sam Gambhir, MD, PhD (email@example.com)
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