2012 Nanobiotechnology Seminar Series

Seminar & Discussion 5:30 - 6:30 pm
Reception 6:30 - 6:50 pm

January 12, 2012
Munzer Auditorium

Julia Ljubimova, MD, PhD

Director of Nanomedicine Research Center
Deptartment of Nuerosurgery
Cedars-Sinai Medical Center

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Nanobiopolymers Designing for Primary and Metastatic Cancer Treatment

A new nanobioconjugate drug delivery platform poly(b-L-malic acid)(PMLA) having built-in membranolytic activity for cancer intracellular drug delivery and cell/tissue targeting is introduced for treatment of primary brain and brain metastasis in vivo. Our goal was to engineer the new drug variants for systemic treatment of brain tumors and HER2-positive brain metastases to enhance the efficacy of trastuzumab/Herceptin® for crossing blood brain barrier/blood tumor barrier (BBB/BTB). Methods: Nanobioconjugates were characterized as to their absolute molecular weight, size, and ζ potential. Membranolytic activity was measured using artificial liposome assays. Primary human glioma U87MG, T98G and breast tumor MDA-MB-231 and MDA-MB-474 cell lines were used for cytotoxicity assays and tumor treatment. In vivoimaging analysis and confocal microscopy were used to confirm tumor targeting and tissues distribution. Results: Membranolytic activity was measured for two PMLA conjugates, P-LLL and P-LOEt [PMLA modified with pendant 40% trileucine (LLL) and 40% leucine ethyl ester (LOEt), respectively]. Only P-LLL induced significant liposome leakage at endosomal gradient pH (pH 5–6), but not at physiological pH 7.4. In vivoimaging revealed enhanced drug accumulation in tumors treated with the lead drug. The lead version bearing both Herceptin and antisense to HER2 produced strong life longevity, compared to Herceptin alone (P<0.001). For brain cancer treatment, the drug variant crossed BTB and reduced intracranial brain tumor size 10-fold. Summary: The new versions of Polycefin family nanobioconjugate drugs could be promising next generation of multifunctional vectors for treating brain and breast primary and metastatic cancers.

February 9, 2012
LPCH Freidenrich Auditorium

Lino Gonzalez, Jr., PhD

Protein Chemistry Scientist
Genentech, Inc

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Uncovering New Biology Using Secretome-Based Expression and Protein Microarray Screening Platforms for Receptor/Ligand Discovery 

My lab focuses on identifying novel receptor-ligand or co-receptor interactions. Now that the human genome is complete, one of the next steps is to understand the interactions between all transmembrane and secreted proteins, which represent about one-third of all human genes. This knowledge would greatly aid in characterizing the biological function of many receptors/ligand pairs and their potential as therapeutic targets. Surprisingly, a significant number of these receptors still remain orphans. In order to identify candidate partners, we have utilized Genentech's SPDI (Secreted Protein Discovery Initiative) protein library, consisting of over 1,000 purified, secreted proteins. In the past, we have used surface plasmon resonance (SPR) and Bio-layer interferometry (BLI) technology to screen hundreds of interactions per day. More recently, we have adapted and validated the assay in a protein microarray format, enabling the screening of thousands of extracellular interactions per day. To date this work has led to the identification of several novel interactions that are now being evaluated for their therapeutic potential. Development of our screening platforms and examples of interaction identified will be discussed.

March 8, 2012
LPCH Freidenrich Auditorium

C. Jeffrey Brinker, PhD

Distinguished Professor
Department of Chemical Nuclear Engineering
University of New Mexico

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Protocells: Mesoporous Silica Supported Lipid Bilayers for Targeted Delivery of Multicomponent Cargos to Cancer 

