Life Sciences - Monachino

National Cancer Institute Dedicated to discovery aimed at the eradication of cancer

Where would we like to be? Detection and Diagnosis Year 0

Prevention

Malignant Tumors With Metastases Year 3

Year 6

Year 10

NCI Initiatives in Nanotechnology •Mechanical/Sensors •Cantilever, Nanowires, AFM, CNT •Biological •Nanoshells, nanoparticles, quantum dots •Molecular Analysis/Diagnostics •Structure, size, orientation, sequence •Functional •Detection, contrast enhancement, treatment, monitoring •Smaller enables operations on the molecular scale. •Less power, more sensitivity, parallel tests •In vivo, detection to treatment, non-intrusive, one visit

Cantilever

Quantum Dot

X

Target Molecule

X

Y ZnS

CdSe

CO2H DNA-DNA, Protein-Protein, DNA-Protein interactions can be studied on one platform No molecular label required Direct color-based visual readout

AFM/CNT single molecule detection enables both SNPs and haplotypes to be determined. high-resolution analysis of 1001000 kb in single shot.  no sample amplification required.

SH NH2

Quantum Dots can be transferred to water and functionalized with Specific affinity molecules.

Smart Nano-Device Therapeutic • Targets to Tumor • Imaging Capability to Document Presence in Tumor • Senses Tumor Cells for Pathophysiologic Defects • Selects Therapeutic Agents Based on Tumor Characteristics • Non-invasive External Trigger Releases Therapeutics • Documents Response to Therapeutic • Identifies Residual Tumor cells

Example of a Nanoparticle Single Dendrimer Agent (5.0nm in diameter) Contrast Agent

Target Director

Sensing Fluorochrome

Trigger Mechanism/ Nanocomposite

Dendrimer Cluster Agent (approx. 18 nm in diameter) Sensing Fluorochrome Module Contrast Module

Target Director Module

Therapeutic

•Target to tumor •Imaging Capability to document presence of tumor •Therapeutic agent delivered •Documents response to therapeutic •Identifies residual tumor cells

Interior-carried Therapeutic or Nanocomposite

Light-activated Therapeutic

Nanotechnology Benefit •Diagnostics •Real time, at home, disposable •Early warning •More sensitive (measure subtle changes) •Less sample required •Less sample preparation (no PCR, no amplification) •Rapid screening •thousands of molecules in drop of blood •thousands of drug candidates at once •In parallel: •1 person all diseases •1 disease, 1000 people •1 disease, 1000 drug candidates •1000’s of genes/proteins sequenced

Patient Benefit

•Real time diagnosis •Real time patient care, treatment, and monitoring response to treatment •Minimizes invasiveness and pain •Minimizes multiple visits •Cancer detection at it’s earliest stages •Potential to end chemotherapy and radiation treatment as we know it today

Nano Science and NanoTechnologies: NIH priorities for 2002 Nanomaterials: nano materials science to interface with living tissues, passive delivery of pharmaceuticals, enable tissue engineering, and for contrast and biologically active agents. Nano-imaging: real-time intracellular imaging of structure, function and metabolism. Cell biology: nano-scale research of cellular processes, including biophysics of molecular assemblies, membranes, organelles, and macromolecules. Molecular and Cellular Sensing/Signaling: technologies to detect biological signals and single molecules within and outside cells. Nano-motors: understanding fundamental principles of nanomotor structure, function, design and self-assembly. Prosthetics: mechanical, chemical, and cellular implant nanotechnologies to achieve functional replacement tissue architectures. (Active components that replace a biological function, e.g., actuation). Nano-Bio Processor: an implantable nano equivalent of a microprocessor capable of controlling genetic, biological and metabolic processes. Possible applications include; health status monitor, prosthetic control, drug delivery control and status, information extraction and reporting to external source/physician, and electrical stimulation for neural system, etc. Nanosystem Design and Application: fundamental principles and tools to measure and image the biological processes of health and disease, and methods to assemble functional nanosystems. This could also be tools to design nanosystems.

