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PLENARY SESSION II
Sunday, September 8
10:30-3:00


PLENARY SESSION II: Oncological Nanotech
Chairperson: Mr. Ed Monachino, National Cancer Institute

10:30 Micro-and Nano-Technologies That Will Enable the Earliest Detection of the Signatures of Cancer and the Ability to Provide Rapid and Specific Treatment
Mr. Ed Monachino
It has become clear that cancer is a set of diseases that result from changes in the genome and the expressed products of the genome. The pathway of technological opportunity resulting from this fundamental observation can have a profound impact on the management and prevention of cancer.

The first step in this pathway requires defining the molecular signatures of cancer. The National Cancer Institute has launched initiatives, including the Innovative Molecular Analysis Technologies (IMAT) program supporting research projects to develop and carry out pilot applications of novel technologies that will enable the molecular analysis of cancers and their host environments.

NCI is currently looking beyond these near term goals and establishing programs that will pave the way to improved future medical care. The NCI is implementing the Unconventional Innovations Program (UIP) to support high impact, long range technological innovations. The UIP is focused on the development of technology systems that couple minimally invasive sensing of cancer signatures in patients with capabilities for controlled and monitorable intervention specific for these signatures.

Based upon a shared vision for the future of human health care, NASA and NCI have formed a partnership to jointly research and develop biomolecular sensors that will revolutionize the practice of medicine on earth and in space. NCI and NASA are supporting the development of new minimally invasive technologies to scan the body for the earliest signatures of emerging disease and support immediate, specific intervention. These technologies will support a seamless interface between detection, diagnosis and intervention.

11:00 Nanomolecular Biosensors:
Dr. James R. Baker, Jr., University of Michigan
We are developing nanoscale biosensors and bioactuators for use in individual health and safety monitoring, in conjunction with external analytic bioNEMS devices. This involves nanoscale polymer structures less than 20 nm in diameter as the basis of the sensor/actuators. The structures would be designed to target into specific cells of an individual and be able to monitor health issues such as the exposure to radiation or infectious agents. These molecules would also be able to administer therapeutics in response to the needs of the individual, and act as actuators to remotely manipulate a person as necessary to ensure their safety. An example of this latter capability would be to activate muscle movement causing an unconscious person to walk out of harm's way. In addition, these nanosensors could be used to develop cellular-based biochips that would be useful as sensors for the remote detection of life or other scientific analysis. These studies are performed by a multidisciplinary team, involving a fusion of disciplines including nanotechnology-based materials science, bioengineering, bioinformatics and medical sciences. We will use these different disciplines to converge on the design and manipulation of the nanosensors, and the development of non-invasive systems to interact with the sensors through functional MRI or multispectral fluorescence imaging. This latter task would require the engineering of wearable NEMS systems by engineers involved in this project while other members of the project team would test the efficacy of these systems using biologic models, such as experimental animals. Because of these broad requirements, the research would involve the multidisciplinary team from the Medical, Engineering and basic science (LS&A) schools at the University of Michigan, and would train multidisciplinary scientists at the pre-and postgraduate level.

11:30 Magnetic Resonance Molecular Imaging and Targeted Drug Delivery with Site-specific Nanoparticles:
Dr. Gregory M. Lanza, Washington University School of Medicine
Angiogenesis plays a central role in cardiovascular disease and tumor development. a n b 3 -integrin as a marker of angiogenic vessel endothelium. We have reported the development of a ligand-directed perfluorocarbon nanoparticle system for molecular imaging of angiogenesis as well as for detection of intravascular thrombosis or inducible proteins, such as tissue factor, in vivo with magnetic resonance imaging. These unique lipid encapsulated, perfluorocarbon nanoparticles (~250nm) incorporate on their surface up to 60,000 Gd-DTPA complexes / nanoparticle to manifest very prominent T1 effects that overcome partial volume dilution effects at clinical resolutions (1.5 T).

