2009 Nanobiotechnology Seminar Series

January 20, 2009

Dong M. Shin, MD, FACP 
Professor of Hematology/Oncology and Otolaryngology
Dir. Clinical and Translational Cancer Prevention Program
Winship Cancer Institute
Emory University School of Medicine

Novel Nanotechnology Based Therapeutics: An Emerging Treatment Modality for Cancer 

Abstract: 

One of the most common approaches to cancer treatment is the systemic delivery of anti-cancer drugs. However, major challenges for drug delivery are nonspecific systemic distribution of anti-cancer agents and their toxicity, vehicle-free anti-cancer drug delivery, frequent incidence of drug resistance, and suboptimal drug concentrations reaching the tumor cells. A therapeutic anti-cancer drug, ideally, should selectively reach tumor cells with minimal damage to normal cells. There are several key properties of anti-cancer nanoparticles, including nanoparticle size, surface properties, targeting ligands, and different carriers. It is currently thought that the diameter of therapeutic nanoparticles for cancer should be in the range of 10 to 100 nm and they can reach the target cells without elimination through renal tubules in mouse models. Tumor vasculature is poorly operational and macromolecules leak from blood vessels and accumulate, a phenomenon known as the “enhanced permeability and retention (EPR) effect”. Considerable evidence suggests that this phenomenon is also operational in humans. It has been shown that entities in the order of hundreds of nanometers in size can leak out of the blood vessels and accumulate within tumor areas. Several experiments from animal models suggest that sub-150 nm, neutral, or slightly negatively charged entities can move through tumor vasculatures and reach target tissues. Recent data also indicate that nanoparticles in the size of 50 to 100 nm that carry a very slight positive charge can penetrate throughout large tumors following systemic administration. Nanoparticles have high surface-to-volume ratios when compared with large particles, and so control of their surface properties is crucial to their behavior in the human body because their ultimate fate will be determined by the interactions with their local environment, which depend on a combination of their size and surface properties. Thus, when one designs the surface properties of nanoparticles, minimization of nonspecific interactions via steric stabilization and control of surface charge to prevent nanoparticle loss at undesired locations must be considered. Over the last decade, several non-ligand nanoparticles have been developed with certain advantages (i.e., hydrophobic compounds become hydrophilic), but tumor-specific delivery of such particles has not been successfully reached. To deliver nanoparticles specifically to cancer cells, the conjugation of targeting ligands with nanoparticles that provide specific nanoparticle-cell surface interactions may play a critical role in the ultimate localization of the nanoparticles. Therefore, continuous discovery and study of specific ligands that bind exclusively to cancer cells will be critically important in the design of nanoparticles. Currently, ligand-targeted therapeutic strategies including chemotherapeutics, molecularly targeted agents, anti-sense RNAs, immunotoxins, radio-immunotherapeutics, and drug immunoconjugates are being developed. Next, the lecture will also focus on the preclinical development of several promising therapeutic novel nanoparticles, and their clinical uses of the earlier generation of nanoparticle therapeutics and their limitations, and review those on the near horizon for cancer therapeutics. 

February 17, 2009

Daniel Rugar, PhD
Manager, Nanoscales Studies IBM Research Division
Almaden Research Center

Nanoscale Magnetic Resonance Imaging – The Quest for a Molecular Structure Microscope

Abstract:

Can a microscope be built that can directly image the 3D atomic structure of individual biomolecules? Motivated by this question, we are working to dramatically enhance the resolution of magnetic resonance imaging (MRI) using a technique called “magnetic resonance force microscopy” or MRFM. MRFM achieves a 100 million-fold improvement in sensitivity over conventional MRI by replacing the traditional inductive pickup with ultrasensitive detection of magnetic force. Combining this sensitivity improvement with novel methods for spin manipulation, we have successfully detected nanoscale ensembles of nuclear spins, such as 1H, 13C, 19F and 31P. By carefully measuring the magnetic force from the nuclear spins as a function of position, a 3D image of nuclear spin density can be reconstructed. As a first demonstration, we show a 3D reconstruction of the hydrogen in a test sample of tobacco mosaic virus particles. Spatial resolution on the order of 4 nm was obtained. Prospects for pushing the resolution below 1 nm and turning this technique into a useful tool for structural biology will be discussed. 

