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

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193.9

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HeartDiseases

CerebrovascularDiseases

Pneumonia/Influenza

Cancer

19502003

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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

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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