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The Workings of NCI Nanotechnology Alliance for Cancer –an Opportunity for a New Class of Diagnostic and Therapeutic Solutions Based on Nanotechnology
nanoUtah 2007October 26, 2007
Piotr Grodzinski, Ph.D.Director, NCI Nanotechnology Alliance
National Cancer Institute
We Must Accelerate Progress Against CancerWe Must Accelerate Progress Against Cancer
21.9
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48.1
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193.9
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0
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HeartDiseases
CerebrovascularDiseases
Pneumonia/Influenza
Cancer
19502003
Dea
th R
ate
Per
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Unlike Other Major Disease Killers, Cancer Continues to Take the Nearly Same Toll As In 1950
Source for 2005 deaths and diagnoses: American Cancer Society (ACS) 2005 Cancer Facts & Figures; Atlanta, GeorgiaSource for 2003 age-adjusted death rate: National Center for Health Statistics, U.S. Department of Health and Human Services, NCHS Public-use file for 2003 deaths.
Nanotechnology is a “disruptive technology”which will drive a new generation of cancer
diagnostic and therapeutic products, resulting in dramatically improved cancer outcomes
The Potential of Nanotechnology in CancerThe Potential of Nanotechnology in Cancer
Early detection – highly sensitive and specific sensors
In-vivo imaging – new contrast agents, localization
Therapeutics – local, on-particle delivery
Nanotechnology is an Enabler of New Solutions for CancerNanotechnology is an Enabler of New Solutions for Cancer
Early detection Imaging Therapy
• Molecular imaging and early detection
• In vivo imaging
• Reporters of efficacy
• Multifunctional therapeutics
• Prevention and control
• Research enablers
Focus Areas:
Highly talented multi-disciplinaryresearch teams
Sciences, medicine, and engineeringCompetition and collaboration
Synergy and difference
Can we build a bigger whole?
NCI Nanotechnology AllianceThe OpportunityNCI Nanotechnology AllianceThe Opportunity
• promote the development of state-of-the-art nanotechnologies for cancer applications
• accelerate the translation of the discoveries into clinically relevant diagnostics and therapeutics
Major Programs of the Alliance:
Centers of Cancer Nanotechnology Excellence
Multidisciplinary Research Teams• Training• Interagency Collaborations
Nanotechnology Platforms for Cancer Research
Nanotechnology Characterization Laboratory
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NCI Nanotechnology Alliance - StrategiesNCI Nanotechnology Alliance - Strategies
NCI Nanotechnology Alliance - AwardsNCI Nanotechnology Alliance - Awards
Centers of Cancer Nanotechnology Excellence (8)
Cancer Nanotechnology Platform Partnerships (12)
Nanotechnology Platform for Targeting Solid Tumors, The Sidney Kimmel Cancer Center, San Diego, Calif.
Detecting Cancer Early with Targeted Nano-probes for Vascular Signatures, University of California, San Francisco, Calif.
Nanotechnology Platform for Pediatric Brain Cancer Imaging and Therapy, University of Washington, Seattle, Wash.
Near-Infrared Fluorescence Nanoparticles for Targeted Optical ImagingUniversity of Texas M. D. Anderson Cancer Center, Houston, Texas
Hybrid Nanoparticles in Imaging and Therapy of Prostate Cancer, University of Missouri, Columbia, Mo.
DNA-linked Dendrimer Nanoparticle Systems for Cancer Diagnosis and Treatment, University of Michigan, Ann Arbor, Mich.
MetallofullereneNanoplatform for Imaging and Treating Infiltrative Tumor, Virginia Commonwealth University, Richmond, Va.
Novel Cancer Nanotechnology Platforms for Photodynamic Therapy and Imaging, Roswell Park Cancer Institute, Buffalo, N.Y.
Multifunctional Nanoparticles in Diagnosis and Therapy of Pancreatic Cancer, State University of New York, Buffalo, N.Y.
Integrated System for Cancer Biomarker Detection, Massachusetts Institute of Technology, Cambridge, Mass.
NanotherapeuticStrategy for MultidrugResistant Tumors, Northeastern University, Boston, Mass.
Photodestructionof Ovarian Cancer: ErbB3 Targeted Aptamer-NanoparticleConjugate, Massachusetts General Hospital, Boston, Mass. Carolina Center
of Cancer Nanotechnology Excellence, University of North Carolina, Chapel Hill, N.C.
NanosystemsBiology Cancer Center, California Institute of Technology, Pasadena, Calif.
Center of Nanotechnology for Treatment, Understanding, and Monitoring of Cancer, University of California, San Diego, Calif.
