2011 Nanobiotechnology Seminar Series

Seminar & Discussion 4:30 - 5:30 pm
Reception 5:30 - 6:00 pm


February 22, 2011
Li Ka Shing, LKSC LK 130

James Baker, MD

Director, Michigan Nanotechnology Insitute for Medicine and Bio. Sci and Ruth Dow Doan Endowed Professor in Biologic Nanotechnology
University of Michigan

Will Nanotechnology Fulfill its Promise for Treating Human Disease? 
Abstract: 

Nanotechnology for Cancer Approaches the Clinic
Our group has developed a number of dendrimer-based targeted therapeutics for epithelial, lung and ovarian cancers. These macromolecules are actively targeted to tumors that over-express receptors for a number of receptors for small molecule ligands including folate, riboflavin, RGD and EGF. Our first generation therapeutics used a dendrimer scaffold combined with linking multiple targeting and therapeutic molecules to produce multifunctional combinatory therapeutics. Unfortunately, the complexity of these molecules prevented their entry into clinical trials. We have re-designed the platform using a simplified approach; polyvalent small molecule therapeutics which also act as ligands to target the nanoparticle and kill cancer cells. The revised scaffold still uses a dendritic polymer that is uniquely suited to biomedical applications in that it can be uniformly produced and yet has a diameter les than 10 nanometers. Our linker mechanism utilizes a more complex and extended linker to conjugate ligands, drugs and imaging agents to the dendrimer. The goal of this work is to develop several polyvalent therapeutics and imaging agents and advance these materials through preclinical animal efficacy and toxicity trials. If this approach is successful in vivo, it can facilitate the concept of targeting many small molecule drugs on nanoparticles to address varied tumor types with different genetic or enzymatic alterations associated with individual cancers. Thus, the polyvalent drug approach would yield common, interchangeable therapeutic platforms that transcend any single tumor type or cellular abnormality.


March 15, 2011
Clark Auditorium

Chun Li, PhD

Professor
Department of Experimental Diagnostic Imaging
The University of Texas MD Anderson Cancer Center

The Seek and Treat Strategy: Targeting Nanoparticles for Cancer Theranostics 
Abstract:

The development of biocompatible nanoparticles for molecular imaging and targeted cancer therapy is an area of considerable current interest across a number of disciplines. The premise is that nanoparticles possess unique structural and functional properties that are not available from either discrete molecules or bulk materials. However, successful delivery of nanomaterials to the tumor sites requires overcoming many biological barriers, including extravazation from tumor vasculature and dispersion of nanoparticles from perivascular area. In my presentation, I will share our experiences towards enhanced delivery of nanoparticles to solid tumors, the development of multi- functional nanoplatforms for image-guided multimodal therapy, and the use of radiation and near-infrared laser as external energy source to facilitate tumor delivery of anticancer drugs mediated by nanoparticles. My discussion will be exemplified by three classes of nanomaterials: water-soluble polymer-drug conjugates, hollow gold nanospheres, and semiconductor nanoparticles.


April 19, 2011
Li Ka Shing, LKSC LK 130

Gang Zheng, PhD

Associate Professor of Medical Biophysics
Division of Biophysics and Bioimaging
Ontario Cancer Institute

Multimodal Organic Nanophotonics as Cancer Theranostics 
Abstract: 

Optically active nanomaterials promise to advance a diverse range of biophotonic techniques through nanoscale optical effects and integration of multiple imaging and therapeutic modalities. We recently discovered 'porphysomes', a class of multimodal organic nanophotonics (Nature Materials 2011). Porphysomes are formed from self-assembled porphyrin bilayers that generated large, tunable extinction coefficients, structure-dependent fluorescence self-quenching, and unique photothermal and photoacoustic properties. These bilayered nanovesciles facilitated sensitive visualization of lymphatic systems using photoacoustic tomography. Near-infrared fluorescence generation could be restored upon dissociation, creating opportunities for low-background fluorescence imaging. As organic nanoparticles, porphysomes were enzymatically biodegradable and induced minimal acute toxicity in mice with intravenous doses of 1000 mg/kg. Like liposomes, the large aqueous core of porphysomes could be passively or actively loaded. Following systemic administration, porphysomes accumulated in tumors of xenograft-bearing mice and laser irradiation induced photothermal tumor ablation. In addition, the metal chelating ability of the porphyrin bilayer opens the door for other imaging and therapeutic modalities. Perhaps more importantly, all these capabilities are intrinsic to the new nanostructures, rather than having to be tacked on, thus representing a new "one-for-all" approach for cancer theranostics.

