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Cancer Nanotheranostics

Xiaoyuan (Shawn) Chen, PhD, Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD

Thursday, October 19, 2017, 12:00 PM Eppley Science Hall (ESH 3010)

Theranostics (Rx/Dx) aims to develop molecular diagnostic tests and targeted therapeutics with the goals of individualizing treatment by targeting therapy to an individual's specific disease subtype and genetic profile. It can be diagnosis followed by therapy to stratify patients who will likely respond to a given treatment; it can also be therapy followed by diagnosis to monitor early response to treatment and predict treatment efficacy; it is also possible that diagnostics and therapeutics are co-developed (nanotheranostics). This talk will give examples of optotheranostics, magnetotheranostics and immunotheranostics. The translational potential of Nanotheranostics will also be briefly discussed.

Personalized Tumor-homing Stem Cell Therapies for Cancer

Shawn Hingtgen, PhD, Assistant Professor, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill

Friday, March 31, 2017, 12:00 PM Center for Drug Discovery and Lozier Center for Pharmacy (PDD 1002)

 

Zwitterionic Materials in Nanomedicine

Shaoyi Jiang, PhD, Boeing-Roundhill Professor of Chemical Engineering & Adjunct Professor of Bioengineering, University of Washington, Seattle, WA

Thursday, March 16, 2017, 1:00 PM Eppley Science Hall (ESH 3010)

An important challenge in many applications is the prevention of nonspecific biomolecular and microorganism attachment on surfaces. To address this challenge, our goals are twofold. First, we strive to provide a fundamental understanding of nonfouling mechanisms at the molecular level. Second, we aim to develop biocompatible ultra low fouling materials based on the molecular principles learned. As a result, we have shown that zwitterionic and mixed charge materials and surfaces are highly resistant to nonspecific protein adsorption, cell adhesion and bacteria adhesion/biofilm formation from complex media.

Zwitterionic-based polymers have now been used widely as nonfouling materials. Unlike poly(ethylene glycol) (PEG), there exist diversified zwitterionic molecular structures to accommodate various properties and applications. Furthermore, zwitterionic materials are superhydrophilic while their PEG counterparts are amphiphilic. In this talk, how zwitterionic materials stabilize nanoparticles (e.g., gold, ion oxide and quantum dot) and how zwitterionic polymer-PLGA copolymers and zwitterionic polymer-lipids form stable micelles and liposomes in complex media will be presented. Zwitterionic polymer conjugation and encapsulation of therapeutic enzymes (e.g., uricase for gout treatment) and protective enzymes (e.g., enzyme hydrolyzing organophosphates for nerve agent prophylaxis) will be further demonstrated for maintained bioactivity, prolonged circulation and minimized immunological response.

Antibody Drug Conjugates – From Early Stage Research to a Clinically Approved Drug

Peter Senter, PhD, Vice President, Chemistry and Senior Distinguished Fellow, Seattle Genetics, Inc.

Friday, January 13, 2017, 12:00 P.M., Michael F. Sorrell Center (MSC room 1005)

Monoclonal antibodies (mAbs) have played a major role in cancer medicine, with active drugs such as trastuzumab (Herceptin), cetuximab (Erbitux), bevacizumab (Avastin) and rituximab (Rituxan) in a wide range of therapeutic applications. The mechanisms of these agents involve such activities as direct signaling, interactions with Fcg receptors on effector cells, and complement fixation. Several approaches have been explored to improve antibody-based therapies for cancer treatment by optimizing such activities and by conscripting their selectivity profiles for the delivery of high potency cytotoxic drugs. The field has advanced significantly in the past few years, with the approval of Adcetris (brentuximab vedotin) for the treatment of relapsed Hodgkin and anaplastic large cell lymphomas. The drug is comprised of a potent antimitotic agent, monomethyl auristatin E (MMAE), conjugated to an anti-CD30 mAb through a lysosomally cleavable dipeptide linker. The inspiration behind the ADC cytotoxic component came from the marine natural product, dolastatin 10. This presentation will describe the discovery and development of Adcetris, and will overview advancements in the field of ADCs for cancer therapy.

 

Nanoparticle Delivery of Drugs and Genes to Desmoplastic Tumors

Leaf Huang, PhD, Fred Eshelman Distinguished Professor, Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapell Hill

Friday, September 23, 2016, 12:00 p.m., Michael F. Sorrell Center (MSC room 2010)

A desmoplastic tumor, such as pancreatic and bladder cancers, is enriched with fibrous stroma structure with tumor cells growing in clusters called tumor nests. Due to the extensive stroma structure and the presence of the tumor vessels in the stroma and the high interstitial fluid pressure, drug delivery to this type of tumor is very difficult. Using a large (> 300 mm3) bladder cancer model, we have shown that cells in the tumor that take up IV injected nanoparticles are mostly tumor associated fibroblasts (TAFs) and little is taken up by the tumor cells. This is especially the case when the NPs are targeted with the anisamide ligand. It turns out that TAFs, similar to the tumor cells, over-express the sigma receptor to which anisamide binds. Thus, the strong uptake by TAFs forms a delivery barrier preventing NPs from accessing the tumor cells in the nests. This is called a “binding site barrier”. Off-target uptake of cisplatin NPs by TAFs also induces the secretion of Wnt16, a survival factor for the tumor cells, resulting in drug resistance of the tumor. siRNA against Wnt16 can be co-delivered with cisplatin to inhibit Wnt16 production and enhance the tumor growth inhibition. To turn the delivery problem into an opportunity, we have delivered to TAFs a plasmid DNA encoding the secretory TRAIL (sTRAIL) using LPD NPs. sTRAIL produced by TAFs diffuses a short distance to the tumor nests and kills the tumor cells. sTRAIL gene therapy also results in a significant reduction of the desmoplasia of the tumor which facilitates a second wave delivery of cisplatin NPs. This can be a new strategy in the therapy for desmoplastic tumors. Supported by NIH grants CA149387 and CA198999.

Biomedical Nanotechnology: New Opportunities for Image-Guided Cancer Therapy and Surgery

Shuming Nie, PhD, Professor and Wallace H. Coulter Distinguished Faculty Chair in Biomedical Engineering, Emory University and the Georgia Institute of Technology

Thursday, April 21, 2016, 1:00 p.m., Eppley Science Halll (ESH room 3010)

Nanotechnology is an area of considerable current interest in biomedical engineering because of its broad applications in biomedical imaging, in-vitro diagnostics, and targeted therapy. The basic rationale is that nanometer-sized particles such as quantum dots, colloidal gold, and polymeric nanomicelles have functional and structural properties that are not available from either discrete molecules or bulk materials. When conjugated with targeting ligands such as monoclonal antibodies, peptides or small molecules, these nanoparticles can be used to target malignant tumor cells and the tumor microenvironment (such as tumor stroma and tumor vasculatures) with high specificity and affinity. In the “mesoscopic” size range of 10-100 nm, nanoparticles also have large surface areas for conjugating to multiple diagnostic and therapeutic agents, opening new possibilities in imaging, therapy, and surgery.  At the present, however, there are several fundamental problems and technical barriers that must be understood and overcome. In this talk, I will discuss the major challenges and opportunities in the development of nanomedicine for intraoperative cancer detection, molecular diagnostics, and image-guided surgery. This work was supported by grants from the US National Institutes of Health (U54 CA119338, RC2 CA148265, and R01CA163256).