National Nanotechnology Investment in the FY2003 Budget Request by the President

DoD DARPA; nanostructures in biology & info, Chem/Bio sensors USAF; nanocomposites, nanoprocessing, nanoenergetics, nanoelectronics, nanophotonics USA; nanomaterials for soldier protection DOJ -Wearable Chem/Bio sensors -Chip based or microdevice technologies to analyze DNA in forensic applications DOT -Sensors to detect explosives & hazardous chemicals including chem/bio weapons (a/p chkpt) EPA -Sensors for environmental monitoring, and food safety USDA -New materials (textiles and polymers) -DNA –enzyme interactions, single molecule interactions -Biosensors & sensing systems DOE -Facilities for synthesis, processing, fabriaction, and analysis of materials at nanoscale -Computational tools for nanoscale science -Sensors

National Nanotechnology Investment in the FY2003 Budget Request by the President NASA -Materials and structures -Nanoelectronics and computing -Sensors & spacecraft components NIH -Sensors & tools for understanding at molecular level & cellular level -Detection, treatment, monitoring of disease NIST -Nanomaterials -Nanocharacterization (standards & tools) -Information technology, replacing semiconductors NSF -Electronics, optoelectronics -Biology -Advanced materials & engineering -Education -Nanoscale manufacturing

National Nanotechnology Investment in the FY2003 Budget Request by the President -Sensors (Chem/Bio/Explosives, Environmental, Health, Molecular) -Materials (Composites, Polymers, Magnetics, Photonics, Electronics)

-Fabrication (Tools, Standards, Process)

Structure future efforts to minimize redundancy, and maximize the expertise of the government agency

NIH Funding Mechanisms Research Projects -P01 -R01-R37 -R41-R44 -U01-U44 -P20-P50

Integrated, Multiproject Research Research SBIR/STTR Cooperative Agreement Centers

Research Training Opportunities -T32-T35 Institutional Research Training -F31-F33 Individual Fellowships -K01-K30 Career Development Programs Contracts Most announcements are open to all (university, small/large business, government agency)

Decision Tree to Determine Technology Maturation End Goals Is commercialization the end goal?

yes

Possible End Goals: 1. License technology 2. Technology/IP exchange 3. Partnership 4. Start a business

Is the technology aimed at clinical applications?

yes Possible End Goals: 1. Clinical research tool 2. Clinical medical product If successful, where can the results make the greatest impact.? Determine what kind of collaborator I need?

no Possible End Goals: 1. Disseminate information to public domain 2. Research tool/know-how for the community

no Possible End Goals: 1. Bench Research tool

FDA approval (animal trials, Human trials) What metrics to evaluate whether my goal is still appropriate?

Require resources from NCI, state, or university?

Commercialization Assistance Program (CAP)  Program offered by Agencies  individuals and companies to which they have provided R&D funding

 No cost to program participant for services  Participants invest considerable time  Must participate in 1-3 events

 Objective - Increase likelihood of commercializing technology & obtaining private sector funding & partnerships  Develop business plan, presentation materials  Culminates in investor /partnering event

Process for assisting companies • Assigned to a portfolio manager – Highly experienced individual – Provides guidance, feedback, preliminary market research

• Business Planning for Scientists & Engineers text used as guide • Highly interactive program – Interact around selected activities called Interim Reports • E-mail, phone

Overview of CAP

•Outreach •Kick-Off •Interactive Business Planning (5) •Biz Plan Critique •Recommendation & Selection •Advanced Commercialization Workshop •Plan Revisions & Presentation Materials •Investor Outreach •Presentation •Workshop •Forum •Follow-Up

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Multidisciplinary

• Curriculum • Research • Centers

Summary • Life Sciences Focus: • Provided a list of NIH priorities • Analysis and Functionality on the Molecular Scale • Provided a high level summary based on Presidential Budget • Materials, Sensors, Fabrication

• How to Accelerate the Transition of Science to Application • • • •

Combination of Grants and Contracts Universities, small/large business, government agencies Multidisciplinary support Get the researcher thinking commercialization early (e.g. CAP)

• How Should They Compete for Funding • Task each government agency with a focus area that maximizes their expertise and limits redundancy

BACKUP

The Genetic Basis of Cancer • Cancer results from the gradual accumulation of multiple genetic changes in single cells

Cancerous cells undergo a gradual transformation and often go undetected for years Detection and Diagnosis Year 0

