Nanotechnologies in Cancer Diagnosis, Therapy, and Prevention

Agenda

* Presentation titles and times are subject to change.

Abstracts

Day 1 — Tuesday, June 11, 2013

Targeted Gold Nanoparticles for Melanoma Therapy
Jay Nadeau, PhD, McGill University

Ultra-small gold nanoparticles are taken up readily by cells and cell nuclei. Conjugated to cytotoxic drugs, they are able to overcome mechanisms of drug resistance related to anti-apoptotic proteins and efflux pumps. Conjugation of gold to doxorubicin reduces the EC50 of doxorubicin more than 20-fold in doxorubicin-resistant cells, but leaves it essentially unchanged in doxorubicin-sensitive cells. We have investigated the mechanisms of resistance using a genome-wide shRNA screen in resistant B16 murine melanoma cells, identifying a panel of genes that are related to resistance to gold-doxorubicin. Intratumoral injection of gold-doxorubicin into B16 xenografts in immunocompetent mice leads to a greater than two-fold improvement in tumor response compared to doxorubicin alone. However, intravenous delivery of ultra-small particles leads to rapid clearance by the kidneys and difficulty of achieving a therapeutic concentration in the tumor. We have experimented with a variety of coating and targeting strategies in order to improve tumor delivery while minimizing toxicity to non-target tissues. Specific peptides targeting the fibroblast growth factor receptor increase the uptake rate of particles by cells, and PEGylation increases circulation time. We present preliminary results on FGF-targeted gold particles in vitro and in vivo. Gold can also amplify the dose of delivered radiation by enhancement of the photoelectric effect. The greatest barrier to such gold-assisted radiation therapy is the large amount of gold that must be delivered to the tumor to obtain a significantly improved response. However, doxorubicin is also sensitized by ionizing radiation. We compare the in vitro results of gold alone versus golddoxorubicin.

Nanotechnology for Cancer Imaging and Image-Guided Cancer Surgery
Shuming Nie, PhD, Emory University and Georgia Institute of Technology

The development of biocompatible nanoparticles for in-vivo molecular imaging and targeted therapy is an area of considerable current interest across a number of science, engineering, and biomedical disciplines. The basic rationale is that nanometer-sized particles have functional and structural properties that are not available from either discrete molecules or bulk materials. When conjugated with biomolecular targeting ligands such as monoclonal antibodies, peptides, or small molecules, these nanoparticles can be used to target malignant tumors with high specificity and affinity. In the “mesoscopic” size range of 10–100 nm diameter, nanoparticles also have large surface areas for conjugating to multiple diagnostic (e.g., optical, radioisotopic, or magnetic) and therapeutic (e.g., anticancer) agents. Recent advances have led to the development of biodegradable nanostructures for drug delivery, iron oxide nanocrystals for magnetic resonance imaging (MRI), quantum dots (QDs) for multiplexed molecular diagnosis and in-vivo imaging, and nanoscale carriers for short-interfering RNA (siRNA) delivery. We have developed biocompatible and nontoxic nanoparticles for in-vivo tumor targeting and detection based on self-assembled nanostructures and pegylated colloidal gold. In particular, colloidal gold has been safely used to treat rheumatoid arthritis for 50 years, and has recently been found to amplify the efficiency of Raman scattering by 14–15 orders of magnitude. Here we show that large optical enhancements can be achieved under in-vivo conditions for tumor detection in live animals. A major finding is that small-molecule Raman reporters such as organic dyes are not displaced but are stabilized by thiol-modified polyethylene glycols. These pegylated SERS nanoparticles are considerably brighter than semiconductor quantum dots with light emission in the near-infrared window. When conjugated to tumor targeting ligands such as single chain variable fragment (ScFv) antibodies, the conjugated nanoparticles are able to target tumor biomarkers such as epidermal growth factor receptors (EGFR) on human cancer cells and in xenograft tumor models.

Developing Upgraded MRI-based Platforms for Tumor Targeting and Drug Delivery
Sylvain Martel, PhD, Polytechnique Montréal

Clinical Magnetic Resonance Imaging (MRI) scanners can be more than just imaging modalities but also contribute to enhance the delivery of therapeutic agents being combined with magnetic nanoparticles (MNP) towards tumoral sites. Indeed, the high magnetic strength of the homogeneous magnetic field combined with the superposed 3D magnetic gradients inside the tunnel of a clinical MRI scanner provide a suitable magnetic environment to allow depth independent computer controlled navigation of MNP and therapeutic carriers through the vascular network. This new approach known as Magnetic Resonance Navigation (MRN) has been successfully tested in animal models. Deeper regions accessible through narrower vessels can be targeted with ultra-high gradients scanners or by the use of an additional insert providing higher directional gradients. Furthermore, the targeting efficacy of such theranostic agents can be assessed using the same scanner. In targeting drug delivery interventions requiring lower rate of changes in directional fields, a new approach dubbed Fringe Field Navigation (FFN) that exploits the fringe field outside the scanner and generated by the superconducting magnet of the same platform, can also be used. In FFN, extremely high directional gradients with relatively high field strengths required to bring the magnetic material of the MNP closer to saturation for enhanced induced forces, can be achieved. To go beyond the limits of MRN and FFN and to enhance targeting efficacy, special carriers containing MNP and drug-loaded self-propelled biological carriers in the form of Magnetotactic Bacteria (MTB) can be released and guided through the microvasculature and towards deep tumoral regions.