Immunological Properties of Engineered Nanomaterials and Challenges in their Preclinical Characterization

Marina A. Dobrovolskaia, PhD, Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research

Thursday, March 17, 2016, 1:00 p.m., Wittson Hall (WHM room 3034)

Nanomedicine is rapidly growing field. Many nanoformulations have been granted regulatory approval for use in medical applications, while many more are in various phases of preclinical and clinical development. This presentation will review data regarding nanoparticle-mediated immunological and hematological compatibility, which I will use to highlight common challenges in preclinical characterization of nanoparticles. Case studies demonstrating how manipulation of nanoparticle physicochemical properties can influence their interaction with components of the immune system will be discussed. The presentation will focus on areas such as effects on blood coagulation system, activation of complement and effects on immune cell function. I will discuss nuances and challenges associated with preclinical immunological characterization of engineered nanomaterials. Specifically, I will focus on endotoxin detection and quantification, pyrogenicity testing nanoparticle depyrogenation, sterility and sterilization, nanoparticle interference with traditional immunological tests, and applicability of traditional in vivo immune function tests to engineered nanomaterials. I will also present case studies demonstrating the significance of comprehensive physicochemical characterization of engineered nanomaterials prior to their toxicological evaluation as well as correlation between toxicological in vitro assays and relevant in vivo tests. 

At the Nanotechnology Characterization Laboratory  Dr. Dobrovolskaia directs characterization related to a nanomaterials' interaction with components of the immune system. She monitors acute/adverse effects of nanoparticles as they relate to the immune system, both in vitro and in animal models. Dr. Dobrovolskaia is also responsible for the development, validation and performance qualification of in vitro and ex vivo assays to support preclinical characterization of nanoparticles, and for monitoring nanoparticle purity from biological contaminants such as bacteria, yeast, mold and endotoxin. Additionally, she leads structure activity relationship studies aimed at identifying the relationship between nanoparticle physicochemical properties and their interaction with macrophages, components of the blood coagulation cascade, and complement systems.

Plasmid DNA Delivery with Electrotransfer and Potential Translational Applications

Richard Heller, PhD,  Frank Reidy Research Center for Bioelectics Professor and Eminent Scholar, School of Medical Diagnostics and Translational Sciences, Old Dominion University

Thursday, January 21, 2016, 11:00 a.m., DRC Auditorium (DRC1 room 1002)

Development of Sn-2 Lipase Labile Prodrugs for Targeted Nanotherapy

Gregory Lanza, MD, PhD, FACC,  Professor of Medicine, Biomedical Engineering, and Biology and Biomedical Sciences, Cardiovascular Division, Washington University School of Medicine, St. Louis MO

Thursday, November 19, 2015, 11:00 a.m., DRC Auditorium (DRC1 room 1002)

Gregory M. Lanza1, Deepti Soodgupta1, Christine Pham1, Grace Cui1, Angana Senpan2, Xiaoxia Yang1, Michael H. Tomasson1, Dipanjan Pan2

1 Department of Medicine, Washington University Medical School, St. Louis, MO
2 Bioengineering and Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, IL


Dissolving lipid soluble drugs into phospholipid membranes or hydrophobic cores of lipid-based can produce relatively stable formulations based on in vitro dissolution testing but often in vivo, most of the drug is lost prematurely from the agent in circulation to the targeted tissue. We have reported a drug delivery approach, termed “contact facilitated drug delivery”, that utilizes nanoparticle lipid surfactant components to transfer therapeutic compounds to the targeted cell membrane through a hemifusion complexation. In effect, the CFDD mechanism allows lipid-encapsulated nanoparticles to deliver a “kiss of death” without the requisite cellular internalization and lysosomal drug escape commonly employed. Recent development of phospholipid Sn 2 prodrugs that stabilize and sequester the drug into the hydrophobic aspect of the outer lipid membrane of nanocolloids to prevent premature drug escape or metabolism during circulation to the target cell, despite the prevalence of lipase activity in plasma. Transfer of the monolayer components to the target cell membrane through CFDD, allows cytosolic phospholipases to enzymatically cleave the Sn 2 ester and liberate the active drug into the cell.  

            Sn-2 lipase labile prodrugs have been successfully developed and demonstrated in vivo for fumagillin (antiangiogenic compound), docetaxel (a microtubule inhibitor), and a novel cMyc-transcription factor inhibitor, for liquid and solid cancers and rheumatoid arthritis.  This presentation will introduce this concept through these application highlights then focus specifically on the development and delivery of a VLA-4-targeted Sn 2 lipase-labile Myc-inhibitor nanotherapy as an illustrative example in metastatic multiple myeloma.

            Briefly, a novel Sn 2 phosphatidylcholine-cMyc-Max antagonist prodrug (M1-PD) was designed, synthesized, characterized and evaluated in vitro and in vivo. In vitro, titrated free M1-PD was compared to free Myc-antagonist in human MM cell lines (H929 and U266) and mouse MM (5TGM1). M1-PD was incorporated into two lipid-based nanoparticle genera (<20nm and ~200nm) that were functionalized for MM targeting using a peptidomimetic VLA-4-lipid ligand. The nanoparticles were physico-chemically characterized and evaluated for their relative pharmacokinetics in vivo.  Effectiveness of the two VLA-4-targeted M1-PD nanotherapies were evaluated in MM cell cultures, correlated with VLA-4 expression levels, and then studied in C57BL/KaLwRij mice with metastatic 5TGM1.  

            Bioactivity of free M1-PD was several orders magnitude more potent that the free cMyc antagonist in cell culture. Binding and efficacy of M1-PD nanoparticles correlated with integrin expression in target cells. VLA-4-M1-PD nanoparticles (<20nm and ~200nm) equivalently inhibited MM cell growth in vitro compared to controls. In C57BL/KaLwRij mice with metastatic 5TGM1, VLA-4-MI1-PD 20nm micelles conferred significant survival benefit (T/D) over the 20nm targeted no drug (T/ND) or untreated controls (NT/ND) (52 days vs. 29 days, p=0.001) and versus the 200nm VLA-4-MI1-PD nanocolloid and its controls.

            Collectively, these findings support the feasibility and broad potential of Sn 2 lipase labile lipid prodrugs for the CFDD of potent targeted nanotherapeutics, such as in the recent example of a VLA-4-directed cMyc prodrug to disrupt MYC-MAX dimerization and improve MM survival.

Antibiotic-Eluting Devices to Address Implant Infections

Dr. David W. Grainger,  University Distinguished Professor, Department Chair, and Inaugural George S. & Dolores Doré Eccles Presidential Endowed Chair of Pharmaceuticals and Phamaceutical Chemistry, and Professor of Bioengineering Health Sciences, University of Utah

Friday September 4, 2015, 11:00 a.m., Michael Sorrell Center Room 2018

Increasing numbers of medical devices now available for clinical implant use, often in aging populations and increasingly in developing countries, have become a significant health care issue due to enhanced infection incidence intrinsically related to implanted medical devices.  These devices are also implanted against a background of increasing antibiotic-resistant bacterial populations. Progressively more antibiotic-resistant infections, requiring ever more refined treatment options, are therefore predicted to emerge with greater frequency. Improvements in the prevention, diagnosis and treatment of these device-associated infections will remain priority targets both for clinicians and the translational research community charged with addressing these challenges.

Improved methods are required to assess infections and to implement new technologies that reduce implant-associated infections. A classic problem is lack of in vitro-in vivo correlation, validation or efficacy for any given method or approach.  A second issue is the lack of commercial enthusiasm to take any approach forward in a regulatory pathway toward clinical use.  This presentation will review antimicrobial experimental designs, approaches to endowing medical devices with antimicrobial properties, including on-board antibiotic-releasing depots and some examples of device translation in vivo.