Year 3

Malignant Tumors With Metastases

Year 6

Therapy

Year 10

Innovative Molecular Analysis Technologies Program Creating the Toolkit to Enable Molecular Discovery and Speed Cancer Research Technologies suitable for in vitro, in situ, in vivo, and in silico analysis of: –alterations and instabilities in genomic DNA –expression of genes and gene products –cellular localization, post-translational modification, and function of proteins; and –monitoring major signal transduction networks involved in cancer

Phased Innovation Awards • Single submission and evaluation of both the R21 and the R33 as one application, including: • R21 phase – including measurable milestiones • R33 phase – including a credible development plan

• Flexible staging of feasibility and development phases • R21 phase up to 2 years • R33 phase 1 to 3 years • 4 year maximum

• Parallel solicitation utilizing the SBIR and STTR mechanisms for small business • Three receipt dates a year: March, July, November

Nanomechanical Biosensors for High-Throughput Molecular Analysis 200

[BSA] = 1 mg/ml s

Target Molecule

[nm]

Quantitative Detection of PSA

Phenomenon

150 100

fPSA Cantilever: 600 µ m long, 0.65 µ m thick

50

Steady-state Deflection, h

10-2

Cantilever: 366 µ m long, 0.65 µ m thick

fPSA cPSA fPSA

Cantilever: 200 µ m long, 0.5 µ m thick

0

200 µ m Long, 0.5 µ m Thick Silicon Nitride Cantilever

Clinical Threshold of PSA Concentration (4 ng/ml)

10-1 100 101 102 103 104 PSA Concentration [ng/ml]

•Guanghua Wu, Arun Majumdar (Mechanical Engineering, UC Berkeley) •Karolyn Hansen, Hifeng Ji, Thomas Thundat (Biophysics, Oak Ridge Natl. Lab.) •Ram Datar, Richard Cote (Cancer Pathology, U. Southern Cal.)

Supported by NCI: Innovative Technology Program

105

Nanowire Nanosensors nanowire

nanowire

substrate

substrate

 Binding of chemical or biological species to the surface of a nanowire will result in depletion or accumulation of carriers.  The change in carrier concentration due to binding can be directly monitored by measuring the nanowire conductance.

DNA Analysis with Nanotube Probes Charles Lieber Harvard University

 single molecule detection enables both SNPs and haplotypes to be determined.  high-resolution analysis of 100-1000 kb in single shot.  no sample amplification required. Woolley & Lieber, Nature Biotech (2000) Hahm & Lieber, submitted PNAS (2002)

QUANTUM DOTS – A NOVEL LUMINESCENT LABEL FOR CELLULAR IMAGING Homogenous, highly crystalline Material with extraordinary optical Properties. They can be transferred to water and functionalized with Specific affinity molecules. X Y X ZnS ZnS

CdSe

CdSe

CO2H

SH NH2

LABELING OF SPECIFIC BREAST CANCER MARKERS WITH CONJUGATED NANOCRYSTALS Antigen/ Cell Type

Label

P53 SKBR3 cells

-535nm Savnanocrystal

Estrogen receptor MCF7 cells

- 535nm Savnanocrystal

Her2 Breast cancer Tissue section

-630nm Savnanocrystal Hugh Daniels Quantum Dot Corporation

Unconventional Innovations Program:Technical Goal • Technology platforms integrating: > non-invasive sensing of molecular alterations in vivo > transmission of information to an external monitor > controlled intervention specific for the molecular profile > monitoring of intervention

Breast Adenocarcinoma Therapeutic Device FGF receptor MUC1, Her2, or mutated p53 Sensing Module

Gadolinium Contrast Agent Module

Interior-carried Therapeutic: Light-releasable Cis-platin or Taxol

Folate Receptor EGF receptor Muc1 FGR receptor 2 C-Met nCAM Muc1 Her2

Fluorogenic Apoptosis Sensing Module

UNIVERSITY OF MICHIGAN Raoul Kopelman, Ph.D. This contract targets the development of advanced nanoparticles (10 to 100 nm) that link the functions of detection and therapeutics. Specifically, targeted MRI, optical imaging, and photodynamic therapy will be supported by the same dynamic nano-platforms (DNP); nanoparticles with conserved cores. Activities will focus on making and implementing conserved, multipurpose systems, using novel concepts of hybrid chemical materials, to make DNP that combine several functions. These functions will include multiple targeting, magnetic contrast, luminescence, and photodynamic therapy through direct massive delivery of reactive oxygen species. .