March 17, 2009

Quentin Pankhurst, PhD 
Professor
Department of Physics and Astronomy
University College London

Healthcare Biomagnetics: In Vivo Sensing, Moving and Heating of Magnetic Nanoparticles for Diagnosis and Therapy

Abstract:

The emerging field of ‘endomagnetics’ – the sensing, moving and heating of magnetic nanoparticles in the human body for diagnostic and therapeutic purposes - will be reviewed. Examples will be given for each of the modalities:, including the following:

Sensing: A high-Tc SQUID based sensor system, with a room temperature hand-held probe, designed for use in a hospital operating theatre to detect breast cancer sentinel lymph nodes (Figure 1). The system is being evaluated in patients, and has been used successfully in twelve operations to date.

Moving: A high field-gradient magnetic actuator designed to capture magnetic nanoparticle loaded haematopoetic stem cells for the treatment of atherosclerosis. Bench-top (Figure 2) and animal trials are under way to establish the efficacy of such a therapy, with promising results.

Heating: Magnetic field hyperthermia treatment for superficial and, as a long term goal, metastatic cancer, using antibody-targeted magnetic nanoparticles. Work is progressing on several fronts: the synthesis of improved magnetic particles for heat transduction (Figure 3), the engineering of new high-frequency drive circuits to produce rf fields in controlled geometries, and cell and animal studies of antibody-nanoparticle conjugation and tumour targeting.

Apr 7, 2009
Munzer Auditorium

Jinwoo Cheon, Ph.D., F.R.S.C.
Horace G. Underwood Professor
Dept. of Chemistry
Yonsei University, Seoul, Korea

New-Generation Magnetic Nanoparticles as Platform Materials for Multimodal Diagnostics 

Abstract: 

The development of next generation nanomaterials for the study of biological targets is of interest. Among many types of nanoparticles, magnetic nanoparticles possess interesting nanoscale phenomena including superparamagnetism, tunable coercivity and magnetic moment. In this talk, I will discuss our recent studies on the chemical design of ultra-sensitive MRI and multi-modal nanoparticle probes. Nanoscale magnetism effects of size, dopant, and magnetocrystallity on the MR signal enhancements are to be described. Currently developed new MEIO magnetic nanoparticles provide the highest MR contrast effects (r2=860 mM-1s-1) reported to date which is roughly 8-14 times larger than conventionally iron oxide contrast agents. Hence, magnetism optimized nanoparticles are very useful as key platform materials for high performance multi-modal imaging (e.g. MRI-optical, MRI-PET), drug and gene delivery, cell trafficking, and bio-sensing and actuations. I will show a few examples of how these were successfully utilized for in vitro and in vivo imaging and therapeutics.

April 21, 2009

Donald Ingber, MD, PhD
Director, Wyss Institute for Biologically Inspired Engineering
Judah Folkman Prof. of Vascular Biology,
Harvard Medical School & Children's Hospital
Prof. of Bioengineering, Harvard School of Engineering and Applied Sciences Vascular Biology Program
Harvard University

From Biological Design Principles to Bioinspired Nanotechnologies 

Abstract: 

The burgeoning field of Nanotechnology offers exciting new approaches to attack fundamental questions in biology, create smart medical devices, and positively impact human health. Creation of biologically-inspired nanotechnologies also could revolutionize how materials are designed and manufactured for industrial, aerospace and military applications. But the fields are constrained by a lack of understanding of how living cells and tissues are constructed so that they exhibit their incredible organic properties, including their ability to change shape, move, grow, and self-heal. These are properties we strive to mimic, but we cannot yet build manmade materials that exhibit these features, or develop devices to selectively control these behaviors. To accomplish this, we must uncover the underlying design principles that govern how cells and tissues form and function as hierarchical assemblies of nanometer scale components. In this lecture, I will review work from my laboratory and others which has begun to reveal these design principles that permit self-assembly of 3D structures with great robustness, mechanical strength and biochemical efficiency, even though they are composed of many thousands of flexible molecular scale components. We also are beginning to understand that biological materials are simultaneously “structure and catalyst”: the molecular lattices that form the frameworks of our cells and tissues combine mechanical functions and solid-phase biochemical processing activities. In the course of the lecture, I also will describe how recently developed nanotechnologies have been used to create model systems for biological studies, and how they have led to new approaches to interface living cells with microchips, control mammalian cell and tissue development, and probe the process of mechanotransduction – how cells sense mechanical forces and convert them into biochemical responses. Finally, the more fundamental question of how nanoscale structural networks impact information processing (signal transduction) networks to control cellular “decision-making” also will be explored. Understanding of these design principles that govern biological organization is critical for any nanotechnologist who wants to harness the power of biology. 