 References:

  1. Busscher, et al., Sci. Transl. Med. 4, 153rv10 (2012).
  2. Grainger et al., Biomaterials, 2013 34(37):9237-43.
  3. Moriarty et al.,  Eur. Cells Mater. 28 112-128 (2014).
  4. Brooks, et al., in ‪Biomaterials Associated Infection: Immunological Aspects and Antimicrobial Strategies, T. F. Moriarty, S.A.J. Zaat, H. Busscher, eds., Springer, New York, 2012, pp. 307-354; ISBN 978-1-4614-1030-0.
  5. Wu and Grainger, Biomaterials, 27(11):2450-67 (2006).
  6. Brooks et al. Drug Deliv. Transl. Res., (2013) 3(6):518530;
  7. Brooks et al., J. Biomed. Mat. Res. B (Appl. Biomaterials), 2013 102(5):1074-83.
  8. Brooks et al., PLoS One, 2015 27;10(3):e0118696.
  9. Sinclair et al., J. Biomed. Mat. Res. B (Appl. Biomaterials), 2015, in press.
Cell-Based Strategies in Cancer Therapy

Dr. Stefan H. Bossmann,  Professor, Department of Chemistry, Kansas State University

February 6, 2015, 12;00 p.m., Michael Sorrell Center Room 2018

The two major roadblocks to developing truly effective drugs against cancer and infectious diseases consist in effectively targeting the sites of the diseases, and in overcoming physiologic barriers to drug delivery. Chemoherapy relies on systemic administration of the drugs. Consequently, in classic chemotherapy, less than five percent of small molecule drugs reach their target. Nanotherapeutic delivery is capable of increasing this percentage to approx. 10 to 20 percent.  This means tha 80-90 percent of nanoscopic drug formulations are either effectively cleared by the reticuloendothelial system or will cause collaeral damage.  Cell-based delivery strategies will be a potential game changer, because they are capable of transporting more than 50 percent of virtually any drug to its intended target. We are developing cell-based strategies for targeted drug delivery and immune stimulation in cancer therapy.  Three recent approaches will be discussed:

  • Cell-Based Cancer Imaging and Photodynamic Therapy
  • Cell-Based A/C-Hyperthermia
  • Design of Peptide Nanovesicles for Rapid Uptake by Defensive Cells
Opening the Intracellular Target Universe to Biologic Drugs

Patrick S. Stayton, Ph.D.,  Washington Research Foundation Professor, Department of Bioengineering, University of Washington

October 16, 2014, 11;00 a.m., Eppley Science Hall Room 3010

Synthetic polymeric delivery systems for protein and nucleic acid drugs have been developed that mimic the highly efficient intracellular delivery systems found in pathogenic viruses and organisms. The carriers possess a hidden functionality that is expressed in the endosomal compartment to increase cytosolic delivery of macromolecules. The ampholytic carriers are designed like these pathogens to activate via protonation events triggered in the endosome. This endosomal-releasing activity is then built into a multi-functional polymer platform that incorporates targeting elements, conjugation or complexation elements, and a "stealth" component to optimize safety and pharmaco-kinetic properties. These drug delivery systems have been applied to protein therapeutics in cancer immune-therapy and RNA/DNA nucleic acid drug development.

Tumor-Targeted Nanotherapeutics

Tamara Minko, Ph.D., Distinguished Professor and Chair, Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey

September 18, 2014,  11:00 am, Michael Sorrell Center, Room 2018

Several different targeted nanocarriers for intracellular delivery of anticancer drugs, nucleic acids and peptides were developed and characterized in vitro and in vivo. Linear polymers with branched spacers, PAMAM and PPI dendrimers, liposomes, nanostructured lipid, silica mesoporous, Janus and SPIO nanoparticles were used as carriers for nanoscale delivery systems. Modified synthetic decapeptide analog of luteinizing hormone release hormone (LHRH) was served as a targeting moiety for tumor specific delivery. Doxorubicin, paclitaxel, cisplatin and camptothecin were employed as anticancer drugs/apoptosis inducers. A synthetic analog of BCL2 homology 3 (BH3) domain peptide, P-ethoxy-modified antisense oligonucleotides (ASO) and siRNA targeted to MDR1, MRP, CD44 and BCL2 mRNA were used to enhance antitumor activity of the drugs by the suppression of pump and nonpump resistance in cancer cells. The work was supported by R01CA138533, R01CA111766, R01CA100098 grants from NIH.

Putting Nanomaterials to Work for Biomedical Research

Younan Xia, Ph.D., Professor, Brock Family Chair, Georgia Research Alliance Eminent Scholar in Nanomedicine, Department of Biomedical Engineering, Georgia Institute of Technology
April 17, 2014

Molecular Imaging of enzymatic activity in inflammation

Alexei Bogdanov, Ph.D., Dr. S., Professor, Department of Radiology, University of Massachusetts Medical School
January 17, 2014

The seminar will include a review of current molecular imaging techniques and sensors designed  for imaging local cell activation and inflammatory response in vivo. These sensors include various classes of molecules that change imaging characteristics in the presence of the inflammation-associated targets.  We will give examples of the applications of such imaging sensors in imaging animal models of human disease and molecular target validation using time-resolved optical and magnetic resonance imaging in vivo.

Phage Panning, Peptides and Polymers: From ligand identification to in vivo applications for drug delivery

Suzie Pun, Ph.D., Robert J. Rushmer Associate Professor of Bioengineering, University of Washington
October 17, 2013,  11:00 am, Eppley Science Hall Room 3010

We have recently synthesized brush-shaped, peptide-based copolymers by RAFT polymerization of peptide monomers with HPMA.  These materials possess the biological functions contributed by their peptide components with the scalable synthesis of synthetic polymers.   In this presentation, I will summarize our work in bioactive peptide identification, synthesis of peptide-based polymers, and applications of these materials for drug delivery.   In one example, we use a cell-based phage screening method to identify a peptide that preferentially binds to “anti-inflammatory” (M2) macrophage.  We further demonstrate that this peptide recognizes tumor-associated, M2-like macrophage, and that the peptide can be used for drug delivery to these cells.  In a second example, we synthesize multifunctional materials for neuron-targeted delivery of nucleic acids.  These peptide-based copolymers contain motifs for nucleic acid packaging, neuron targeting, and endosomal release.  We also synthesized enzymatically-cleavable polymers using peptide monomers containing cathepsin B-cleavable sequences.  The polymers were tested in vitro by reporter gene delivery to neuron-like, differentiated PC-12 cells and by direct, intraventricular injection in mice. 

Targeting Tumor Microenvironment for Cancer MR Molecular Imaging

Zheng-Rong Lu, Ph.D., M. Frank Rudy and Margaret Domiter Rudy Professor of Biomedical Engineering, Department of Biomedical Engineering, Case Western Reserve University
April 18, 2013, 11:00 am, DRC I, Room 1002

Tumor microenvironment plays a critical role in cancer angiogenesis, proliferation and metastasis.  The unique tumor microenvironment is comprised of various cancer-related biomarkers, which are generally absent in normal tissues.  Molecular imaging of the biomarkers in tumor microenvironment can provide accurate earlier detection and diagnosis of malignant tumors and non-invasive evaluation of anticancer therapeutic efficacy.  Magnetic resonance imaging (MRI) is a powerful clinical imaging modality with high spatial resolution and no ionization radiation.  MRI provides both anatomical and physiological information of soft tissues.  Contrast enhanced MRI can produce high-resolution image contrast between diseased tissue and normal tissue and can measure the physiological properties of tumor tissue.  We have designed and developed peptide targeted MRI contrast agents for detecting a cancer-related biomarker expressed in the extracellular matrix of malignant tumors, and polydisulfide-based biodegradable macromolecular MRI contrast agents for evaluating tumor angiogenesis and the efficacy of cancer therapies.  The effectiveness of these novel MRI contrast agents has been validated in animal tumor models.  The targeted contrast agents specifically bind to the biomarker in tumor extracellular matrix, resulting in strong and prolonged contrast enhancement in the tumor tissue, not in normal tissues.  The biodegradable macromolecular contrast agents are effective for characterizing tumor angiogenesis and non-invasive evaluation of tumor response to cancer therapies, including angiogenesis therapy, with DCE-MRI.

Roles of Chemoresistance, Cancer Stem Cells and miRNA in treating Cancer using Polymeric Nanomedicines

Ram I. Mahato, PhD, Professor, University of Tennessee Health Science Center
April 19, 2012, 11:00 am, DRC I Room 1002

Most cancers relapse due to chemoresistance rendering chemotherapy ineffective. Combination therapy using biodegradable copolymeric systems may treat advanced cancers. In this presentation, I will discuss the role of miRNAs and hedgehog pathway in chemoresistant prostate and pancreatic cancer. Roles of miRNA and cancer stem cells on chemoresistance and the combination therapy to overcome these obstacles will be discussed. I will also discuss why our novel biodegradable copolymers can be used for delivery and targeting.  

