1. Cancer Nanotechnology: New Opportunities for Targeted Therapies FDA Public Meeting October 10, 2006 Piotr Grodzinski, Ph.D. Director, Nanotechnology for Cancer Programs Office of Technology and Industrial Relations National Cancer Institute

2. Provides multi-functionality: targeting, delivery, reporting Provides improved therapeutic index Provides lowered toxic side effects Delivers multiple drugs directly to tumor site Enables nucleic acid delivery Enables non-drug therapies (photothermal, photodynamic) Nanotechnology-based Drug Delivery: Key Benefits Nanomaterial characterization: Responsible, Systematic, Standardized

3. Multi-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)

4. Nanoshells: Photothermal therapy N. Halas, J. West et al, Ann Biomed Eng. 34, 15 (2006) Dendrimers: Targeted delivery of methotrexate Nanoparticle-based Therapies: Different Approaches J. Baker, et al., Cancer Res. 65, 5317 (2005)

5. Uncertainties of Moving Multi-Functional Nanoparticles to the Clinic Differences exist between the development and regulatory pathway for multi-functional nanoparticles and “traditional” drugs and devices. Need to: Define the classification (decision tree) in order to determine the characterization process ahead of the submission Provide interfaces within the regulatory agencies Establish uniform, publicly available guidelines for the investigators Determination if therapy is new when it uses an existing drug on a novel delivery platform is a challenge Gap exists between technology development in an academic setting and further technology maturation through clinical development and regulatory approval

6. NCI Strategy: Alliance for Nanotechnology in Cancer A comprehensive, systematized initiative encompassing the public and private sectors, designed to accelerate the use of the best capabilities of nanotechnology to cancer applications Centers of Cancer Nanotechnology Excellence (CCNEs) and Cancer Nanotechnology Platform Partnerships (CNPPs) To develop novel technologies to deliver drugs more effectively To develop new, highly sensitive and specific diagnostic techniques Nanotechnology Characterization Laboratory (NCL) To develop a standardized assay cascade for preclinical characterization To identify physical parameters and structure-activity relationships for biocompatibility Not to address animal efficacy, SAR, PK or PD studies, or manufacturing

7. Next step Adapted from Challenge and Opportunity on the Critical Path to New Medical Products (http://www.fda.gov/oc/initiatives/criticalpath/ whitepaper.html) Nanoparticle Translation Mechanism: From Early Development to the Clinic Opportunities: Leverage NCL capabilities Scale up the material manufacturing (GMP) Provide studies towards IND filing Initiate Phase 0/Phase I trials Challenges: High cost Low interest in academic environment, where most of the innovation resides Partnerships with the industry needed Nanotechnology Alliance, NCL

8. Nanotechnology: Environmental and Safety Considerations Hazard identification In vitro toxicity Acute in vivo toxicity Subchronic/chronic toxicity Route of exposure Dose response External dose Internal dose Biologically effective dose Exposure assessment Human exposure Nanomaterials production Chronic exposure of the worker Nanomaterials use for biomedical applications Preclinical studies

9. Interagency Collaborations Characterization Critical path development Training Public Interface Interpret Data on Environment, Health and Safety Shared Data and Platforms Standards/Precision Measurement Capabilities Nanobiotechnology Training