The Fusion of MolecularThe Fusion of MolecularImaging into ClinicalImaging into ClinicalMedicine: A role forMedicine: A role for

AAPM?AAPM?

Gary D. Fullerton, Ph.D., FACR, FAAPM, FISMRMGary D. Fullerton, Ph.D., FACR, FAAPM, FISMRMMalcolm Jones Distinguished Professor of RadiologyMalcolm Jones Distinguished Professor of Radiology

ViceVice--Chair for ResearchChair for ResearchRadiology Department, UTHSCSARadiology Department, UTHSCSA

Molecular ImagingMolecular Imaging

�� Broadly defined as the spatially and temporallyBroadly defined as the spatially and temporallymeasured set of measurements of biological processesmeasured set of measurements of biological processesat the cellular and molecular level when visualized as anat the cellular and molecular level when visualized as anoptical image by the human observer.optical image by the human observer.

�� Probes or measures of molecular abnormalities that areProbes or measures of molecular abnormalities that arethe basis of disease rather than imaging the end productthe basis of disease rather than imaging the end productof these molecular deficiencies.of these molecular deficiencies.

�� Molecular imaging has only recently come into clinicalMolecular imaging has only recently come into clinicalapplication at the most rudimentary level and mostapplication at the most rudimentary level and mostpresent research is preclinical.present research is preclinical.

�� Why is this so?Why is this so?�� Is there a role for AAPM members?Is there a role for AAPM members?

Molecular Imaging

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R Weissleder and UMahmoud (2001)Radiology

Foundationfor MolecularImaging inGeneticResearch

• Diverse genetic error combinations• Disease is highly individual• Diversity offer many biomarkers• Imaging biomarkers – FDA approval• Approval restricts availability• Individualized biomarkers - SLOW

R Weissleder and U Mahmoud (2001) Radiology

Target Selection for MolecularTarget Selection for MolecularImagingImaging

R Weissleder and U Mahmoud (2001) Radiology

Molecular Imaging StrategyMolecular Imaging Strategy 1. Target Screening1. Target Screening –– VEGFVEGFConjugation of DOTA toConjugation of DOTA to AntibodyAntibodyAvastinAvastin + Radiolabeling with+ Radiolabeling with 6464CuCu

Wipke BT, Wang Z, et al. Nature Immunology, 2002, 3, 366-372.

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TARGET ANGIOGENESIS

5. Imaging System5. Imaging System -- PreclinicalPreclinicalSmall Animal ModelsSmall Animal Models

6.6. Target AssessmentTarget Assessment -- PET/CT FDG vs.PET/CT FDG vs.6464CuCu--Avastin imagingAvastin imaging SolidSolid TumorsTumors

Courtesy Dr. Jim WangCourtesy Dr. Jim Wang--RadiochemistRadiochemist, UTHSCSA, UTHSCSA

4. Amplification Strategy4. Amplification Strategy --LiposomeLiposome NanoparticleNanoparticle

LiposomesLiposomes-- spontaneously forming lipid bilayer spheres used for spontaneously forming lipid bilayer spheres used for drug delivery applications drug delivery applications 90nm to 200 nm.90nm to 200 nm.

Different surface modifications of liposomes or other nanoparticDifferent surface modifications of liposomes or other nanoparticles les to optimize biodistribution characteristics. to optimize biodistribution characteristics.

Molecular Imaging + TherapyDoxil – Pegylated Liposomes

Containing Doxorubicin

+ Avastinand/or99mTc

or+ 186Re

or+ 188Re

3. Delivery Barriers3. Delivery Barriers –– Solid TumorsSolid Tumors

@ Injection

SPECT/CT images 4 hours post injection

Xavier Garcia-Rojas, MD

IntratumoralIntratumoral InjectionInjectionofof 186186ReRe--DoxilDoxil

1. Excess deposition of ECM and collagen2. Elevated pressure ~ 20 mmHg3. Reduced blood flow4. Hypoxia – resistance to radiation RX5. Reduced delivery of chemotherapeutics6. Heterogeneous delivery due to barriers7. Refractory to cancer therapy options

Possible Solutions1. Ultrasound irradiation2. Systemic hyluronidase3. Systemic collagenase4. Combine with RF abalation5. Image guided intratumoral delivery

Imaging and Rx ofImaging and Rx ofSmall Animal ModelsSmall Animal Models

Systemic Therapies:- Liposomes with Doxorubicin or 186Re- Designer Molecules

Intratumoral Therapies:- Radiofrequency Ablation- Liposomes with Doxorubicin or 186Re

Ande Bao, PhD and Xavier Garcia-Rojas, MD

Imaging canquantitativelymeasure drugdelivery anddistribution in tumor

CHEMODOSIMETRYis possible but needsdevelopment

3D Distribution Of IntratumorallyAdministered 186Re Doxil

Passive Targeting Active Targeting Hyper Targeting

Cancer Drug TargetingCancer Drug Targeting

~3 Fold Increase ~9 Fold Increase ~45 Fold Increase

NanoparticlesAnti-Angiogenesis

AntibodyDirect Convection-Mediated Injectionof Nanoparticles

~3X ~9X ~45X

Control at 8 days afterthe start of the treatmentstudy

30 days Post Treatment

60% maximal tolerated dose

Control Treated with Intratumoral186Re-Doxil

Performance of PercutaneousIntratumoral Therapy

Intratumoral Therapy vs Tumor Size(avg data only for time points with 100% survival)

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Liposomes + 186Re + RFA

Slide from Xavier Garcia-Rojas and Ande Bao

Performance of Systemic TherapyPerformance of Systemic Therapy

Comparison of Change in Tumor Volume

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Control

Clinical TranslationClinical Translation -- ProstateProstateCancerCancer -- 3.0T Dual coil3.0T Dual coil

A.Jung

Molecular 3.0T MRSMolecular 3.0T MRS -- 3D CSI3D CSIMRI and MR SpectroscopyMRI and MR Spectroscopy

A.Jung

Molecular Imaging of MetabolicMolecular Imaging of MetabolicChangesChanges

Healthy voxel: Cancerous voxel:

• Voxel size ~ 0.16 - 0.30 cc’s

A.Jung

Medical physics is positioned todevelop an image guided tumortreatment program that can:

1. Percutaneously deliver RXagents to treatment sites

2. Assess if Rx agentsaccumulate at the treatment site

3. Assess if there is earlyresponse or failure to the agents

4. Obtain repetitive functionallydirected biopsies of targettissues

Molecular Image-GuidedTumor Treatment Program

AAPM Members have an ImportantAAPM Members have an Importantand Challenging Role to Playand Challenging Role to Play

�� Members CAN participate in the design andMembers CAN participate in the design andtesting of new instrumentation for bothtesting of new instrumentation for bothpreclinical/animal and human uses.preclinical/animal and human uses.

�� Members CAN use well documented AAPMMembers CAN use well documented AAPMmethods for developing nationally acceptablemethods for developing nationally acceptablestandards and procedures for assuring thestandards and procedures for assuring thequality of quantitative imaging data.quality of quantitative imaging data.

�� MembersMembers CANCAN work to assure the quality of datawork to assure the quality of dataintended for use by regulatory agencies such asintended for use by regulatory agencies such asthe FDA to prove the safety and efficacy of newthe FDA to prove the safety and efficacy of newmethods of human medical care.methods of human medical care.