Polymeric prodrugs for nucleic acid delivery

David Oupicky, Ph.D., Associate Professor, Director of Graduate Studies, Department of Pharmaceutical Science, Wayne State University
January 30, 2012, 11:00 am, Eplley Science Amphitheater Hall Room 3010

(joint seminar with Department of Pharmaceutical Sciences, College of Pharmacy)

Nonviral gene delivery vectors based on DNA complexes with synthetic polycations (polyplexes) show promise for cancer gene therapy but they often cause adverse toxic effects and show poor therapeutic response due to low transfection activity. To help address the toxicity and low transfection activity, we have investigated new approaches to the design of polycations for gene delivery. The traditional design paradigm aims to synthesize biodegradable polycations that are degraded into safe low-molecular-weight byproducts to overcome the adverse toxicity. Our alternative approach to this traditional paradigm has been to synthesize biodegradable polycations that either degrade into active pharmacologic agents or function as pharmacologic agents themselves prior to biodegradation. This approach not only reduces toxicity of the polycations but it also enhances activity of the polyplexes when combined with properly selected therapeutic genes. Such combination approaches have the potential to greatly enhance the efficacy of non-viral gene therapy by the possibility to overcome low transfection by targeting multiple disease pathways. I will describe progress made towards development of non-viral gene delivery vectors based on (1) polycationic prodrugs targeting dysregulated polyamine metabolism in cancer and (2) polycationic cyclam-based antagonists of CXCR4, a chemokine receptor involved in cancer metastasis.

NON-ATTRITION NANOPARTICLE DISPERSIONS FOR ORAL DELIVERY OF ANTIRETROVIRAL DRUGS

Andrew Owen, Ph.D.,Senior Lecturer, Department of Pharmacology and Therapeutics, University of Liverpool, UK.
June 16, 2011, 11:00 a.m., Eppley Science Amphitheater, ESH 3010

(joint seminar with Department of Pharmaceutical Sciences, College of Pharmacy)

There are many potential benefits associated with nanoformulation of drugs, which include increased dissolution kinetics, increased bioavailability, slow release and reduced dose. For the pharmaceutical industry, poor solubility is a growing issue spanning both new chemical entities and existing therapies. Nanoformulation may alter pharmacokinetics and pharmacodynamics of therapies and confer favorable properties to antiretroviral drugs such as the ability to target sanctuary sites. However, for the same reasons, they must be fully evaluated to ensure safety. Regulatory agencies agree that there is currently a deficit in adequate safety data for nanoparticles. This presentation will discuss how particle properties such as size and zeta potential impact upon biological properties such as cytotoxicity, cellular permeability and activity. Recent pre-clinical data generated at Liverpool will be presented. Nanomedicine is entering an exciting era in which the physicochemical properties of nanoparticles and how they relate to pharmacological properties are being explored. There may be potentially negative properties of nanoparticles but with careful scientific study the potential benefits are likely to be great.

Polymeric Micelles for Multiple Drug Delivery

Glen S. Kwon, Ph.D., Professor, Pharmaceutical Sciences Division, School of Pharmacy,University of Wisconsin

May 19, 2011, 11:00 a.m., Eppley Science Amphitheater, ESH Room 3010

Polymeric micelles have attracted a lot attention in drug delivery due to proven safety and rapid progress in drug solubilization, especially in the cancer area. Poly(ethylene glycol)-block-poly(lactic acid) (PEG-b-PLA) micelles have entered phase II clinical trials in the USA and have gained approval in Korea as a vehicle for paclitaxel (Genexol-PM®), offering a safer vehicle for this poorly water-soluble cancer drug over Cremophor EL (Taxol®). In this work, we show that PEG-b-PLA micelles can take up and solubilize multiple cancer drugs: paclitaxel, 17-allylamino-17-desmethoxygeldanamycin (17-AAG) and rapamycin in aqueous solution. 2- and 3-drug combinations of paclitaxel, 17-AAG and rapamycin enabled by PEG-b-PLA micelles exert synergistic cytotoxicity against A549 non-small lung and MCF-7 breast cancer cells, possibly by co-targeting complementary survival signaling pathways. Thus, PEG-b-PLA micelles offer a simple, safe, soluble and sterile option for the multiple drug delivery of paclitaxel, 17-AAG and rapamycin, aiming for synergy in cancer therapy.

Use of High Throughput Discovery at the Nano/Bio Interface to Improve Nanotherapeutics and Nanosafety

Andre Nel, M.D., Ph.D., Professor of Medicine, Chief, Division of NanoMedicine,Director of the UC Center for the Environmental Impact of Nanotechnology, University of California, Los Angeles

October 27, 2011, 12:15 p.m., Eppley Science Hall Amphitheater, Room 3010

In both the design of safe and improved nanocarrier systems for delivery of drugs as well as safety assessment of commercial nanoparticles such as metals, metal oxides and carbon nanotubes, it is required that we understand how the physicochemical characteristics of the engineered nanomaterials relate to biological responses such as cellular uptake, biodistribution, bioavailability and the catalysis of potentially useful or hazardous biological responses the nano/bio interface. While this is a potentially rewarding platform for discovery, the number of perturbations at the nano-bio interface are potentially overwhelming and require the use of high content and high throughput screening approaches to do some modeling. My talk will delineate the implementation of high throughput methodology for cells and zebrafish and describe how the systems can be used for the safety assessment of nanomaterials in general as well as the improvement of nanoparticles that can be used for drug and siRNA delivery. I will describe how the use of compositional and combinatorial nanomaterial libraries are being used to elucidate the material properties that drive biological injury response pathways as well as how to use a multifunctional mesoporous silica nanoparticle drug delivery system to improve safety, biodistribution and therapeutic efficacy through redesign of size, shape, and surface functionalization. I will also show how in silica data transformation and decision-making tools can help to speed up the rate of discovery.

Approaches for enhancing the delivery of bioactives to solid tumors: Does definition at the nanoscale matter?

Hamid Ghandehari, Ph.D., USTAR Professor, Departments of Pharmaceutics & Pharmaceutical Chemistry and Bioengineering, Co-director, Nano Institute of Utah, Director, Utah Center for Nanomedicine, The University of Utah
November 15, 2012, 11:00 a.m.,  DRC I, Room 1002

Advances in materials science and nanotechnology have created the opportunity to design constructs with a higher degree of definition at the nanoscale. Such definition can be exploited for rational drug delivery. In this talk two such systems will be presented. First, efforts in the utility of plasmonic photothermal therapy mediated by gold nanorods for enhanced delivery of polymer therapeutics to solid tumors will be discussed. Second the use of recombinant silk-elastinlike hydrogels for localized gene delivery will be presented.

KNOCKING AT THE BACK DOOR: INTRACELLULAR TARGETING OF NANOCARRIERS ANCHORED TO NON-ENDOCYTIC ENDOTHELIAL MOLECULES

Vladimir R. Muzykantov, M.D., Ph.D., Professor of Pharmacology and Medicine, and Director of Targeted Therapeutics Program, School of Medicine, University of Pennsylvania
May 19, 2010, 9:00 a.m., CDDN/COBRE Retreat, Lied Lodge, Nebraska City, NE

Intracellular delivery is needed to achieve therapeutic effects of many drugs, especially specific and labile biotherapeutics such as enzymes and genetic materials. Different cell types exert distinct repertoire of internalization mechanisms involving formation of vesicles on the intracellular side of the plasmalemma. Drug delivery nanodevices may employ either passive (i.e., using fluid phase uptake via constitutive plasmalemma recycling) or active (i.e., using receptor-mediated endocytosis or phagocytosis) entries into intracellular vesicles. The itinerary of subsequent intracellular trafficking and ultimate sub-cellular destination, effect and fate of delivered cargoes depend on both biological characteristics of the employed internalization pathway and design of a delivery system. In most cases, nanodevices targeted to receptors involved in a specific endocytic pathway enter cells via such a pathway, but this is not always the case. For example, endothelial cells do not internalize antibodies to Ig-superfamily cell adhesion molecules ICAM-1 and PECAM-1, but very effectively internalize supramolecular conjugates of these antibodies and nanodevices targeted to ICAM and PECAM. Mechanism of internalization differs from known classical endocytic, pinocytosis and phagocytic pathways, permits intracellular delivery of carriers ranging from 50 nm to 5-10 micron and provides intracellular effects of delivered enzymes and other cargoes in cell cultures and animals. Modifications of nanocarrier size, shape and affinity to specific epitopes on cell adhesion molecules further modulate the rate of internalization and sub-cellular destination of carriers and their cargoes. Therefore, cell surface molecules that are not involved in natural internalization processes can be used for intracellular delivery. Utilization of such “non-physiological” mechanisms and fine-tuning of design parameters of delivery systems offer novel approaches for sub-cellular addressing of drugs.

