Multi-modal contrast agents: a first step

IAN 2006 SNS - ORNL 1

Multi Modal Contrast AgentsMulti Modal Contrast Agents

Kenneth L WatkinKenneth L Watkin

University of Illinois at UrbanaUniversity of Illinois at Urbana--ChampaignChampaignCollege of Applied Health SciencesCollege of Applied Health Sciences

&&BioBio--Imaging Science GroupImaging Science Group

Beckman Institute for Advanced Science and TechnologyBeckman Institute for Advanced Science and Technology


Outline

1.1. Medical Imaging Contrast AgentsMedical Imaging Contrast Agents2.2. Functionalized Contrast AgentsFunctionalized Contrast Agents3.3. Multi Function Contrast AgentsMulti Function Contrast Agents4.4. Multi Modal Contrast AgentsMulti Modal Contrast Agents


Magnetic Resonance CAs

MRA contrast


Contrast AgentsContrast Agents• Type –

– Designed for imaging modality– CT; MRI, Ultrasound; PET; SPECT; OCT

• Size• Large – 3 µm• Medium -- .250 - 1 µm• Small -- < .150 µm


Contrast AgentsContrast Agents

• Composition

– Protein

– Lipids

– Silica

– Particulates

– Magneto-


Multi Functional Multi Functional CAsCAs

• Contrast Agent• Delivery Agent

– Passive– Active

• Therapeutic Compounds– Contained

• Within the core• Within the shell• Attached to the outside


Therapeutic CompoundsTherapeutic Compounds

• Chemotoxins• Genes• Alternative Medicines


Nano Liposomes


Nano Liposomes (NLs)

500 nm

DLS

TEM

core

ChemotoxinsChemotoxinsPlant ExtractsPlant ExtractsParticulatesParticulates

110nm


Nano Liposomes (NLs)

500 nm

DLS

TEM

ChemotoxinsChemotoxinsRNAiRNAi

110nm


Combination Nano Liposomes (cNLs)

500 nm

DLS

TEM

ChemotoxinsChemotoxinsRNAiRNAiParticulatesParticulatesAlternative MedicinesAlternative Medicines

110nm

core


Functionalizing CAs


Functionalizing CAs

Fluorescence Light MicroscopeLight Microscope

x40

Small green dots are immuno-nanoliposomes(110 nm) attached to cancer cells using IGF-R1 MAb

x40

Cancer cells adhering toOpticell membrane

Floatingcells


EnlargementLight Microscope Fluorescence Light Microscope


Active DeliveryActive Delivery• Ultrasound mediated delivery of therapeutic compounds

• Poor selectivity of chemotherapeutic drugs for neoplastic cells leads to:

– dose-limiting side effects – compromised clinical outcomes

• What is needed???? A method that –

– Reduces the systemic dose of therapeutic agents– Increases the concentration of drugs at the appropriate tissue target site– Permits the visualization of the target tissue– Delivers the therapeutic on command


Ultrasound Delivery of Therapeutics

• Specially modified ultrasound machine – “Point and Shoot” capabilities – simultaneous imaging of targeted

contrast agents – quick release of their payload at

the targeted imaging sites

Aloka SSD 5500 PHD RF








Medical Diagnostic Ultrasound

BEFOREInsonation

AFTERInsonation

Watkin, 2003


Cell InvasionCell Invasion

Matrigel Invasion ChamberMatrigel Invasion Chamber

cells

Matrigelmatrixcoating

8 µmPorous

membrane


Active Active vsvs Passive NL DeliveryPassive NL Delivery

0.002.004.006.008.00

10.0012.0014.0016.0018.0020.00

MCF7 T47d Hs578t MB-231

Perc

ent I

nvas

ion

(%)