In this talk, our recent progress on lipoprotein-inspired nanoparticles and photodynamic molecular beacons will also be presented.


May 17, 2011
Li Ka Shing, LKSC LK 130

Young-wook Jun, PhD

Assistant Professor
Department of Otolaryngology
UCSF

Plasmonic Nanocrystal Molecules for Single Molecule Study of Biomolecular Dynamics 
Abstract: 

Nanocrystal molecules, a well-defined grouping of coupled individual nanocrystal artificial atoms, exhibits new characteristics that are markedly distinct from those of the component nanocrystals. Their chemical and physical properties are a function of interparticle couplings, and hence a function of the interparticle distance, the bonding mode, and the nanocrystal-molecule geometry (e.g. symmetry). The coupling phenomena of the nanocrystal molecules can be used to construct a new type of biological probe for monitoring complex biomolecular behaviors. Unlike conventional nanocrystal bio-probes that only report the spatial distribution of target biomolecules, nanocrystal molecules use the interparticle- and symmetry- distance dependent coupling properties between the component nanocrystals that provide optical and magnetic transduction of dynamic structural and environmental changes across a single linker biomolecule. In this presentation, I will present some examples of nanocrystal molecule probes for monitoring the assembly and deformations of biomolecular complexes in live cells. The nanocrystal molecule probes can report dynamic assembly of proteases and membrane receptors such as caspases and receptor tyrosin kinases (RTKs) at the single molecule level.


June 21, 2011
Clark Auditorium

Joseph DeSimone, PhD

Chancellor's Eminent Professor of Chemistry
University of North Carolina at Chapel Hill

Co-opting Moore's Law: Vaccines and Medicines Made from a Wafer
Abstract: 

In 1965, Gordon Moore, co-founder of Intel, described the trend that the number of components in integrated circuits had doubled every year since 1958. This trend has continued to today, enabled by advances in photolithography which has taken the minimum feature size of transistors down from about 10 microns in 1970 to 0.045 microns (45 nm) today. In biological terms, this corresponds to going from the size of a red blood cell to the size of a single virus particle! As such, this top-down nano-fabrication technology from the semiconductor industry is, for the first time, in the size range to be relevant for the design of medicines, vaccines and interfacially active Janus particles. This lecture will describe the design, synthesis and efficacy of organic nano- and micro-particles using a top-down nano-fabrication technique we developed called PRINT (Particle Replication in Non-wetting Templates). PRINT is a continuous, roll-to-roll, high resolution molding technique that allows the fabrication of precisely defined micro- and nano-particles in a continuous manner with control over chemical composition, size, shape, deformability and surface chemistry. With these ‘nanotools’, we are establishing definitive biodistribution maps to elucidate the interdependent roles that size, shape, deformability and surface chemistry play on particle distribution as a function of different dosage forms (IV, IP, inhaled, subcutaneous, intramuscular, etc). This information is setting the stage for the design of highly effective chemo-therapeutics, chemo-preventions and cancer vaccines which will be described.