Methods: In this report, paramagnetic molecular imaging of angiogenesis in vivo and the potential for targeted, quantifiable drug delivery are demonstrated. In part one, paramagnetic nanoparticles either covalently complexed with an a n b 3 -integrin specific ligand (targeted; n=3) or nontargeted (control; n=3) were injected intravenously (ear vein) in New Zealand rabbits bearing hindleg Vx-2 carcinoma tumors (~250 mm3). Tumor vasculature was imaged in vivo by MRI (1.5 T) using a T1-weighted, fat-suppressed, 3-D, fast field echo sequence. In part two, the antiproliferative effects and dissolution release of paclitaxel (Taxol) from nanoparticles targeted with a specific tissue factor (TF) antibody to cell-surface TF proteins on vascular smooth muscle cells (VSMC) are presented.

Results: Angiogenesis was detected with a n b 3 -targeted nanoparticles in asymmetric regions along the outer tumor capsule and in neighboring vessels and tissues. a n b 3 -targeted nanoparticles enhanced 8.17 ± 0.86% of the tumor area vs. 1.65 ± 1.74% (p<0.05) in the control (nonspecific accumulation). MRI signal from the angiogenic vasculature increased 69.2 ± 3.4% over baseline. The overall contrast enhancement (CEI) of targeted tumors was 8-fold greater than controls. Muscle did not enhance with either targeted or control nanoparticles. Corresponding a n b 3 -expression was confirmed by immunohistochemistry (LM609).

VSMC were treated with either control or paclitaxel nanoparticles that were targeted specifically to tissue factor receptors or were co-incubated with without ligand targeting. Tissue factor targeted paclitaxel-nanoparticles inhibited (p<0.05) VSMC proliferation where as control or nontargeted paclitaxel nanoparticles had no effect on cell growth. Fluorine spectroscopy was used to confirm the delivery of nanoparticles to targeted cells and may be used to estimate delivered paclitaxel nanoparticle concentrations.

Conclusion: Molecular imaging of angiogenesis, whether stimulated by vascular disease (i.e., myocardial ischemia, atherosclerotic plaque development, or peripheral vascular insufficiency), tumors, wounds or therapy (i.e., pharmacological or gene therapy), may be detected in vivo with ligand-targeted paramagnetic nanoparticles using a clinical MRI scanner (1.5 T). Moreover, these nanoparticles present a unique opportunity to treat this broad range of pathology with a targeted and noninvasively quantifiable system.

12:00-1:30 Lunch (on your own)

1:30 Novel Implanted Drug Delivery Device Based on Constrained Diffusion through Microfabricated NanoPORE™ Membranes:
Dr. Frank Martin, iMEDD, Inc.
Top-down microfabrication methods have been used to create "NanoPORE"membranes with parallel rectangular channels which, in their smallest aspect, range from 4-50 nm. Diffusion rates of various solutes through such membranes have been measured. Figure 1 shows the cumulative flux of glucose through NanoPORE membranes fabricated with channel widths ranging from 7 nm to 27 nm. For the 7 nm and 13 nm membranes, flux rates of glucose from one chamber to a receiver chamber (which initially had no glucose) conform to zero-order kinetics. That is, the cumulative movement of glucose through the membrane is linear with time. This pattern is unexpected since the diffusion gradient is decaying with time and thus the driving force for diffusion would be expected to decay as well. At 20 nm and 27 nm, the glucose flux becomes Fickian, that is, the rate slows in a predictable fashion as the gradient decays.