Ultrasmall Silica Inorganic Nanoparticle Platform for Targeted Molecular Imaging of Cancer
Michelle S. Bradbury, PhD, Memorial Sloan-Kettering Cancer Center

Despite recent advances in imaging probe development for biomedicine, the translation of targeted diagnostic platforms remains challenging. Nanomaterials platforms currently under evaluation in oncology clinical trials are largely non-targeted drug delivery vehicles or devices to thermally treat tissue; these are not typically surface-modified for direct detection by clinical imaging tools. New tumor-selective platforms need to satisfy critical safety benchmarks, in addition to assaying targeted interactions with the microenvironment and their effects on biological systems. Metabolic imaging/analysis tools, such as PET, are essential for providing quantitatively accurate data sets for whole-body distributions, targeting kinetics, and clearance profiles of new agents transitioning into early-phase clinical trials. The application of these methods to a new class of renally-cleared, fluorescent inorganic (silica) nanoparticles, Cornell dots (C dots), surface-modified with radioiodine and integrin-binding ligands, has led to a clinically-translatable product for cancer detection, staging, and targeted therapeutics. A first-in-human PET study showed no adverse events in melanoma subjects. Pharmacokinetic behavior and mean organ absorbed doses were comparable to those found for other commonly used diagnostic radiotracers. Average effective absorbed doses in human subjects were equivalent to those measured in our human-based preclinical data. Particles demonstrated bulk renal clearance; no appreciable whole-body activity was seen by 72-hour post-injection. Further, by exploiting the enhanced photophysical properties of the encapsulated dye, this dual-modality platform has enabled real-time optical imaging of lymphatic drainage patterns when injected locally about the tumor site, which can improve visualization of the surgical field and simplify SLN mapping procedures for surgeons. Sentinel lymph nodes have been localized in spontaneous melanoma miniswine models using an intraoperative portable fluorescence camera system, with pre-operative PET and histologic correlation. Using these state-of-the art technologies, improved detection sensitivity and discrimination of metastatic tumor burden within PET-positive neck nodes has been found relative to standard-of-care tracers for cancer staging. The possibility of visualizing nodal disease spread and tumor extent in relation to critical structures, while performing extended real-time intraoperative mapping procedures, has important implications for disease staging, prognosis, and treatment planning.

Do Nanotherapies Need Companion Diagnostics? Evaluation of the EPR Effect in Canines with Spontaneous Tumors
Thomas L. Andresen, PhD, Technical University of Denmark

Nanoparticles are well established as effective drug delivery systems and have potential in biomedical imaging as a diagnostic tool. We have recently developed a highly efficient method for utilizing liposomes as agents in positron emission tomography (PET) imaging giving high resolution images and allowing direct quantification of liposome tissue distribution and blood clearance. Our approach is based on remote loading of a copper-radionuclide (⁶⁴Cu) into preformed liposomes and copper entrapment by an encapsulated copper-chelator. We show that the ⁶⁴Cu-liposomes provide quantitative in vivo imaging in canines with spontaneous tumors using PET. Seven canines with spontaneous tumors were included in the study where the main focus was to evaluate the EPR effect in large animals with spontaneous tumors and the performance of the developed liposome imaging agent. None of the included dogs displayed any anaphylactic, toxic or adverse reactions. Liposome circulating half-life ranged from 24.2 hours to 54.2 hours, with a mean half-life of 35.0 ± 4.24 hours. The study showed that the EPR effect assures substantial tumor accumulation in some but not all spontaneous tumors in canines. The included carcinomas displayed higher mean and maximum uptake levels of liposomes relative to the included sarcomas. The ⁶⁴Cu-liposomes have potential as a diagnostic tracer in cancer diagnostics and in particular in companion diagnostics for nanotherapy. We envision that the ⁶⁴Cu-liposomes will be an important tool for evaluating liposome performance in future and may become an important tool in selection of cancer patients for nanoparticle based chemotherapy.

Nanoscale Interface between Engineered Matter, and Living Organisms: Understanding the Biological Identity of Nanosized Materials
Kenneth Dawson, PhD, University College Dublin

Nanoscale materials can interact with living organisms in a qualitatively different manner than small molecules. Crucially, biological phenomena such as immune clearance, cellular uptake, and biological barrier crossing are all determined by processes on the nanometer scale. Harnessing these endogeneous biological processes (for example, in the creation of new nanomedicines or nanodiagnostics) will therefore require us to work on the nanoscale. This ensures that nanoscience, biology, and medicine will be intimately connected for generations to come, and may well provide the best hope of tacking currently intractable diseases.
 