May 12, 2009
2:00pm Clark

Charles Lieber, PhD
Mark Hyman Professor of Chemistry
Departments of Chemistry and Chemical Biology
Harvard University

Nanoelectronic-Biology Interfaces: From Ultrasensitive Detection to New Biomaterials 

Abstract: 

Advances in nanoscale materials can enable unique opportunities at the interface between chemistry, physics and the life sciences. The interface between nanoscale electronic devices and biological systems makes possible interactions at length scales natural to biology, and thus maximizes communication between these two diverse yet complementary systems at the length scale relevant to biological function. In this presentation, the development of nanowire nanoelectric devices and device arrays and their application as powerful tools for the life sciences will be discussed. The application of nanowire nanoelectronic arrays for ultra-sensitive, label-free, detection of disease markers will be described, as well as the development of high-sensitivity real-time kinetic assays and efforts pushing the sensitivity of these nanodevices to limits that enable new applications in detection of single molecules and DNA sequence analysis. In addition, the development of two-way electronic interfaces between nanowire nanoelectronic devices and cells, tissue and organs will be described. Multiplexed measurements made from nanowire device arrays fabricated on flexible and transparent plastic substrates show that signal propagation across the myocardium can be mapped, in flexible conformations with high spatial and temporal resolution. The application of dense nanowire arrays to high spatiotemporal resolution multiplexed measurements from individual cardiomyocyte cells and cellular arrays will also be discussed. In addition, we will show that one- and two-dimensional arrays of nanowire transistors with flexible spatial configurations on optically-transparent substrates can be reliably interfaced with specific regions of acute brain slices to detect localized potential changes due to neuron activities simultaneously across many length scales with high temporal resolution. Applications of these nanoelectronic devices will be discussed as well as prospects for blurring the distinction between inorganic devices and living systems in the future. 

May 19, 2009

Gordon B. Mills, MD, PhD
Ransom Horne Professor in Cancer Research
University of Texas M.D. Anderson Cancer Center

A Systems Biology Approach to Personalized Medicine 

Abstract: 

The realization of the promise of personalized molecular medicine will require the efficient development and implementation of novel targeted therapeutics. The overall likelihood of response to particular drugs represents the interaction between predictors of sensitivity with predictors of resistance. The phosphatidylinositol 3’kinase (PI3K) pathway is aberrant at multiple levels across a wide variety of tumors making it the most common activating aberration in cancer. This has led to the development and now early clinical testing of drugs targeting multiple components of the pathway. The efficient utilization of these drugs will require the ability to accurately determine mutation and activation status in tumors as well as determining the interaction between the PI3K pathway and other pathways in driving tumor pathophysiology. The PI3K pathway is critically important to cellular function and is thus under exquisite homeostatic control. The feedforward and feedback loops in the pathway determine the response to perturbation of the pathway by mutation or therapeutic intervention. Strikingly inhibition of the pathway at the level of mTOR or AKT results in the activation of potent feedback loops resulting in activation of multiple cell surface tyrosine kinases, PI3K itself and AKT. This may contribute to the observation that mTOR inhibitors appear to make some patient tumors grow more rapidly an unexpected and disappointing consequence. Our preliminary systems biology-based mathematical and experimental models of the PI3K signaling network accurately predict these consequences as well as the biochemical processes involved. Further, the models suggest combinations of targeted therapeutics likely to reverse the negative effects of the mTOR inhibitors converting the outcome from negative to positive in terms of tumor growth. 

June 16, 2009

Sangeeta N. Bhatia, M.D., Ph.D. 
Professor
Health Sciences and Technology/
Electrical Engineering & Computer Science, M.I.T.
Department of Medicine
Brigham & Women's Hospital

Towards Next-Generation Nanoparticles 

Abstract: 