Nanoimaging for protein misfolding diseases

Yuri Lyubchenko, Ph.D., D.Sc, Professor, Department of Pharmaceutical Sciences, University of Nebraska Medical Center
September 16, 2010, 11:00 am, Eppley Science Hall Amphitheater, Room 3010

Misfolding and aggregation of proteins are widespread phenomena leading to the development of numerous neurodegenerative disorders such as Parkinson’s, Alzheimer’s, and Huntington’s diseases. Each of these diseases is linked to structural misfolding and aggregation of a particular protein. The aggregated forms of the protein induce the development of a particular disease at all levels, leading to neuronal dysfunction and loss. Since protein refolding is frequently accompanied by transient association of partially folded intermediates, the propensity to aggregate is considered a general characteristic of the majority of proteins. X-ray crystallography, NMR, electron microscopy, and AFM have provided important information on the structure of aggregates. However, fundamental questions, such as why the misfolded conformation of the protein is formed, and why this state is important for self-assembly, remain unanswered. Although it is well known that the same protein under pathological conditions can lead to the formation of aggregates with diverse biological consequences, the conditions leading to misfolding and the formation of the disease prone complexes are unclear, complicating any development of efficient prevention of the diseases. Misfolded states exist transiently, so answering these questions requires the use of novel approaches and methods. Progress has been made during the past few years, when recently developed single molecule biophysics techniques were applied to the problem of the protein misfolding. In this talk, I review impacts of nanoimaging studies on understanding of mechanisms of the protein self-assembly into aggregates and outline the prospects for the development of treatments of AD, PD and other neurodegenerative diseases.

Protein Radiohalogenation Chemisty and its Impact on Targeted Radiotherapy

Michael R. Zalutsky, Ph.D., Jonathan Spicehandler M.D. Professor of Neuro-Oncology, Professor of Radiology, Radiation Oncology and Biomedical Engineering, Duke University Medical Center
January 20, 2011, 11:00 am, Eppley Science Hall Amphitheater, Room 3010

Targeted radiotherapy utilizes a vector such as a monoclonal antibody (MAb) to selectively deliver a radionuclide to malignant cell populations.  The central hypothesis of our laboratory has been that novel radiochemistry strategies are the foundation for the development of more specific and potent labeled compounds for the treatment of cancer and other diseases.  Two approaches will be discussed – labeling strategies that maximize retention of the label in tumor cells after receptor binding and alpha-particle emitting radionuclides that not only are more cytotoxic but also more focal in their effects.  The presentation will briefly describe radiochemical studies; however, it will primarily focus on the effect of these radiochemistry approaches on the molecular recognition properties of the labeled molecule, its cytotoxic potential, pharmacokinetics and metabolism, and clinical potential for the treatment of brain tumors.

Advantages of Nanoparticles in Developing Tumor-Imaging and Phototherapeutic Agents

Ravindra Pandey, Ph.D., Professor and Distinguished Member, Cellular Stress Biology, Roswell Park Cancer Institute, Buffalo
April 15, 2010, 11:00 am, Eppley Science Hall Amphitheater, Room 3010

Nanotechnology provides an opportunity to develop "multifunctional agents" for tumor detection and therapy, which is otherwise difficult to achieve. It is easier and more effective to change the overall lipophilicity of the nanovectors and introduce the desired targeting moiety at the surface of the nanoparticles than to change the individual molecules responsible for imaging and therapy. The encouraging preliminary results obtained by using certain nanoparticles will be presented.

From Inorganic Proteins, to Neuroprosthetic Implants, and 3D Tissue Models

Nicholas Kotov, Ph.D., Professor, Chemical Engineering Department, University of Michigan, Ann Arbor
October 21, 2010, 11:00 am, Eppley Science Hall Amphitheater, Room 3010

In this talk I will give an overview of nanobiotechnology efforts in my group advancing along three basic directions
1. Replication of protein functions by inorganic nanoparticles;
2. Engineering of materials with critical combination of properties for  application as neuroprosthetic devices;
3. Development of 3D tissue models using inverted colloidal crystal scaffolds

Direction 1: Over the period of last decade we demonstrated that complex 1D, 2D, and even 3D systems form from nanoparticles by spontaneous assembly in aqueous media.  When strongly anisotropic interactions are present, self-assembly phenomena occur with particles with wide size distribution and in mild conditions (Fig. 1). The comparison of the processes in solution of CdTe, CdS, Au, ZnO, and other nanocolloids reveals surprising complexity of the produced structures and allow us to establish the basic approaches and rules how to control them.  From that, replication of other biological functions by NPs can be envisioned.

Direction 2:  Layer-by-layer assembly (LBL) is a new technique for design and manufacturing of composite materials based on sequential adsorption of nanometer scale layers of polymers and inorganic colloids.  LBL is a universal method which provides unique uniformity and structural control to the resulting hybrid composites. This technique can resolve hard challenges of materials science related to mechanical, electrical, optical, and biological properties.  One of the most promising areas is the preparation of neural implants for stimulation of brain tissues. It will be demonstrated that the careful design of these materials lead to the combination of properties that are unavailable in other state-of-the-art materials used currently for neural implants. These properties include mechanical compliance, bio compatibility, low impedance, corrosion resistance, and charge injection capacity.  Other applications as smart fabrics/papers, energy storage, and energy conversion can also be discussed if time permits.  

Direction 3: On the basis of numerous experimental data it is clear that standard 2D tissue cultures on flat surfaces have a lot of limitations.   New approaches taking into account the organization of cells in 3D space must be developed.  Additionally, a combination of multiple characteristics is required in them which makes this task particularly challenging. In this part I will review the effort on the 3D tissue cultures in inverted colloidal crystal geometry.  Unlike many other 3D systems they are suitable for high-throughput screening and replication of complex tissues, such as bone marrow.  The function of several organs have been replicated in ICC scaffolds.  Special attention will be paid to evaluation of the toxicology of NPs in 3D replicas of liver tissue.