Emory-Georgia Tech Nanotech-nology Center for Personalized and Predictive Oncology, Atlanta, Ga.
Nanomaterials for Cancer Diagnostics and Therapeutics, Northwestern University, Evanston, Ill.
The Siteman Center of Cancer Nanotechnology Excellence at Washington University, St. Louis, Mo.
Center for Cancer Nanotechnology Excellence Focused on Therapy Response, Stanford University, Palo Alto, Calif.
MIT-Harvard Center of Cancer Nanotechnology Excellence, Cambridge, Mass.
NCI Alliance for Nanotechnology in Cancer: Project Make-upNCI Alliance for Nanotechnology in Cancer: Project Make-up
Year 1
2006
Year 2
2007
• Major changes (>30%)• Melanoma (4 9)• Lung cancer (4 8)• Brain cancer (6 9)
• Additional changes• Breast cancer (19 23)• Prostate cancer (15 18)• Lymphoma (5 7)• Ovarian cancer (5 7)• Color cancer (4 5)
*Red indicates increase in incidence for 2007
• Nanoparticles• Quantum dots• Polymer particles• Dendrimers• Magnetic particles• Nanoshells• Nanotubes• Virus engineered particles
Clinical Applications Using NanoparticlesClinical Applications Using Nanoparticles
• Multiple functions• Tissue targeting
• Tumor-specific binding• Sensing or imaging capability
• Improved sensitivity• Multi-modal imaging
• Non-invasive treatment• Therapeutic localized delivery• Localized cell kill• Lower dose administered• Improved side effect profile
Nanotechnology for Cancer: Evolution and ProgressNanotechnology for Cancer: Evolution and ProgressTr
eatm
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1) ‘Nano’ in-vitro sensorsEarlier diagnostics
2) Traditional therapy
1) ‘Nano’ in-vitro sensorsEarlier diagnostics
2) Localized nano-therapyMore effective treatment
Reduced side effects
1) Quantitative in-vivonano-sensors
Further improved diagnostics
2) Localized nano-therapyMore effective treatment
Reduced side effects
Nanotechnology will allow for the development of:Highly accurate in-vitro and in-vivo sensors andPlatforms for localized therapy
Alivisatos et al.
Q-dots
Nanocrystals for E-chem det.
Nicewarner-Pena et al., Science 294, 137 (2001)
J. Wang, Analytica ChimicaActa 500 (2003) 247
Multiplexed Diagnostic AssaysMultiplexed Diagnostic Assays
G. Wu and A. Majumdar, Nature Biotech 19, 856 (2001)
Nanorods
Cantilevers
In-vitro DiagnosticBiomarker Recognition
1. Up to one million times more sensitive than conventional ELISAs.
2. Evaluate new biomarkers for diagnosing and following human diseases (e.g. Cancer, HIV, Alzheimer’s Disease).
3. Single-cell protein expression experiments.
Stoeva, Thaxton, Mirkin, Multiplexed DNA Detection with Biobarcoded Nanoparticle Probes, Angew Chem Int 45, 3303 (2006)
Cheng, Cuda, Bunimovich, Gaspari, Heath, Mirkin, Ferrari et al., Nanotechnologies for biomolecular detection and medical diagnostics, Curr Opin Chem Biol. 10, 11 (2006)
Bio-barcode Assay for DNA and Protein DetectionBio-barcode Assay for DNA and Protein Detection
Biomolecule Detection Technologies –Sensitivity ComparisonBiomolecule Detection Technologies –Sensitivity Comparison
Colorimetric/Enzymatic ChemistryBlood Sugar (Diabetes)
ELISA & ChemiluminescenceTroponin, CK-MB, BNP, βHCG
Bio-barcode TechnologyCancer: Prostate, Ovarian, BreastAlzheimer’s Disease, Mad CowPulmonary Disease, Cardiovascular Disease
Quantification and Comparison of Breast Cancer Biomarkers Using Ab-Conjugated QDsQuantification and Comparison of Breast Cancer Biomarkers Using Ab-Conjugated QDs
• ER, PR, and HER2 can be detected using multiplex QDssimultaneously on specimens of breast cancer cell lines
• ER, PR and HER2 detected using QD-Abs can be quantified using spectrometry
• Detection/quantification of ER, PR and HER2 using QD-Abs correlated well with standard methods (IHC and Western Blotting)O’Regan et al., submitted to PNAS
Microfluidics for DiagnosticsMicrofluidics for Diagnostics
R.Liu, P. Grodzinski et al., Anal Chem 76, 1824 (2004)
Gao and Nie, Nature Biotech 22, 969 (2004)
Human prostate cancer growing in nude mice
QDs functionalized with PSMA
In vivo fluorescence images of tumor using QD probes
Multi-color imaging using the same excitation source
Quantum Dots for In-vivo ImagingQuantum Dots for In-vivo Imaging
Wide range of wavelength coverage using different materials
Michalet and Gambhir, Science 307, 538 (2005)
In-vivo DiagnosticImaging of Tumor
Tissue
Novel Quantum Dots That Do Not Require External IlluminationNovel Quantum Dots That Do Not Require External Illumination
• Quantum dots conjugated with fluorescent proteins bioluminesce in response to an enzyme-catalyzed reaction
• Bioluminescence resonance energy transfer (BRET) is shown for the first time with quantum dots
• Blood does not interfere with quantum dot signal
So, Gambhir, Rao et al., Self-illuminating quantum dot conjugates for in vivo imaging,Nat. Biotechnol. 24, 339 (2006)
Nanoparticles (dextran-coated iron oxide crystals, Combidex) injected into the circulation travel to the lymph nodes. Metastatic tumors growing in the nodes interfere with particle distribution, and this is detectable by MRI. 80 men undergoing surgery or biopsy for prostate cancer had MRI exams both with and without the nanoparticles before surgery. 33 of the men actually had metastatic lymph nodes. MRI with the particlesidentified all 33, whereas MRI without the particles missed more than half of them.