Encapsulation of drugs within nanocarriers that selectively target malignant cells promises to mitigate side effects of conventional chemotherapy and to enable delivery of the unique drug combinations needed for personalized medicine. To realize this potential, however, targeted nanocarriers must simultaneously overcome multiple challenges, including specificity, stability, and a high capacity for disparate cargos. We recently developed a new class of hierarchical nanocarriers termed protocells that synergistically combine features of mesoporous silica nanoparticles and liposomes. Fusion of liposomes to a spherical, high-surface-area, mesoporous silica core followed by modification of the resulting supported lipid bilayer (SLB) with multiple copies of a targeting peptide, an endosomolytic peptide, and PEG results in a nanocarrier construct (the ‘protocell’) that, compared with liposomes, the most extensively studied class of nanocarriers, improves on capacity, selectivity, and stability and enables targeted delivery and controlled release of high concentrations of multicomponent cargos (chemotherapeutic drugs, siRNA, dsDNA, toxins, etc.) within the cytosol or nucleus of cancer cells. Specifically, owing to its high surface area (>1000 square meters per gram), the mesoporous silica core possesses a higher capacity for therapeutic and diagnostic agents than similarly sized liposomes. Furthermore, owing to the substrate–membrane adhesion energy, the mesoporous silica core suppresses large-scale membrane bilayer fluctuations, resulting in greater stability than unsupported liposomal bilayers. In addition to conferring higher stability, the nanoporous support also results in enhanced lateral bilayer fluidity compared with that of either liposomes or SLBs formed on non-porous particles. We show the enhanced fluidity yet stability of the SLB enables dynamic reconfiguration of the surface allowing membrane bound ligands to engage in complex multivalent interactions with the target cell at very low targeting peptide densities. The synergistic combination of materials and biophysical properties organized over several hierarchical length scales enables high delivery efficiency and enhanced targeting specificity with a minimal number of targeting ligands, features crucial to maximizing specific binding, minimizing nonspecific binding, reducing dosage, and mitigating immunogenicity. The enormous capacity of the high-surface-area nanoporous core combined with the enhanced targeting efficacy enabled by the fluid supported lipid bilayer enable a single protocell loaded with a drug cocktail to kill a drug-resistant human hepatocellular carcinoma cell, representing a million-fold improvement over comparable liposomes.

April 12, 2012
Li Ka Shing, LK 130

Mihail C. Roco, PhD

Chair, US National Science and Technology Council
Nanoscale Science, Engineering and Technology (NSET)
Senior Advisor for Nanotechnology
National Science Foundation (NSF)

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Twenty years to Develop Nanotechnology: 2000 - 2012

Twenty years is the estimated time scale to develop nanotechnology from basic interdisciplinary concepts in 2000 to create a general purpose technology with mass and sustainable use by 2020 ("Nanotechnology Research Direction" NSTC 1999). This presentation outlines the outcomes in the last ten years, what has worked and was not, the current status, and most importantly how we prepare now for the future (see "Nanotechnology Research Directions for Societal Needs in 2020" Springer 2011 www.wtec.org/nano2/). There is an increased focus on nanoscale science and engineering integration, convergence with biology and other scientific domains, and establishing a general-purpose technology. Use of “direct” investigative tools and fundamental knowledge progress through breakthroughs remain essential in still formative phase of development of nanotechnology in 2012. The labor and markets are estimated to double each three years, reaching a $3 trillion market encompassing 6 million jobs by 2020. It will be imperative over the next decade to focus on four distinct aspects of nanotechnology development: better comprehension of nature and communication leading to knowledge progress; technology, economic and societal solutions leading to material progress; international collaboration on sustainable development and quality of life leading to global progress; and people working together for equitable governance leading to moral progress.

May 10, 2012
Li Ka Shing, LK 130

Peter Searson, PhD

Department of Materials Science and Engineering
Johns Hopkins University

Quantitative Profiling of Cancer Biomarkers and Biomedical Imaging using Quantum Dots

The detection of cancer biomarkers is important for diagnosis, disease stage forecasting, and clinical management. Since tumor populations are inherently heterogeneous, a key challenge is the quantitative profiling of membrane biomarkers, rather than secreted biomarkers, at the single cell level. The detection of cancer biomarkers is also important for imaging and therapeutics since membrane proteins are commonly selected as targets. Here we demonstrate quantitative profiling, spatial mapping, and quantitative multiplexing of molecular biomarkers associated with precursor lesions of pancreatic adenocarcinoma at the single cell level using quantum dots. We also discuss advances in quantum dots for biomedical imaging.