Relevant References.
1. Z. Tang, N. A. Kotov, M. Giersig, Science 2002, 297, 237-240.
2. Tang, Z.  Zhang, Z.; Wang Y.; Glotzer, S. C.  Kotov, N. A., Science, 2006,  314 (5797) 274-278.
3. J. Lee, A. O. Govorov, N. A. Kotov, Angew. Chem. Intern. Ed.  2005, 44, 7439-7442.
4. J. Lee, A. O. Govorov, N. A. Kotov, Nature Materials. 2007, 6(4),  291-295.
5. S. Srivastava,  A. Santos, K. Critchley,  K.-S. Kim, P. Podsiadlo,  K. Sun, J. Lee,  C.Xu, G. D.Lilly,  S. C. Glotzer, and N. A. Kotov, Science, 2010, 327, 1355 (2010); 1355-1359.
6. Podsiadlo P., Kaushik A. K., Arruda E. M., Waas A. M., Shim B. S., Xu J., Nandivada H., Pumplin B. G., Lahann J., Ramamoorthy A.,  Kotov N. A., , Science, 2007,318, 80-83;
7. N. A. Kotov, J. O. Winter, I. P. Clements, E. Jan, B. P. Timko, S. Campidelli, S. Pathak, A. Mazzatenta, C. M. Lieber, M. Prato, R.V. Bellamkonda, G. A. Silva, N. W. S. Kam, F. Patolsky, L. Ballerini,  Nanomaterials for Neural Interfaces, Advanced Materials, 2009, 21, 1–35

NANOTECHNOLOGY APPLICATIONS IN DISEASE DIAGNOSIS AND THERAPY

Mansoor M. Amiji, RPh, PhD, Distinguished Professor and Chair,  Department of Pharmaceutical Sciences, Co-Director, Nanomedicine Education and Research Consortium (NERC), Northeastern University
March 18, 2010, 11:00 am, Eppley Science Hall Amphitheater, Room 3010

 There has been tremendous recent interest in nanotechnology application for disease prevention, diagnosis, and treatment. For many diseases, such as cancer, early diagnosis and overcoming biological barriers and target specific delivery are the key challenges. Additionally, newer generation of molecular therapies, such as gene therapy oligonucleotides, and RNA interference, require robust and highly specific intracellular delivery strategies for effective therapeutic outcomes. In this presentation, I will provide an overview of our work over few years in nanotechnology for target specific delivery of drugs and genes. We have developed metal, polymer, and lipid-based nano-platforms for diagnosis and delivery of therapeutics and image contrast agents. Peptide-modified gold nanostructures were developed for early cancer detection. Using biodegradable polymers, we have formulated nanocarriers for systemic delivery of hydrophobic anticancer drugs and therapeutic genes. Additionally, we have developed nanoemulsions, using oils rich in omega-3 polyunsaturated fatty acids, which can facilitate drug delivery across different biological barriers, such as the blood-brain barrier.

PROBING DISEASE AT THE TISSUE, CELLULAR, AND MOLECULAR LEVEL WITH MAGNETIC NANOPARTICLES

Andrew Tsourkas, Ph.D., Department of Bioengineering, University of Pennyslvania
January 21, 2010, 1:00 pm, DRC I, Room 1004

The study of human health and disease at the molecular level has led to tremendous advancements in the development of therapeutics and clinical diagnostics.  It is now possible to distinguish between healthy and diseased states by patterns of gene expression, levels of enzymatic activity, and the structural makeup of tissue.  This knowledge is now being extended to aid in the design of novel probes that are capable of sensitively and specifically detecting diseased states in living subjects using readily available medical imaging platforms.  In this talk, I will discuss how magnetic resonance contrast agents are being used to identify various disease pathologies at the tissue, cellular, and molecular level.

Bioactive Nanostructures for Regenerative Medicine and Cancer Therapies

Samuel I. Stupp, Ph.D., Board of Trustees Professor of Materials Science, Chemistry, and Medicine, and Director, Institute for BioNanotechnology in Medicine, Northwestern University
May 21, 2009, 11 a.m., Eppley Science Hall Amphitheater, Room 3010

Bioactive nanostructures molecularly crafted to signal cells in vitro or in vivo have the potential to emerge as the elements of future therapies to regenerate tissues and cure disease.  The chemistry of such nanostructures should allow them to interact specifically with cell receptors or intracellular structures.  Ideally, they should also disintegrate into nutrients within an appropriate time frame.  The organization of these nanostructures at larger length scales comparable to cells and large colonies of cells will also be critical to their function.  Our laboratory has developed an extensive family of amphiphilic molecules that self-assemble into nanofiber architectures with capacity to display a large diversity of signals to cells (1-5).  This lecture will illustrate the use of nanoscale molecular features in these systems to regenerate axons in the central nervous system for spinal cord injuries and other brain disorders, bone, and blood vessels in cardiovascular therapies.  With the appropriate supramolecular design, these nanostructures could also be used as the functional elements in cancer and gene therapies.  The lecture will also demonstrate their future potential to create niches for stem cells in regenerative medicine as the nanostructures self-assemble across scales forming constructs with macroscopic dimensions.

References: (1) Science 2001, 294 (5527), 1684-1688; (2) Proc. Natl. Acad. Sci. USA 2002, 99 (8), 5133-5138; (3) Science 2004, 303, 1352-1355; (4) Nano Letters 2006, 6 (9), 2086-2090; (5) Biomaterials 2007, 28(31), 4608-4618.

Mini-robots: Use in Surgery

Dmitry Oleynikov, MD., Associate Professor of Surgery and Director of Education and Training for the Center for Minimally Invasive and Computer Assisted Surgery, College of Medicine, UNMC
January  9, 2009, 12:00 p.m., Sorell Center, Room 1005

(joint seminar with the Department of Pharmaceutical Sciences , College of Pharmacy)

Real-Time Imaging of Signal Transduction Pathways and Drug Action In Vivo

David Piwnica-Worms, M.D., Ph.D., Professor of Molecular Biology & Pharmacology and Director, Molecular Imaging Center, Washington University School of Medicine

March 19, 2009, 11: a.m., Eppley Science Hall Amphitheater, Room 3010

 

Genetically-encoded imaging reporters introduced into cells and transgenic animals enable noninvasive, longitudinal studies of dynamic biological processes in intact cells and living animals. This new set of molecular probes, detection technologies and imaging strategies, collectively termed “molecular imaging”, is providing biologists with exciting new opportunities to perform noninvasive and longitudinal studies of dynamic biological processes. When cloned into promoter/enhancer sequences or engineered into fusion proteins, imaging reporters enable fundamental processes such as transcriptional regulation, signal transduction cascades, protein-protein interactions, cell trafficking and targeted drug action to be temporally and spatially registered in vivo and may provide new insight into mechanisms of pharmacological activity within the contextual environment of the whole animal.

Nanomedicines that "Break the Mucus Barrier"

Justin Hanes, Ph.D., Professor of Chemical & Biomolecular Engineering, The Johns Hopkins University
September 17, 2009, 11:00 a.m., Eppley Science Hall Amphitheater, Room 3010

Targeted delivery can significantly improve drug effectiveness while reducing side effects by concentrating medicine at selected sites in the body.  However, drug and gene delivery to specific tissues is currently limited by a lack of suitable polymeric materials and inefficient nanoparticle transport within complex extra- and intracellular biological environments.  This talk will focus on our fundamental work to understand the mucus barrier, and how this knowledge has guided our synthesis of polymeric nanoparticulate drug carriers capable of overcoming it.  Applications to diseases that affect mucosal surfaces, such as the lungs and female reproductive tract, will be discussed.

Targeting paclitaxel to tumors: Preclinical studies of a novel nanoparticle delivery system

Stephen B. Howell, M.D., Professor of Medicine, University of California, San Diego and Moores UCSD Cancer Center
January 15, 2009, 11:00 a.m., Eppley Science Hall Amphitheater, Room 3010

Both polymers and nanoparticles can accumulate in tumors due to their altered vascular structure. The clinical success of Abraxane has demonstrated that directing paclitaxel to tumors using nanoparticles can enhance therapeutic efficacy. Nexil is a novel poly (L-glutamylglutamate) polymer that, when loaded with paclitaxel, spontaneously forms nanoparticles in aqueous environments. Preclinical pharmacology studies of Nexil demonstrate increased accumulation of paclitaxel in tumors. Efficacy studies demonstrate superiority to Abraxane in several different tumor models.

