The Workings of NCI Nanotechnology Alliance for Cancer – an Opportunity for a New Class of Diagnostic and Therapeutic Solutions Based on Nanotechnology nanoUtah 2007 October 26, 2007 Piotr Grodzinski, Ph.D. Director, NCI Nanotechnology Alliance National Cancer Institute
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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
180.7
48.1
586.8
193.9
53.3
190.1231.5
0
100
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HeartDiseases
CerebrovascularDiseases
Pneumonia/Influenza
Cancer
19502003
Dea
th R
ate
Per
100,
000
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
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
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)
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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Days after Treatment
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Taxol
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Anti-tumor EffectsAnti-tumor Effects
PRINTTM Particles: CDI-Activated PEG for Functional Targeting
PRINTTM Particles: CDI-Activated PEG for Functional Targeting
O
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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