image reconstructiongreen: normalred: malignant
malignant
normal
Conventional MRI
Nanoparticle imaging
NEJM, 2003, 348:2491-2499
Nanoparticle-based Detection of Lymph Node MetastasisNanoparticle-based Detection of Lymph Node Metastasis
Ralph Weissleder (MGH, Harvard Medical School) Jean de la Rosette (Netherlands)
Magnetic Nanoparticles for Ultra-Sensitive Magnetic Resonance Imaging
Magnetic Nanoparticles for Ultra-Sensitive Magnetic Resonance Imaging
12 nm size of various ferrite nanoparticles
Cheon et al. Nature Medicine 2007, 13, 95Tom Meade et al, Northwestern U.
Pegylated particles After MMP cleavage do not assemble assembly occurs
Nanoassemblies provide for:
Magnetic susceptibility
T2 relaxivity
Diffusivity
MRI Detection of Tumor Derived Cells via ProteolyticActuation of Nanoparticle AssemblyMRI Detection of Tumor Derived Cells via ProteolyticActuation of Nanoparticle Assembly
• Nanoparticles assemble only in the presence of two enzymes associated with tumorigenesis: 1) MMP2 – associated with tumor metastasis, invasion, and angiogenesis; 2) MMP7 -promotes an anti-apoptotic phenotype in the tumor milieu
• Initial restriction of assembly is achieved through attachment of MMP2 peptide-PEG or the MMP7 peptide-PEG polymers to biotin and neutravidin particles, respectively
Harris, Ruoslahti, Bhatia et al., Proteolytic Actuation of NanoparticleSelf-Assembly Angew. Chem. Int. 45, 3161 (2006)
Multi-Functional Nanoparticle-based TherapiesMulti-Functional Nanoparticle-based Therapies
• Multi-functional platforms: • Targeting• Delivery• Reporting, biosensing
In one package
Free drug formulations do not possess multi-functional
characteristics
First generation of nano-delivered drugs (no targeting) approved by FDA – Abraxane®
M. Ferrari, Nature Reviews 5, 161 (2005)
Nanoshells:Photothermal therapy
N. Halas, J. West et al, Ann Biomed Eng. 34, 15 (2006)
Dendrimers: Targeted delivery of methotrexate
Nanoparticle-based Therapies: Different ApproachesNanoparticle-based Therapies: Different Approaches
J. Baker, et al., Cancer Res. 65, 5317 (2005)
Free MTX30 mg/kg total
Nanodevice MTX3 mg/kg total MTX
Kukowska-Latallo, Baker et al., Cancer Research, 65, 5317 (2005)
Multi-Functional Nanoparticle Platforms:Find – Detect - TreatMulti-Functional Nanoparticle Platforms:Find – Detect - Treat
Docetaxel-Encapsulated PLGA Nanoparticle-AptamerConjugatesDocetaxel-Encapsulated PLGA Nanoparticle-AptamerConjugates
Aptamers are non-immunogenic chemically processed DNA or RNA oligonucleotides that bind to antigen with high affinity and specificity; nanopaticle-aptamer conjugates have been developed for Prostate Specific Membrane Antigen (PSMA)
Farokhzad, Cheng, Langer et al., Targeted nanoparticle-aptamer bioconjugatesfor cancer chemotherapy in vivo, Proc Natl Acad Sci 103, 6315 (2006)
NP-Apt Conjugates: Comparative Efficacy StudyNP-Apt Conjugates: Comparative Efficacy Study
LNCaP s.c. xenograft nude mouse model of PCa; single intratumoral injection (day 0)
NP-Apt conjugates show greater efficacy in a xenograft mouse model than non-targeted nanoparticles
Tumor-activated Pro-drug Delivery and TargetingTumor-activated Pro-drug Delivery and Targeting
The anti-cancer agent is conjugated to a biocompatible polymer via an ester bond. The linkage is hydrolysed by cancer-specific enzymes or by high or low pH at the tumor site, at which time the nanoparticle releases the drug.