July 19, 2011
Clark Auditorium

Sir J Fraser Stoddart, PhD

Professor
Department of Chemistry
Northwestern University

Mechanized Mesoporous Silica Nanoparticles as Potential Drug Delivery Systems
Abstract:

With the growth of nanomedicine, one can envisage the possibility in theranostic medicine of fabricating a vector that is capable of releasing simultaneously powerful therapeutics and diagnostic markers selectively to diseased tissue. In our design of new theranostic delivery systems, we have focused on using mesoporous silica nanoparticles (SNPs). The stability of the SNPs allows them to be functionalized with responsive mechanically interlocked molecules (MIMs) such as bistable rotaxanes and psuedorotaxanes, yielding mechanized silica nanoparticles (MSNPs). These MIMs can be designed in such a way that they either change shape or shed off some of their parts in response to a specific stimulus, allowing a theranostic payload to be released from the nanopores to a precise location at the most ideal time. All MSNPs have three primary components: they are – (i) a solid support, (ii) a payload of cargo, and (iii) external machinery. Typically, SNPs are chosen as the solid support for MSNPs, since they are rigid, robust, chemically inert, and relatively easy to fabricate as 100-200 nm diameter nanoparticles. The cargo is typically drugs or imaging agents. The external machinery consists of a monolayer of MIMs in the form of rotaxanes which consist of the following components – (a) linear stalks anchoring the bistable rotaxanes to the surfaces of the SNPs, (b) gating rings, e.g., cucurbiturils, which encircle the stalks and trap the cargo within the nanopores (ca. 2 nm diam) of the MSNPs, (c) an alternative ring binding site or weak, cleavable point along all the stalks that are susceptible to some specific stimulus to force the rings to distance themselves from the pores, and (d) stoppers at the ends of the stalks. The individual components employed in the fabrication of MSNPs are highly modular, a situation which means that their customization is straightforward – a major advantage of these integrated systems over other delivery vehicles.

Timeline showing the evolution of MSNPs
See: Mechanised nanoparticles for drug delivery Nanoscale.20091, 16–39.


August 16, 2011
Li Ka Shing, LKSC LK 120

Kostas Kostarelos, BSc, DIC, PhD

Chair of Nanomedicine
Head, Center for Drug Delivery Research
The School of Pharmacy
University of London

How to Transform Novel Nanomaterials to Pharmacologically-relevant and Toxicologically-acceptable Tools: The Nanocarbon Paradigm
Abstract:

Great effort is currently invested in the development of various types of nanomaterials such as quantum dots, metallic and semi-conducting nanoparticles, various nanocarbons, all designed for a variety of biomedical applications. A lot of novel nanomaterials (e.g. nanotubes, nanofibers, nanosheets) differ dramatically in terms of structural characteristics (diameter, length, size distribution), surface (chemical composition of coated or grafted groups, aspect ratio, hydrophobicity) and colloidal properties (degree of aggregation, dispersibility). These differences result in diverse biological profiles in vitro and in vivo. Even within the same type of nanomaterial, dramatic structural, surface and chemical differences exist based on manufacturing or chemical treatment specifications that will determine their biological profiles in vivo. This leads to the need for very careful determination of the material characteristics and their correlation with pharmacological performance and any toxicologically adverse effects that may occur.

The nanometer-scale dimensions of nanocarbons (fullerenes, carbon nanotubes, graphene sheets) make quantities of milligrams consist of a large number of nanoparticles, with a concurrent high total surface area. The effective aspect ratio in vivo will also depend on their degree of bundling and aggregation of nanotubes in solution. Concerning the toxicity of nanocarbons, in vitro studies have indicated that chemically functionalised material, carbon nanotubes in particular, produce less cytotoxic effects than aqueous dispersions of pristine material (non-covalently functionalised). In this seminar, specific examples of surface-engineered nanocarbons to achieve control over their pharmacology (localisation and retention in specific tissues) on administration and their toxicological impact will be shown. Such engineering exercises are considered essential for the conclusion of specific rules that will help the transformation of nanomaterials into clinically-relelvant tools for medical applications.