Our laboratory is interested in how the integration of diagnosis and therapy on multifunctional nanoparticles might transform the diagnosis and treatment of cancer. In particular, we aim to exploit nanomaterials with nanoscale properties and knowledge of the tumor microenvironment to explore this paradigm. We have studied three nanoparticle cores that harness features of the nanoscale: semiconductor quantum dots that exhibit size-based optical properties, dextran-coated iron oxide particles whose assembly alters the spin-spin relaxation time of hydrogen protons on magnetic resonance imaging, and polymer-coated gold nanorods that interact resonantly with near-infrared light. Collectively, we have explored the capabilities of these multifunctional nanoparticles by studies on targeting, triggered self-assembly, remote actuation with radiofrequency fields, sensing of kinase activity, and delivery of short interfering RNAs. To control the trafficking of these nanoparticle cores, we have decorated the surface with peptides in combination with polymers that prevent their nonspecific uptake in the liver and spleen. The peptides we have explored are screened in collaboration with Erkki Ruoslahti (Burnham Institute), using in vivo phage display. To explore the self-assembly of these particles, we have used strategies inspired by platelets—natural microparticles that normally circulate in a latent form but can home to sites of injury and transform to an activated state, whereby they adhere and recruit more platelets. This results in assemblies of magnetic nanoparticles that may then acquire emergent properties, allowing either their enhanced visualization or remote actuation of drug delivery. We have also emulated biological systems where biological components remotely communicate via biological intermediates, such as tissue-resident macrophages that participate in the recruitment of circulating neutrophils. The resultant nanoparticle formulations then act as a "system" to produce emergent behaviors for enhancing diagnosis and therapy. Ultimately, we anticipate that the next-generation therapeutics will be both multifunctional, in that they are diagnostic and therapeutic, and modular, in that they can be customized for different types of tumors and stages of tumor progression.

July 21, 2009

Miqin Zhang, PhD 
Professor
Department of Materials Science and Engineering
University of Washington

Multifunctional Nanoparticles for Brain Tumor Diagnosis and Treatment 

Abstract: 

Treating malignant brain tumors remains a formidable challenge due to the difficulty in differentiating between tumors and healthy brain tissue, intrinsic cellular resistance of tumors to drugs, and the blood brain barrier (BBB) preventing the passage of drugs and contrast agents. Targeted delivery of contrast agents and therapeutic payloads using nanoparticles is a promising approach that may overcome these barriers. Our research aims to develop multifunctional nanoparticle systems that can serve as imaging markers, targeting agents, and drug delivery vehicles for non-invasive diagnosis, treatment, and therapy-response monitoring of brain cancers. In the past few years, we have developed several multifunctional nanoparticle systems that demonstrate an ability to specifically target brain tumors across the BBB, and exhibit innocuous toxicity profiles and sustained retention in tumors, as established through uptake assays, in vivo magnetic resonance and biophotonic imaging, and histological and biodistribution analyses. A typical multifunctional nanoparticle system in our design comprises a superparamagnetic iron oxide core that enables magnetic resonance imaging, a biodegradable polymeric shell that stabilizes the nanoparticle and provides functional groups for biomolecule conjugation, and a targeting ligand for specific binding of target cells. My talk will focus on our recent research in development of nanoparticle systems, including design and characterization of these nanoparticle systems, and their in vitro and in vivo performance.

August 18, 2009

Steven A. Curley, MD, FACS 
Professor, Surgical Oncology
The University of Texas
MD Anderson Cancer Center

Targeted Nanoparticles and RF-Induced Thermal Destruction of Cancer Cells 

Abstract: 

Shortwave (MHz range) radiofrequency (RF) energy is nonionizing, penetrates deeply into biologic tissues with no adverse side effects, and heats gold nanoparticles efficiently. Targeted delivery of gold nanoparticles to cancer cells should result in hyperthermic cytotoxicity upon exposure to a focused, noninvasive RF field. We have demonstrated that gold nanoparticles conjugated with cetuximab (C225) are quickly internalized by Panc-1 (pancreatic adenocarcinoma) and Difi (colorectal adenocarcinoma) cancer cells overexpressing epidermal growth factor receptor (EGFR). Panc-1 or Difi cells treated with naked gold nanoparticles or nonspecific IgG-conjugated gold nanoparticles demonstrated minimal intracellular uptake of gold nanoparticles by transmission electron microscopy (TEM). In contrast, there were dense concentrations of cytoplasmic vesicles containing gold nanoparticles following treatment with cetuximab-conjugated gold nanoparticles. Exposure of cells to a noninvasive RF field produced nearly 100% cytotoxicity in cells treated with the cetuximab-conjugated gold nanoparticles, but significantly lower levels of cytotoxicity in the two control groups (P <0.00012). Treatment of a breast cancer cell line (CAMA-1) that does not express EGFR with cetuximab-conjugated gold nanoparticles produced no enhanced cytotoxicity following treatment in the RF field. Conjugation of cancer cell-directed targeting agents to gold nanoparticles may represent an effective and cancer-specific therapy to treat numerous types of human malignant disease using noninvasive RF hyperthermia. We are now studying antibodies or peptides that target hepatocellular, pancreatic, colorectal, breast, prostate, and carcinoid cancers, in addition to melanoma and leukemia, to determine 1) their conjugation efficiency and stability with gold nanoparticles, 2) their targeting specificity for malignant compared to normal cells, and 3) the tumor-specific killing in vivo. 