These same scientific observations lead to widespread concern about the potential safety of nanomaterials in general. Early unfocused concerns have diminished, leaving a more disciplined and balanced scientific dialogue. In particular a growing interest in understanding the fundamental principles of bionano-interactions may offer insight into potential hazard, as well as the basis for therapeutic use.
 
Whilst nanoparticle size is important, the detailed nature of the nanoparticle interface is key to understanding interactions with living organisms. This interface may be quite complex, involving also adsorbed proteins from the biological fluid (blood, or other), leading to a “protein corona” on the nanoparticle surface that determines its “biological identity.” We discuss how this corona is formed, how it is a determining feature in biological interactions, and indeed how in many cases can undermine efforts at targeting nanoparticles using simple grafting strategies. Thus, nanoparticle interactions with living organisms cannot be fully understood without explicitly accounting for the interactions with its surroundings (i.e., the nature of the corona).

Nanoparticles Can Cause DNA Damage Across a Cellular Barrier
Charles Patrick Case, PhD, University of Bristol

Increasing use of nanoparticles in medicine has raised concerns over their ability to gain access to privileged sites in the body. Nanoparticles can damage human fibroblast cells and human embryonic stem cells across an intact cellular barrier without having to cross the barrier. The damage was mediated by a novel mechanism involving transmission of purine nucleotides such as ATP and intercellular signaling within the barrier through connexin gap junctions or hemichannels and pannexin channels and the generation of mitochondrial free radicals.
 
This indirect damage depended on the thickness of the cellular barrier. Indirect damage was seen across both trophoblast and corneal cell barriers. Signaling, including cytokine release, occurred only across bilayer and multilayer barriers. Indirect toxicity was observed in mice and using ex vivo explants of human placenta. The outcome, which included DNA damage without significant cell death, was different from that observed for direct exposure of cells to nanoparticles. Our results suggest the importance of indirect effects when evaluating the safety of nanoparticles. The potential damage to tissues located behind cellular barriers needs to be considered when using nanoparticles for targeting diseased states.

Challenges in Preclinical Characterization of Engineered Nanomaterials
Marina A. Dobrovolskaia, PhD, Nanotechnology Characterization Laboratory, Advanced Technology Program for SAIC-Frederick Inc., NCI-Frederick

Nanomedicine is a rapidly growing field. Nanoparticles are being developed for many industrial and biomedical applications. The clear benefits of using nanosized products in these applications are often challenged by questions regarding safety of these materials. One area of interest involves the interactions between nanoparticles and the components of the immune system. Nanoparticles can be engineered to either avoid immune system recognition or to specifically interact with the immune system. This presentation will review data regarding nanoparticle-mediated immunostimulation and immunosuppression, 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 interaction with erythrocytes, 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 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.

Implications of Nanoparticle-Mediated Complement Activation in Cancer: Can they Accelerate the Disease?
SM Moghimi, PhD, University of Copenhagen

The complement system is a key effector of both innate and cognate immunity and is responsible for rapid detection and elimination of particulate intruders in nano- and micro-size ranges. Complement triggering primes the intruders’ surface for rapid recognition and clearance by phagocytic cells. It also induces inflammatory responses, but such responses arising from uncontrolled complement activation could be life threatening. Complement recognizes danger signals primarily through pattern recognition. This is of prime concern in the design and engineering of nanomedicine as these entities are often composed of polymeric components and other patterned nanostructures. Indeed, there is compelling evidence that complement activation may be a contributing factor in eliciting acute-like reactions to regulatory-approved cancer nanomedicines, including stealth entities, in sensitive individuals. Mechanistic issues pertaining these responses will be discussed in relation to stealth liposomes and polymeric nanospheres, PEGylated carbon nanotubes, graphene oxide, and other related entities. Finally, contrary to the conventional belief that complement can be used to kill cancer cells, recent studies have demonstrated that intratumoural complement activation help tumor growth and progression. This is partly due to the ability of the complement anaphylatoxin C5a to recruit myeloid-derived suppressor cells into malignant tumors. Accordingly, intratumoral nanoparticle-mediated complement activation (either directly or through cell death-mediated processes) with resultant C5a generation could complicate nanomedicine-based tumor therapy. Such concerns may also apply to particulate entities that target resident clotted plasma proteins located in tumor vasculature and subsequently amplify their own homing through introduction of further clot formation. Notably, extrinsic proteases such as kallikerin and thrombin can directly cleave C3 and C5. Rational approaches for design and engineering of novel and effective cancer nanomedicines should start to take the concept of complement-mediated tumor growth into account and will be discussed.

Travel & Lodging

Event Location

Rockefeller Research Laboratories Auditorium
1st Floor
430 East 67th Street
New York, NY 10065

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