UntreatedsiRNA-NLsiRNA-NL+US

Non Metastatic Metastatic

p<0.01


Multi Modal Contrast Agents

1 µm

Philips CM2000 TEM Philips CM2000 TEM PeltierPeltier--cooled cooled TietzTietz (TVIPS) 2kx2k CCD camera(TVIPS) 2kx2k CCD cameraNegatively stained with 2%phosphotungstic acidNegatively stained with 2%phosphotungstic acidParticulate size 9 Particulate size 9 –– 20 nm 20 nm Ultra thin sectioning of LX 112 epoxy resin blocks Ultra thin sectioning of LX 112 epoxy resin blocks

Gadolinium oxideZincManganeseMagnesiumCalcium

McDonald, MA and KL Watkin. Invest Radiol, 38(6), 305-310, 2003


Albuminmicrospheres

5.9x106/mlsonicated SPGO

~2.1x1017/mlSPGO

~2.1x1017/mlGOAM

6.2x106/ml

5 MHz

7.5 MHz

10 MHz

B-mode images of contrast agents at 5, 7.5 and 10 MHz.


GdGd22OO3 3 MicrospheresMicrospheres• Relaxometry

• Relaxation rate was linear and concentration dependent• At 4.7T, 200MHz,37°C

• T1 : 6.7 s-1 mM-1

• T2 : 38.5 s-1 mM-1

• Computed Tomography• High atomic weight and high k-edge of Gd• Attenuation was linearly dependent on concentration

• .004 , .160, 4.0 , & 16.0 mmol/L• 3.48, 7.06, 39.83, & 187.33 Hu

• Compared on an equimolar basis with Iopamidol• Provided increased attenuation


GdGd22OO3 3 MicrospheresMicrospheres• Ultrasound

• Compared with SPGO & oil filled albumin microspheres• Velocity 1472 ms-1

• Attenuation .4 dB/cm/MHz• Integrated backscatter 10 dB increase compared to other agents• Video density increases with frequency ; greater than other agents


Small Particulate GdSmall Particulate Gd22OO33

McDonald and Watkin, Investigations into the Physicochemical Properties of Dextran Small Particulate Gadolinium Oxide Nanoparticles, Invest Radiol. 13:421-427.


Some Challenges


Development of CAs for neutron imaging

SP-GdO B

core

SP-GdO BMAb


Cyber Tools for neutron image fusion

Watkin & Bajcsy, NCSA – UIUC 2006


Fusion of imaging modalities

• Ultrasound with Neutron imaging


AcknowledgementsAcknowledgementsMedical Imaging Research Laboratory Targeted Drug Delivery Laboratory

Bioimaging Sciences and Technology Group

College of Applied Life Studies Beckman Institute for Advanced Science and Technology

Gabe Najarro Rachel LucasMonique Mills Rachel KeslerIbrahima Diouf Souheil HakimNicoline Ambrose Ehud Yairi

Gabe Najarro Rachel LucasMonique Mills Rachel KeslerIbrahima Diouf Souheil HakimNicoline Ambrose Ehud Yairi

Souju GosangariMichael McDonaldGopal Anyarambhatla Wei Tian

Souju GosangariMichael McDonaldGopal Anyarambhatla Wei Tian


Research CollaboratorsResearch Collaborators•• S Boppart S Boppart -- UIUC UIUC -- ECEECE•• K Kim K Kim -- UIUC UIUC -- Mat ENGMat ENG•• S S ChoiChoi -- UIUC UIUC -- Mat ENGMat ENG•• S S ChaiebChaieb -- UIUC UIUC -- MSEMSE•• B Cunningham B Cunningham -- UIUC UIUC -- ECEECE•• I Ahmed I Ahmed -- UIUC UIUC -- CNSTCNST•• B Sutton B Sutton -- UIUC UIUC -- BioENGBioENG•• A A OldenbergOldenberg –– UIUC UIUC -- BIBI•• H H FoulyFouly UIUC UIUC -- ACESACES•• D ClaytonD Clayton UIUC UIUC -- IGBIGB

• P Bajcsy - NCSA • L Ciobanu - Pfizer Research• G Raguin -MSU ECE • S Vignesh -Yale Medical School


Thank You

Multi-modal contrast agents: a first step

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