October 20, 2009

Alex Wei, PhD 
Professor of Chemistry and University Faculty Scholar
Dept. of Chemistry
Purdue University

Targeted delivery of gold nanorods and other plasmonic nanostructures: en route to theragnosis 

Abstract: 

Gold nanorods and nanostars can couple with electromagnetic irradiation at visible and near-infrared frequencies, and serve as multifunctional agents in biophotonic applications. These anisotropic nanostructures are capable of both linear and nonlinear optical responses, due in large part to polarization-sensitive modes that can be tuned by various structural and materials factors. Both types of particles have been used in biological imaging, but diverge with respect to their specific application. Gold nanorods are particularly efficient at converting optical energy into heat, and have been used to deliver intense photothermal effects with subcellular precision, guided by two-photon excited luminescence. Gold nanostars can be synthesized with magnetic cores to support a dynamic (gyromagnetic) mode of NIR imaging, effective at enhancing contrast in heterogeneous media such as those encountered in tissues. Recent advances will be presented in the context of their impact on theranostics and nanomedicine. 

November 17, 2009

Teri Odom, PhD 
Associate Professor
Depts. of Chemistry and Matierals Science and Engineering
Northwestern University

Diagnostics and Therapeutics using Multifunctional Nanopyramid Probes 

Abstract: 

This talk will describe how anisotropic, gold nanoparticles—fabricated nanopyramids—can be used for bioimaging and cancer therapeutic applications. Nanopyramids are a new class of asymmetric, metal nanoparticles that (1) show orientation-dependent light scattering properties; and (2) have ultra-sharp tips and edges that "concentrate" and localize light. The first property can potentially be exploited for identifying the distribution of biomarkers on cells surfaces. The second characteristic makes the pyramids ideal probes for photo-thermal cancer therapy using near infrared light. We will discuss how other structural parameters of the nanoparticles should be designed to achieve a maximal photo-thermal response, which is critical for minimizing the amount of material in treatment as well as for reducing the power and time duration of the exposure light so that healthy tissue is not damaged. The opportunities and challenges of using gold nanoparticles in biomedical applications will be discussed. 

December 15, 2009

Jennifer West, PhD
Isabel C. Cameron Professor of Bioengineering
Chair, Dept. of Bioengineering
Rice University

Nanotechnology for Cancer Therapy and Diagnostics 

Abstract:
 
The increasing capability to manipulate matter at the nanoscale is generating new materials with unique properties that promise to address unmet medical needs for future generations. As an example, metal nanoshells are a relatively new class of nanoparticles with highly tunable optical properties. Metal nanoshells consist of a dielectric core nanoparticle such as silica surrounded by an ultrathin metal shell, usually composed of gold for biomedical applications. Depending on the size and composition of each layer of the nanoshell, particles can be designed to either absorb or scatter light over much of the visible and infrared regions of the electromagnetic spectrum, including the near infrared region where penetration of light through tissue is maximal. These particles are also easily conjugated to antibodies and other biomolecules. One can envision a myriad of potential applications of such tunable particles. Several potential biomedical applications are under development, including immunoassays, modulated drug delivery, photothermal cancer therapy, and imaging contrast agents. For example, in photothermal cancer therapy, nanoshells can be injected intravenously, accumulate at tumor sites due to the EPR effect and/or molecular targeting, then generate heat upon illumination with near infrared light, leading to destruction of the tumor. This has shown very promising results in a mouse colon carcinoma model, with 100% survival of nanoshell treated mice at 1 year. These materials are now in phase I human clinical trials. Furthermore, integrated imaging and therapy applications have been accomplished with nanoshells designed to provide both absorption and scattering, potentially enabling "see-and-treat" approaches to cancer therapy.