September 27, 2011
Paul G. Allen Auditorium

Omid Farokhzad, MD

Associate Professor
Department of Anaesthesia
Harvard University 

Engineering of Polymeric Nanoparticles for Medical Applications 
Abstract: 

A variety of organic and inorganic materials have been utilized to generate nanoparticles for drug delivery applications, including polymeric nanoparticles, dendrimers, nanoshells, liposomes, nucleic acid based nanoparticles, magnetic nanoparticles, and virus nanoparticles. The two most commonly used systems are polymeric nanoparticles and liposomes [1, 2]. Controlled release polymer technology has impacted virtually every branch of medicine, including ophthalmology, pulmonary, pain medicine, endocrinology, cardiology, orthopedics, immunology, neurology and dentistry, with several of these systems in clinical practice today such as Atridox, Lupron Depot, Gliadel, Zoladex, Trelstart Depot, Risperidol Consta and Sandostatin LAR. The annual worldwide market of controlled release polymer systems which extends beyond drug delivery is now estimated at $100 billion and these systems are used by over 100 million people each year. Polymeric nanoparticles can deliver drugs in the optimum dosage over time, thus increasing the efficacy of the drug, maximizing patient compliance and enhancing the ability to use highly toxic, poorly soluble, or relatively unstable drugs. These systems can also be used to co-deliver two or more drugs for combination therapy [3]. The surface engineering of these nanoparticles may yield them “stealth” to prolong their residence in blood [4] and the functionalization of these particles with targeting ligands can differentially target their delivery or update by a subset of cells [5], further increasing their specificity and efficacy [6]. The successful clinical translation of therapeutic nanoparticles requires optimization of many distinct parameters including: variation in the composition of the carrier system, drug loading efficiency, surface hydrophilicity, surface charge, particle size, density of possible ligands for targeting, etc., resulting in a large number of potential variables for optimization which is impractical to achieve using a low throughput approach. More recently combinatorial approaches have been developed to precisely engineer nanoparticles and screen multiple nanoparticle characteristics simultaneously with the goal of identifying formulations with the desired physical and biochemical properties for each specific application [7]. The goal of this talk is to review our efforts in the design and optimization of polymeric nanoparticles for medical applications, which formed the foundation for the clinical translation of the first-in-human targeted and controlled-release nanoparticles (BIND-014) for cancer therapy [8].

References 
1. Langer, R., Drug delivery and targeting. Nature, 1998. 392(6679 Suppl): p. 5-10. 
2. Brannon-Peppas, L. and J.O. Blanchette, Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev, 2004. 56(11): p. 1649-59. 
3. Zhang, L., et al., Co-delivery of hydrophobic and hydrophilic drugs from nanoparticle-aptamer bioconjugates. ChemMedChem, 2007. 2(9): p. 1268-71. 
4. Gref, R., et al., Biodegradable long-circulating polymeric nanospheres. Science, 1994.263(5153): p. 1600-3. 
5. Farokhzad, O.C., et al., Nanoparticle-aptamer bioconjugates: a new approach for targeting prostate cancer cells. Cancer Res, 2004. 64(21): p. 7668-72. 
6. Farokhzad, O.C., et al., Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc Natl Acad Sci U S A, 2006. 103(16): p. 6315-20. 
7. Gu, F., et al., Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers. Proc Natl Acad Sci U S A, 2008. 105(7): p. 2586-91.
8. Shi, J., et al., Self-Assembled Targeted Nanoparticles: Evolution of Technologies and Bench to Bedside Translation. Acc Chem Res. 2011 Jun 21. Epub ahead of print.


October 18, 2011
Clark Auditorium

Erkki Ruoslahti, MD, PhD

Distinguished Professor
Department of Biological Sciences
UC Santa Barbara

Targeting tumors with tumor-penetrating peptides 
Abstract: 

This laboratory screens phage libraries in live mice to identify peptides that direct phage homing to a specific target in the body. The homing peptides from these screens have revealed a zip code system of molecular changes in the blood vessels of normal tissues and pathological lesions such as tumors and atherosclerotic plaques. The power of in vivophage screening is illustrated by the recent discovery of the tumor-penetrating peptides. These peptides are capable of taking a payload deep into tumor tissue. Remarkably, the payload does not have to be coupled to the peptide; the peptide activates a bulk transport system that sweeps along any compound that is present in the blood. Treatment studies in mice show improved anti-tumor efficacy and less damage to normal tissues, and improvements in imaging have also been achieved.