September 13, 2012
Li Ka Shing, LK 130

Paula Hammond, PhD

David H. Koch Professor in Engineering, Department of Chemical Engineering
Massachusetts Institute of Technology

Responsive Polypeptides and Sheddable Multilayer Nanoparticles for Controlled Systemic Delivery 

The surfaces of nanoparticles provide a means to introduce mediated interactions with cells that lead to uptake of the nanoparticle, release of drugs in specific regions, and control of the intracellular trafficking of the nanoparticle. Such nanostructured particle systems can be achieved using block copolymer and polyelectrolyte layer-by-layer (LbL) assembly methods. Linear-dendritic block copolymers form micelles capable of controlled cluster presentation of ligand on nanoparticle surfaces; in doing so, we enable the optimization of interactions with cell receptors and the nanoparticle surface by creating blended copolymer "patchy micelles". On the other hand, it is possible to design nanoparticles that consist of several nanolayers wrapped around a core encapsulating material. These polyelectrolyte nanolayer assemblies can be generated to increase the half-life of the particle in the bloodstream by preventing adsorption of proteins via hydrated outer layers, and can also act as a "stealth" layer that prevents recognition of the particle as a foreign body by the body’s defense systems. Nanolayers also can be devised to facilitate cell entry, using the tumor microenvironment as a stimulus to enable the exposure of different functional layers at different points in intracellular trafficking, and enabling nanoparticle uptake by tumor cells. Finally, we have demonstrated the use of an RNA synthesis method known as rolling circle transcription (RCT) to produce extremely long strands of RNA for cellular delivery, and yield active siRNA strands at significant doses, as shown in an animal model. As the RNA strand is synthesized, it folds into a very dense, sponge-like sphere containing up to half a million copies of the same RNA sequence, which can be packed into a single nanoparticle for delivery. 

October 11, 2012
Li Ka Shing, LK 130

Peter Khun, PhD

Associate Professor of Cell Biology
The Scripps Reserach Institute

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The Fluid Phase of Solid Tumors – How does cancer spread? 

The fluid phase of solid tumors is a clinical tool in personalized cancer care and an emerging research tool in basic science cancer discoveries. Utilizing the HD-CTC assay we are undertaking a series of clinical studies investigating the metastatic pathways in cancer patients. We are now coupling the experimental data with a theoretical framework for a more complete description of the disease progression.

The fluid phase of solid tumors is a critical third microenvironment in the development and progression of carcinomas. Cells originating from primary or secondary sites travel through the blood circulatory system to either get cleared out or initiate new tumor growth. Translational research efforts are attempting to identify the various subtypes of circulating tumor cells (CTCs), their origins, their destinations and their impact on the disease. Understanding and characterizing CTCs is a first step towards utilizing them as both biopsy material and directly as a biomarker. It requires approaches of subtyping CTCs at the single cell level using molecular and cellular approaches.

Results will be presented that describe technical developments and validation, clinical validation and clinical utility of the HD-CTC Technology.

November 8, 2012
Li Ka Shing, LK 130

Wenbin Lin, PhD

Kenan Distinguished Professor
Department of Chemistry
Kenan Laboratory
University of North Carolina at Chapel Hill

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Hybrid Nanomaterials for Biomedical Imaging and Cancer Therapy 

Early diagnosis of diseases allows for more effective treatment, giving patients the greatest chance of survival and recovery. By harnessing the power of synthetic inorganic chemistry with that of the latest nanoscience and nanotechnology, the Lin group has developed new hybrid nanomaterials for multimodal imaging and anticancer drug delivery. These biodegradable nanomaterials provide nontoxic and sensitive MRI and optical imaging probes for early and noninvasive detection of cancer and inflammatory arthritis in animal models, which potentially allows for the therapy to be initiated at the most treatable stage. The Lin group is also extending this powerful synthetic strategy to developing hybrid nanoparticles containing potent anticancer drugs such as cisplatin, antifolates, and others. These therapeutic nanomaterials can be selectively and more efficiently delivered to tumors than current chemotherapy, leading to reduced toxicity to normal cells and more effective cancer therapy. 