Sinha R, Kim G, Nie S, and Shin DM Mol Cancer Therapeutics 5, 1909 (2006).
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PRINTTM Particles: CDI-Activated PEG for Functional Targeting
PRINTTM Particles: CDI-Activated PEG for Functional Targeting
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Multiplexed Delivery of Targeted Anticancer Agents
Joe DeSimone, UNC
Cell Motility Studies to Deconstruct Metastasis
• Most anti-cancer therapeutics are anti-proliferativesbut most cancer deaths result from metastasis
• Need to rationally develop anti-metastasis therapeutics
• Metastasis requires directional cell motility• Cells in culture are heterogeneous
• Adhesion targeting assay• YFP-CLIP170 live in B16F1 melanoma cells• Marker for MT plus end• MT turning suggests a guided mechanism
M. Mrksich, U. ChicagoB. Grzybowski, Northwestern U.
Current StatusCurrent Status
• Development of new diagnostic and therapeutic platforms is at different levels of maturity
• Two drugs approved by FDA: 1) Abraxane – paclitaxelbound to albumin (American Pharmaceutical Partners) and 2) Doxil – liposome encapsulated doxorubicin
• Common scheme for therapeutics – use existing drugs and adapt them to nano-based delivery platform
• In-vitro diagnostic tools evaluate clinical samples
• Several companies (2-5) ready to file IND within next 12 months
Abraxis Pharmaceuticals Abraxane Albumin-bound paclitaxel
NSC lung cancer, breast, others Approved IV
Advanced Magnetics
Avidimer
BIND
Calando
Carbon Nanotechnology
Cytimmune
Cytimmune
Dendritic Nanotechnologies
ImaRx Therapeutics
Insert Therapeutics
Introgen
Kereos
Liquidia Technologies
Nanospectra Biosciences
OrthoBiotech
Triton Biosystems
Combidex Iron oxide nanoparticles Tumor imaging NDA filed IV
Platform, ATI-001 Targeted dendrimers Various cancer Pre-clinical IV
Platform technology Targeted PLGA-PEG nanoparticles
Prostate cancer, others Pre-clinical IV
Targeted siRNA Cyclodextrinpolymers- siRNA Cancer, others Pre-clinical IV
DF1 Dendritic fullerene Chemoprotection Pre-clinical IV
Aurimune TNFα-bound colloidal gold Solid tumors Phase I IV
Auritol Taxol and TNFα-bound colloidal gold Solid tumors Pre-clinical IV
Dendrimer-Magnevist PAMAM dendrimer MRI imaging agent Pre-clinical IV
MRX-951 Self-assembling block copolymer Cancer Pre-clinical IV
Cyclosert-camptothecin
Cyclodextrinnanoparticles
Metastatic solid tumors Phase I IV
INGN-401 Liposome Metastatic lung cancer Phase I IV
Platform technology Perfluorocarbonpolymers
Cancer and cardiovascular Pre-clinical IV
Platform technology PRINT™nanoparticles Cancer, others Pre-clinical IV
AuroLase Gold nanoshell Head and neck cancer Pre-clinical IV
Doxil PEGylated liposome Metastatic ovarian cancer Approved IV
TNT-Anti-Ep-CAM Polymer-coated iron oxide Solid tumors Pre-clinical IV
Company Product(s) Material Indication Status Admin.
Priorities and Wish ListPriorities and Wish List
• Biomarker libraries
• Novel and more effective approaches to tumor targeting
• Multiplexed sensors with high sensitivity and specificity
• Multi-modality constructs for imaging
• Therapy – localized delivery should result in lower site effects. Would it result in more effective treatment?
• Nanotechnology and prevention
• Tools to monitor and understand metastasis
• Predictive modeling tools
Travis Earles
Jerry Lee
Linda Molnar
Larry Nagahara
Acknowledgements: NCI Nanotechnology Program OfficeAcknowledgements: NCI Nanotechnology Program Office
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