November 15, 2011
Clark Auditorium

Greg Lanza, MD, PhD

Professor
Department of Medicine and Biomedical Engineering
Cardiovascular Division 
Washington University

Emergent Nanomedicine Drug Delivery and Imaging Technologies 
Abstract: 

Nanomedicine clearly offers unique tools to address intractable medical problems in cancer and cardiovascular disease from entirely new perspectives. Molecular imaging, originally the purview of nuclear medicine, has expanded into all clinically relevant modalities as well as new emergent technologies, such as photoacoustic tomography and spectral CT. These nanotechnologies are considered “theranostic” since they present both diagnostic imaging alone or in combination with drug delivery on the same platform. Theranostics have shown robust potential in vivo for diagnosing, characterizing, treating and following proliferating cancers, progressive atherosclerosis, rheumatoid arthritis and much more. Recently, the combined use of lipase-labile prodrugs in lipid-based nanosystems in combination with a drug delivery mechanism, referred to as “contact facilitated drug delivery”, has overcome some intractable problems, such a premature drug loss and instability in transit associated with lipid based agents. Moreover, these new prodrugs retain highly effective target cell intracellular delivery and release without engaging the endosomal pathway. This review will provide an update on a broad range of image-guided drug delivery technologies and complementary imaging system research ongoing at Washington University (CTRAIN and collaborators).


December 6, 2011
Clark Auditorium

Mark Davis, PhD

Warren and Katherine Schilinger Professor of Chemical Engineering
California Institute of Technology

Systemic Delivery of siRNA to Solid Tumors via Targeted Nanoparticles: Preclinical to Clinical
Abstract: 

One of the major challenges in the development of siRNA-based therapeutics for human use is their effective, systemic delivery. We have been investigating the potential of targeted nanoparticles for the systemic delivery of siRNA in cancer, and have reported that transferrin targeted nanoparticles formulated with a cyclodextrin-containing polycation and anti-EWS-FLI1 siRNA can be effective anti-tumor agents in a mouse model of Ewing’s Sarcoma [1]. Targeted nanoparticles show behaviors that provide advantages in the systemic delivery of siRNA. For example, they can protect and deliver non-chemically modified siRNA, they can deliver a large “packet” of siRNA, they can have tunable binding affinities to target cell surfaces and when correctly assembled can systemically deliver siRNA without immune stimulation. Nanoparticles in the size range of 50-100 nm can circulate and localize in tumors [1,2]. These particles can carry a large amount of siRNA as the polycation protects the RNA from degradation and transports it into cells where the kinetics of gene inhibition are a strong function of the cell doubling time [3]. Using a combination of PET and bioluminescent imaging, the biodistribution of the nanoparticles is shown to not be a strong function of the presence of the targeting ligand, while the uptake and function in tumor cells are critically dependent on the function of the targeting ligand [4]. We have confirmed this behavior with other targeted nanoparticles [5]. Repetitive dosing in monkeys with the cyclodextrin-containing polycation nanoparticles  can be safely accomplished without eliciting complement activation or interferon and other immunostimulatory processes [6]. This delivery system entered a Phase I clinical trial in 2008 [7], and results from the clinical trial [8,9] and how they compare to results from animal studies will be discussed. More recently, we have extended this delivery system to include antibody and antibody fragment targeting agents. The combination of a therapeutic antibody targeting agent and a therapeutic siRNA can provide a dual functioning nanoparticle (results from animal models will be presented).

[1] Hu-Lieskovan S et al., Cancer Res., 65 (2005) 8984-8992. 
[2] Pun SH et al., Cancer Biology & Therapy, 3 (2004) 641-650. 
[3] Bartlett DW and Davis ME, Nucleic Acids Res., 34 (2006) 322-333.
[4] Bartlett DW et al., PNAS, 104 (2007) 15549-15554. 
[5] Choi, CHJ et al., PNAS, 107 (2010) 1235-1240.
[6] Heidel JD et al., PNAS, 104 (2007) 5715-5721.
[7] Davis, ME, Mol. Pharm., 6 (2009) 659-668.
[8] Davis, ME et al., Nature, 464 (2010) 1067- 1070.
[9] Ribas, A et al, ASCO Abstract No. 3022 (2010).


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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