These data indicate that NanoPORE membranes can be engineered to control rates of diffusion by adjusting channel width in relation to the size of solutes. Moreover, when the proper balance is struck, zero-order diffusion kinetics is possible. This discovery prompted us to develop a prototypical drug delivery device (called NanoGATE). The device consists of a reservoir formed from a cylindrical enclosure capped at both ends with polymer plugs. The tubing is fitted with a NanoPORE membrane as the only connection between the internal reservoir of the device and the external medium (Figure 2). The NanoPORE membrane serves to control release rates of drugs loaded into the reservoir. We reckoned that the device would be useful for delivering small molecular weight organic drugs as well as larger peptide- and protein-based biopharmaceuticals. To test the system we selected bovine albumin (MW 60,000 daltons) as a surrogate of a fairly large protein biopharmaceutical. In vitro release of 125I-labeled albumin for NanoPORE membranes of two sizes, 13 nm and 26 nm, is shown in Figure 3. The rates in both cases are zero-order. Interestingly, the rate of albumin diffusion through the 13 nm membrane is approximately twice that of the 26 nm membrane. Note that in both cases the rates deviate from those predicted by Fickian diffusion principles. We next tested the performance of NanoGATE in vivo. Devices fitted with 13 nm membranes and filled with 0.5 mg of 125I-albumin were implanted subcutaneously in the backs of 3 rats. The devices were adjusted to have an in vitro output rate of about 5 g/day and thus were designed to release the albumin for 100 days. The pharmacokinetics of the labeled albumin in blood was measured and compared to a dose of albumin delivered by a standard subcutaneous bolus injection. Figure 4 shows the mean values for blood levels over a period of 46 days after implantation. In the case of the NanoGATE implant group, following an initial period of decline (during the first 9 days), albumin concentration in the central compartment leveled off for the ensuing 4 weeks. The initial decline is attributed the equilibration of the radiolabeled albumin appearing in blood with the albumin pool in the interstitial fluid volume. This equilibration has been reported to have a half-life of 17 days, which is in line with our results. In comparison to the standard subcutaneous injection, albumin delivered in the NanoGATE device was detectable for a substantially longer period. As expected, when the devices were recovered from experimental animals they were encapsulated in fibrous capsule, but the NanoPORE membrane itself was free of any cellular or protein intrusion. The foreign body response did not appear to retard the bioavailability of the albumin released from the device. Moreover, about half the labeled albumin was recovered in each NanoGATE device, which conforms to expectation that half the drug would be released during the 7-week in-life period.

These results encourage us to believe that delivery of a wide range of drugs can be regulated by devices fitted with such NanoPORE membranes. Moreover, since the mechanism of release is attributable to a novel constrained diffusion mechanism provided by the precise geometry of the NanoPORE membranes, and no moving parts such as pistons are required, we believe that drugs can loaded into the device reservoir in a range of physical states including solutions, and crystalline or micronized suspensions. Such flexibility with respect to the physical form of encapsulated drugs provides options to substantially increase the loaded dose and duration of therapy as well as approached to increase the stability of proteins which are intrinsically unstable in aqueous solution at body temperature.

2:00 Photonic Nano-Explorers: From Subcellular Chemical Imaging to Cancer Detection and Therapy:
Dr. Martin A. Philbert, University of Michigan
Live cells exhibit a complex chemistry, which literally determines life, disease and death. While much has been learned by analytical methods that destroy the cell, many important aspects (e.g., the role of oxygen and free radicals) require reliable sensors that are nonperturbative to the cell, both physically and chemically. This has been achieved with nano-devices called PEBBLEs (Probes Encapsulated By Biologically Localized Embedding). These are complex nanoparticles, with biocompatible matrices and with synergistically active interior components, tailor-made for spectrally, spatially and temporally resolved chemical imaging. Similar nano-explorers detect cancer cells (or their vasculature) using tailor-made molecular recognition elements ("molecular targets"). The location is reported via MRI contrast enhancement. Laser light activates the photodynamic components of the nano-platform, turning normal oxygen into singlet (killer) oxygen. In the dark these nano-particles are non-toxic and have a reasonable vascular circulation time.

2:30 Roundtable Discussion: The Clinical Perspective
Moderated by Dr. Carol A. Dahl, Biospect, Inc.
Dr. Michael Caligiuri, Medical Oncologist, The Ohio State University
Dr. Wolfgang Sadee, Department of Pharmacogenomics, The Ohio State University

3:00 Refreshment Break with Exhibit and Poster Viewing

 

 

 


NEW POSTER COMPETITION
Gain visibility for your research by participating in the poster session.
Posters will be judged by a Scientific Advisory Board; over 60 posters are expected to be submitted. Cash prizes will be awarded.
Please fill out the registration form, giving the poster title and the poster's primary author. All submissions will be reviewed for possible inclusion for poster presentation.
Click here for poster instructions
PUBLICATION OF ARCHIVAL PAPERS IN BIOMEDICAL MICRODEVICES
Full-length papers based on podium or poster presentation at the conference will be reviewed for fast-track publication in Biomedical Microdevices. Submitted typed manuscripts are due at the conference.
RELATED CHI LIFE SCIENCE REPORTS 
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