Dec 13, 2012
Li Ka Shing, LK 130

Alexander V. Kabanov, PhD, DrSc

Mescal Swaim Ferguson Distinguished Professor, Divison of Molecular Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC

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Polymeric Micelles and Polyiion Complexes for Drug Delivery: State-of-Art and Future Directions 

Polymeric micelles (PM) and polyion complexes (PC) attracted major attention as nanocontainers for drug delivery. Initial studies focused on core-shell PM (10 to 100 nm) of amphiphilic block copolymers (BC). Hydrophobic drug molecules incorporate in PM through clavable covalent bonds or non-covalent interactions. Latest developments in this field include PM with engineered cores that carry hydrophobic drugs, such as paclitaxel (or multiple drug blends), with loading capacity nearly 100 times greater than that of Taxol®.1 Of significance are interactions of amphiliplic BC with cancer cells. Pluronic BCs 1) inhibit respiration, 2) deplete ATP, 3) inhibit P-glycoprotein (Pgp), 4) activate pro-apoptotic signaling and 5) altogether greatly sensitize multidrug resistant (MDR) cells with respect to the drug.2 The PM formulation of doxorubicin (DOX) with Pluronic BC, SP1049C decreases tumorigenicity of tumor cells in vivo, decreases incidence and number of metastases, and prevents development of MDR during chemotherapy. SP1049C has demonstrated high efficacy in Phase II trial in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction.3 Ionic drug molecules and biomacromolecules (polynucleotides and proteins) incorporate into PM by electrostatic complexation with ionic BC of opposite charge. NANOzymes are PC PM obtained by mixing enzymes and oppositely charged BC. They can be additionally stabilized by covalent cross-links.4 NANOzymes comprising antioxidant enzymes (superoxide dismutase, catalase) are potential therapeutics for numerous diseases associated with overproduction of reactive oxygen species, such as stroke, hypertension, Parkinson’s disease, eye inflammation, influenza virus infection, and others. NANOzyme of organophosphate hydrolase efficiently degrades organophosphorous neurotoxins. (Bio)degradable cross-links in PM core or shell stabilize PM, yet ensure micelles degradation and payload release in the target cells. Of interest are NANOgels - PM with cross-linked polyion cores, which are swollen in water but collapse upon binding a drug. Such micelles display selective entry and toxicity in/to cancer cells but not in/to normal epithelial cells.5 Ionic BC can stabilize magnetic nanoparticles (MNPs) and further linked to enzyme molecules. MNPs can mechanically disrupt macromolecules attached to their surface as a result of forces created by their motion in super low frequency non-heating alternating current (AC) magnetic field (50 Hz, 5kHz and 337 kHz), which induces the realignment of the particles along the field.6 Thus a principal possibility of using MNPs as remote control “relays” for mechanchemical actuation of PM and PC at the nanoscale has been demonstrated. The work was supported by US Naational Institutes of Health (UO1 CA151806, 2RO1 CA89225, 1P20 RR021937) and Ministry of Education and Science of Russian Federation (11.G34.31.0004).

1 Luxenhofer, R., et al. Biomaterials, 31(18):4972-9 (2010).
2 Batrakova, E.V., et al. J. Control. Release 143(3):290-301 (2010).
3 Valle, J.W., et al. Invest. New Drugs, published online Feb. 24 (2010).
4 Klyachko, N., et. al. Nanomedicine: Nanotechnology, Biology and Medicine. 8(1):119-29 (2012).
5 Sahay, G., et al. Biomaterials 31(5):923-33 (2010).
6 Klyachko, N., Sokolsky-Papkov, M., et al. Angew. Chem. accepted (2012).

Sponsored by: Center for Cancer Nanotechnology Excellence and Translation - NIH/NCI U54 (MIPS);

Host: Director, Sanjiv Sam Gambhir, MD, PhD (sgambhir@stanford.edu)

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