Gas-filled microbubbles: targeted contrast agents for molecular imaging and drug delivery

Alexander L. Klibanov, Ph.D., Associate Professor, Division of Cardiovascular Medicine and Department of Biomedical Engineering, University of Virginia
February 15, 2008, 12:00 p.m., Eppley Science Hall Amphitheater, Room 3010

(joint seminar with Pharmaceutical Sciences Graduate Program, College of Pharmacy)

Gas-filled microbubbles, contrast agents for ultrasound imaging, are prepared from insoluble perfluorocarbon gas and stabilized by polymers and lipids. These particles are fully biocompatible; after intravenous injection they stay within the vasculature. Targeting ligands (antibodies, peptides, polysaccharides) can be attached to the microbubble surface to achieve specific targeting. We have prepared microbubbles coated with antibodies against P-selectin or VCAM-1, as well as scVEGF-121 (for targeting to VEGF receptors) and polymeric Lewis x oligosaccharide derivatives that specifically bind to P- and E-selectin. In vitro, in a parallel plate flow chamber setting, microbubbles attached selectively and firmly to the surfaces coated with the receptors listed above. To achieve efficient targeting in fast-flow conditions (WSS >4 dyn/cm2), sialyl Lewis x provided best results, as compared with antibodies. In the TNF-induced murine hindlimb inflammation model, polymeric sialyl Lewis x microbubbles selectively and rapidly accumulated in the inflamed tissue, which was visualized by intravital microscopy and ultrasound imaging. In the apoE -/- mice on a high-cholesterol diet, microbubbles were successfully targeted and imaged by ultrasound in the vasculature, by using a combination of anti-VCAM-1 antibody and polymeric sialyl Lewis x  ligands attached to the microbubble surface for efficient targeting. In the subcutaneous MC38 murine colon carcinoma model, microbubbles targeted with sulfo Lewis x, anti-VCAM-1 antibody and scVEGF-121 (targeting markers of tumor angiogenesis) selectively accumulated and were detected in the tumor vasculature by ultrasound; control nontargeted microbubbles were flowing freely through the tumor vascular bed. Individual microbubbles were observed moving through the tumor vasculature, as a marker of tumor blood supply. Overall, targeted microbubbles are an excellent contrast agent for ultrasound molecular imaging of endothelial markers. Microbubbles in combination with ultrasound can also be applied for targeted/triggered drug delivery.

“Receptor-Targeted Imaging and Therapuetic Agents for Cancer and Autoimmune Diseases

Philip S. Low, Ph.D., Ralph C. Corley Distinguished Professor, Department of Chemistry, Purdue University
September 18, 2008, 11:00 a.m., TBA

Dr. Low has developed methods to target drugs specifically to pathologic cells, thereby avoiding collateral toxicity to healthy cells.  In the case of cancer, they have exploited up-regulation of the folate receptor on malignant cells to target the following pharmaceuticals to cancer tissues in vivo: i) chemotherapeutic agents, ii) protein toxins, iii) gene therapy vectors, iv) antisense oligonucleotides, v) radioimaging agents, vi) siRNAs, vii) liposomes with entrapped drugs, viii) radiotherapeutic agents, ix) immunotherapeutic agents, and x) enzyme constructs for prodrug therapy.  Related ligand-targeted drugs are currently being developed for imaging and therapy of rheumatoid arthritis, Crohn’s disease, atherosclerosis, lupus, osteoarthritis, diabetes, and multiple sclerosis.  Results from both preclinical and clinical studies will be presented.

SWELL GELS: FROM HYDROGEL IMPLANTS TO SELF-ASSEMBLED NANOMATERIALS AND NANOMEDICINES

Jindřich Kopeček, Ph.D., Distinguished Professor, Department of Pharmaceutics and Pharmaceutical Chemistry, Department of Bioengineering, University of Utah
October 16, 2008, 11:00 a.m.,TBA

Supramolecular biological structures are often constructed through self-assembly of natural polymeric building blocks.  In hybrid macromolecules, the interactions between biological parts are usually the driving force for self-assembly.  Rationally designed stimuli-responsive and reversible systems have a potential in drug delivery, tissue engineering, and other biomedical applications.

Engineered Drug Therapies Enabled by Fabrication Processes from the Electronics Industry

Joseph M. DeSimone, Ph.D., Chancellor’s Eminent Professor of Chemistry, University of North Carolina at Chapel Hill,  and William R. Kenan Jr. Distinguished Professor of Chemistry and Chemical Engineering, North Carolina State University
October 15, 2009, 11:00 a.m.,Eppley Science Hall Amphitheater, Room 3010

To translate promising molecular discoveries into benefits for patients, we are taking a pharmaco-engineering systems approach to develop the next generation of delivery systems with programmable multi-functional capability. A key strategy is to apply manufacturing technologies from the microelectronics industry to fabricate polymeric delivery systems that are capable of multiple functions.  A novel method for the fabrication of organic particles on the order of tens of nanometers to several microns will be described.  Our imprint lithographic technique called PRINT (Particle Replication In Non-wetting Templates), takes advantage of the unique properties of elastomeric molds comprised of a low surface energy perfluoropolyether network, allowing the production of monodisperse, shape-specific nanoparticles from an extensive array of organic precursors. 

Angiotensin II and ROS signaling in the brain: Autonomic regulation in heart failure

Irving H. Zucker, Ph.D., Theodore F. Hubbard Professor of Cardiovascular Research and Chairman, Department of Cellular and Integrative Physiology, UNMC
March 20, 2008, 11: 00 a.m., Eppley Science Hall Amphitheater, Room 3010

I will discuss recent data that implicates angiotensin II as an important mediator of augmented sympathetic outflow in the setting of chronic heart failure. Data on alterations in angiotensin II receptors and the production of superoxide anion in discrete areas of the medulla and hypothalamus will be discussed. The role of nitric oxide as a modulator of sympathetic outflow will also be discussed. Finally, the effects of various interventions such as exercise training and statins will be covered in this talk.

State of the Science in Osteoporosis

Robert R. Recker, M.D., M.A.C.P., F.A.C.E., Professor of Medicine and Director, Osteoporosis Research Center, School of Medicine, Creighton University
October 18, 2007, 11:00 a.m., Eppley Science Hall Amphitheater, Room 3010

Forty percent of Caucasian women alive today in the U.S. and Europe will suffer a fracture from osteoporosis during their lifetimes. The pathogenesis of this epidemic of skeletal fragility is incompletely understood, but seems to be due to a combination of defective bone quality, abnormal microstructure and loss of bone material. We will explore these ideas in the context of what we have learned in attempting to treat osteoporosis over the past three decades.

A New Paradigm for Anti-Tumor Drug Delivery: Drug Release from Thermally Sensitive Nanocapsules in the Blood Stream

David Needham, Ph.D., Professor, Department of Mechanical Engineering and Materials Science , Duke University, Durham , NC
May 17, 2007, 11:00 a.m., Eppley Science Hall Amphitheater, Room 3010

Invented in 1996, the temperature-sensitive liposome, is now in Phase I human clinical trials.  This presentation will review earlier work, and present new data that shows unexpected mechanistic features that make this nanoscale triggered release system an emerging new paradigm for drug delivery technology.

Overcoming barriers to nanoparticles in vivo by targeting caveolae in endothelium: Towards rapid penetration of solid tumors and organs

Jan E. Schnitzer, M.D., Professor, Director of Vascular Biology & Angiogenesis Program, Sidney Kimmel Cancer Center, San Diego, CA 
March 15, 2007, 11:00 a.m., Eppley Science Hall Amphitheater, room 3010

New targets and targeting strategies are needed to fulfill the promise of molecular medicine and nanomedicine. The vasculature is the primary conduit by which molecules are distributed throughout the body and the endothelial cells lining these blood vessels form a key barrier restricting access inside most tissues. To focus on inherently accessible targets, a new proteomic imaging strategy  will be presented that integrates tissue subfractionation with subtractive proteomic mapping, bioinformatic interrogation, and molecular imaging in vivo to identify and validate tissue- and tumor-induced endothelial targets that are accessible to intravenous antibodies and nanoparticles and that enable penetration across endothelium into the tissue. Caveolae function as active pumps to concentrate select antibodies in the tissue interstitium. Targeting caveolae may be a worthwhile novel strategy to enhance drug, nanoparticle, and gene delivery in vivo.

Functional proteomics: from rare lysosomal disorders to diabetes

Alexey V. Pshezhetsky, Ph.D.,  Professor, Departments of Pediatrics and Biochemistry, Montreal University
December 14, 2006 11:00 a.m., DRC Room 1004

Proteomics allows all proteins in the cell (the “proteome”) to be studied simultaneously providing a snapshot of a physiological state of the cell. Comparison of proteomes allows therefore the identification of key proteins involved in disease, development, and the regulation of the gene and protein expression. Study of the proteins modified with the residues of phosphoric acid (phosphoproteins) is of particular interest because phosphorylation is recognized to play the most important role in the regulation of the biological processes. The presentation will address development of new proteomic technologies for detection and quantification  of proteins and phosphoproteins as well as application of proteomics for identification of the underlying cause and finding the new therapeutic solutions for different genetic disorders. 

Convective Delivery in the CNS: Implications for Biological Neurosurgery

Edward H. Oldfield, MD, Surgical Neurology Branch, NINDS, NIH, Bethesda, MD
November 15, 2007, 11:00 a.m., TBA

Advances in basic biology in the past 2 decades permit the development of new molecules with therapeutic potential for CNS disorders. An approach for selective delivery to targeted sites in the CNS while providing homogeneous distribution of large and small molecules over clinically-relevant volumes should provide opportunities for biological neurosurgery. However, the application of these agents for treatment has been problematic because their large size prevents them from being delivered to the appropriate brain regions. Convection-enhanced delivery (CED), in which drug is delivered into the extracellular space of the brain, spinal cord, or peripheral nerve by a slow continuous infusion, uses bulk flow to distribute large and small molecules and overcomes many of the obstacles associated with other drug delivery techniques. Convection is being used to deliver and distribute various agents, such as immunotoxins, genetic vectors, exitotoxic amino-acids, and chemotherapeutic molecules in the investigation of new treatments for a variety of CNS disorders. The advantages and limitations of convective-based delivery and its potential utility for new neurosurgical therapies will be discussed.

The objectives of the presentation are 1) to review the limitations of drug delivery to the central nervous system (CNS) and strategies of overcome them and 2) to present the advantages and limitations of using convection to enhance local and regional drug delivery to the CNS.

Medical Applications of Nanomagnets

Diandra L. Leslie-Pelecky, Ph.D., Associate Professor, Department of Physics & Astronomy, Nebraska Center for Materials and Nanostructures, University of Nebraska -Lincoln
April 20, 2007

The use of magnetic nanoparticles in medical applications is increasing, in part because magnetism provides a ‘handle’ by which nanoparticles can be controlled from outside the body.  Magnetic nanoparticles have applications in targeted drug delivery, cell sorting, externally controlled drug release, and magnetic imaging.  Many of the most promising magnetic materials, however, face two problems:  oxidation, which degrades magnetic properties, and possible lack of biocompatibility.  These problems can be exacerbated when other functionalities are added to the particle (for example, drug conjugation or surfactant attachment.  An overview of nanomagnetic and nanotoxicological problems and some potential solutions will be presented.

Building Blocks of Nucleic Acid Nanostructures: Unfolding Thermodynamics of Intramolecular DNA Complexes

Luis A. Marky, Ph.D., Professor, Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center
May 18, 2006 11:00 a.m.  University Hospital Amphitheater UNH 4208

The stable formation of small or large nucleic acid complexes depends primarily on the extent of hydrogen bonding and base-pair stacking contributions but equally important are the contributions of ion and water binding.  Our laboratory is interested in predicting the thermal stability and melting behavior of nucleic acids.  The main objective is to understand how sequence and solution conditions affect the melting behavior of nucleic acid complexes; for this reason, we use a variety of physical techniques to determine complete thermodynamic profiles for the temperature-unfolding of oligonucleotides with known sequence.  Specifically, we will report on the unfolding and hydration properties of intramolecular DNA complexes: single hairpin, three-way junction, pseudoknot, double-hairpin triplexes, G-quadruplexes and i-motifs.  The overall results have a wide number of significant applications in the targeting of nucleic acid using antisense and antigene strategies, improving their interaction with delivering vectors and the targeting of unusual structures, and for the creation of DNA Origama.

Nanoparticle Formation by Flash NanoPrecipitation using Block Copolymer Directed Self-Assembly

Robert K. Prud'homme , Ph.D., Professor, Department of Chemical Engineering and  Director, Program in Engineering Biology, Princeton University
April 20, 2006 11:00 a.m.  University Hospital Amphitheater UNH 4208 


Nanoparticle formulations of hydrophobic drugs present unique opportunities for treatment of solid tumor cancers and aerosol drug delivery. The common requirements of these applications are precise control of particle size and surface functionality. For cancer therapy particles in the size range of 100-200 nm passively pass through defects in the vasculature in tumors and deposit by “enhanced permeation retention”. For aerosol drug delivery particle sizes in the range of 100-200 nm remain in the deep lung and are not cleared – thereby enabling long-term controlled delivery. We will review processes for nanoparticle drug formulation.  We present our new process --Flash NanoPrecipitation – a controlled precipitation process that produces stable nanoparticles at high concentrations using amphiphilic diblock copolymers to direct self-assembly. Uniform particles with tunable sizes from 50-500 nm can be prepared. The key to the process is the control of time scales for micromixing, polymer self-assembly, and particle nucleation and growth. The diffusion-limited assembly enables particles of complex composition to be formed. Examples of particle formation for controlled delivery of multiple drugs from nanoparticles will be presented, as well as formulations of nanoparticles in micro particles for aerosol drug delivery. A novel strategy for producing nanoparticles from soluble active compounds is demonstrated that enables the simultaneous encapsulation and controlled release of both hydrophobic and hydrophilic actives. This enables the simultaneous, controlled release of multiple drug “cocktails” from nanoparticles for the treatment of cancers and HIV. The incorporation of gold nanoparticles and fluorophores and drugs into a single nanoparticle enables simultaneous delivery and medical imaging. Finally, the ability to dry the nanoparticles by lyophilization or spray drying and to reconstitute them without aggregation greatly enhances the applicability of the technology.

 

Strategies for the Design and Readout of Ultrahigh Density Immunodiagnostic Platforms

Marc Porter, Ph.D., Professor, Departments of Chemistry and Chemical Engineering, Institute for Combinatorial Discovery, and Ames Laboratory-USDOE, Iowa State University
January 19, 2006, 11:00 a.m.  University Hospital Amphitheater UNH 4208 

The drive for early disease detection, the growing threat of bioterrorism, and a vast range of challenges more generally in biotechnology have markedly amplified the demand for ultrasensitive, high-speed diagnostic tests. This presentation describes efforts to develop platforms and readout methodologies that potentially address demands in this arena through a coupling of nanometric labeling with surface enhanced Raman spectroscopic, micromagnetic, and scanning probe microscopic and readout concepts.  Strategies will be described for both the fabrication and read-out of chip-scale platforms that can be used with each novel readout modality.  Examples will focus on the use of protein arrays as platforms targeted for immumoassays in early disease diagnosis and the rapid, ultralow level detection of cancer markers and viral pathogens.  Each example will also discuss challenges related to sensitivity and nonspecific adsorption and to fluid manipulation at micrometer length scales.

Shell crosslinked block copolymer micelles: Robust nanostructured materials for fundamental studies and applications in nanomedicine

Karen L. Wooley, Ph.D., Professor, Department of Chemistry, Washington University in Saint Louis

November 16, 2006 11:00 a.m., DRC 1004

The covalent stabilization of supramolecular assemblies of block copolymers in solution allows for the establishment of robust nanoscale objects, which are showing significant promise as well-defined probes to investigate general issues related to nanomedicine, for example biodistribution and tissue targeting.  The supramolecular assembly process provides access to nanoscale structures having interesting sizes, shapes and morphologies, and the covalent stabilization procedure “fixes” such initial structures to then allow for further physical and chemical manipulation.  This presentation will highlight the latest advances toward the application of such complex materials (having 10-100 nm dimensions and spherical, cylindrical, cage-like, toroidal or discoidal shapes), together with various bioconjugation strategies, in the detection and treatment of acute pulmonary and vascular injury and also cancer, with emphasis upon the fundamental chemical designs and biological assays.

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