YALE TRANSLATIONAL RESEARCH IMAGING CENTER (Y-TRIC)- MULTI-MODALITY AND MOLECULAR IMAGING AND IMAGE-GUIDED INTERVENTIONS

Transcript

• 00:00Alright. And then last but
• 00:02not least, we're gonna move
• 00:03to the heart.
• 00:05Is Al here? Yes. Doctor
• 00:07Al Senussis graduated from RPI
• 00:09and earned his medical degree
• 00:11from Vermont, completed residency at
• 00:12University of Oklahoma,
• 00:14cardiac fellowship at Virginia,
• 00:16then around the country.
• 00:17Joined Yale, since nineteen ninety.
• 00:19Served as a director of
• 00:20Weitrick.
• 00:21He's also he also run
• 00:23the radiation safety,
• 00:25the IRB,
• 00:26the human safety. And, he's
• 00:29a true consummate radiologist and
• 00:30cardiologist.
• 00:31Underpaid radiologist, I guess. So
• 00:33let's talk about the heart.
• 00:35Alright. Thank you.
• 00:41So these are current, grant
• 00:43funding and also relationships with
• 00:46industry.
• 00:47So, in two thousand and
• 00:49ten, we established the Yale
• 00:51Translational Research Imaging Center and
• 00:53we have a unique set
• 00:54of, imaging systems. One, a
• 00:56solid state CZT spec sixty
• 00:58four slice CT scanner for
• 01:00focused and whole body imaging.
• 01:02We also have a digital
• 01:03cath lab,
• 01:05and we have now a
• 01:06prototype lower extremity scanner that
• 01:09was built,
• 01:10with,
• 01:11an an r o one
• 01:12grant in collaboration with the
• 01:13engineers at the University of
• 01:15Illinois.
• 01:16And shown here is the
• 01:17system uncovered and covered, and
• 01:19this sits over the table
• 01:20of a conventional scanner to
• 01:22do cardiac and leg imaging.
• 01:24We also have,
• 01:26a state of the art
• 01:27ultrasound system integrated with our
• 01:29cath lab as well as
• 01:30rodent ultrasound and micro spec
• 01:33scanning. So in my lab,
• 01:34we're focused on three principal
• 01:36areas of invest investigation, post
• 01:38myocardial
• 01:39remodeling,
• 01:40lung injury and fibrosis, and
• 01:42peripheral vascular disease. And we've
• 01:44been evaluating a number of
• 01:46molecular targeted,
• 01:48sort of, molecular
• 01:50targets including alterations in the
• 01:52extracellular matrix, in particular matrix
• 01:55metalloproteinases,
• 01:56evaluating angiogenesis,
• 01:58evaluating fibrosis,
• 02:00and fibroblast
• 02:01activation, looking at reactive oxygen
• 02:04species, and more recently,
• 02:06mitochondrial membrane potential in collaboration
• 02:09with George's group. And so
• 02:10we have a number of,
• 02:12SPECT and PET agents that
• 02:13we're evaluating in these conditions.
• 02:16I wanted to highlight some
• 02:17of the other work from,
• 02:19Mehron Sadeghi in cardiology. He
• 02:21also
• 02:22is sort of a cardiac
• 02:23molecular imager, and his lab,
• 02:26focuses,
• 02:27again,
• 02:28on,
• 02:29activation of matrix metalloproteinases
• 02:31and tissue remodeling more in
• 02:33the vascular space than the
• 02:34cardiac space. He also is
• 02:36developing some collagen based imaging
• 02:39agents to look at fibrosis
• 02:41and and a more targeted,
• 02:43agent to look at MMP
• 02:45twelve.
• 02:45And this involves looking at
• 02:47aortic aneurysms, pulmonary fibrosis, and
• 02:50granulomatous
• 02:51lung disease. And he's been
• 02:52working
• 02:53at both SPECT and PET
• 02:55agents and has one,
• 02:57sort of agent that they're
• 02:58moving to first in man
• 02:59in collaboration
• 03:00with WashU.
• 03:04And then also just to
• 03:05highlight some of the work
• 03:06that George has been doing
• 03:07in the cardiovascular
• 03:09space. So he's developed a
• 03:10novel,
• 03:11radio labeled pet agent that
• 03:13looks at mitochondrial membrane potential.
• 03:16And he's sort of developed
• 03:17the quantitative tools associated with
• 03:19this agent, developing,
• 03:22complex kinetic modeling, optimizing the
• 03:24acquisitions,
• 03:25evaluating the use of this
• 03:27agent in models like chemotherapy
• 03:29induced cardiotoxicity,
• 03:31and has moved it into
• 03:32first in man, and has
• 03:33now has an active IND
• 03:35in this space. And we've
• 03:36been helping him do some
• 03:38of the preclinical work to
• 03:39finish up the work that
• 03:40he initiated at MGH.
• 03:44So I wanted to kinda
• 03:45talk primarily about our work,
• 03:47in theranostics
• 03:49in the cardiovascular
• 03:50space, and this
• 03:51is based on the use
• 03:52of theranostic
• 03:53hydrogels.
• 03:54Talk about how we deliver
• 03:55these hydrogels to the heart,
• 03:58how these hydrogels can modulate
• 04:00post infarct remodeling,
• 04:02and how they're a vehicle
• 04:03for delivering,
• 04:04therapies. Well, we're also applying
• 04:06some of these in lung
• 04:08injury models,
• 04:09and developing,
• 04:11percutaneous
• 04:12non invasive approaches to deliver
• 04:14these theranostic hydrogels.
• 04:16So these hydrogels can be
• 04:18engineered
• 04:19to adjust a biocompatibility,
• 04:21degradation, mechanical properties,
• 04:24their conductivity, as well as
• 04:26our focus has been on
• 04:27making them imageable
• 04:29so that we can, highlight
• 04:30where they're delivered.
• 04:32They've been used to address
• 04:34a number of targeted molecular
• 04:36processes, and they do offer
• 04:37some basic mechanical support.
• 04:40When we deliver these agents,
• 04:41they can be delivered either
• 04:43by a catheter,
• 04:44into the endocardial of the
• 04:46heart or they can be
• 04:47delivered
• 04:48pericardially
• 04:49or epicardially
• 04:50or they can be delivered
• 04:51into the coronary arteries.
• 04:54We've been focused on the
• 04:55local delivery of in inhibitors
• 04:57of matrix metalloproteinases.
• 05:00So again, when we we
• 05:03there were shear thinning, hydrogels
• 05:05that were developed by the
• 05:06group at UPenn, and we
• 05:07wanted to make those imageable.
• 05:08And we had to make
• 05:09sure that when we added
• 05:11iodinated
• 05:11agents to these polymers, it
• 05:13didn't change the mechanical properties
• 05:15of those agents.
• 05:17And so, initial studies were
• 05:19done in acute, in an
• 05:21acute
• 05:22setting of infarction, uninfarcted
• 05:24animals,
• 05:25delivering them surgically with a,
• 05:27kind of a guiding grid
• 05:28that it would assure us
• 05:29that we could deliver these
• 05:31intramyocardial.
• 05:32And so you can see
• 05:33here,
• 05:34I don't know if you
• 05:35can see my pointer here,
• 05:36you can see these iodinated
• 05:38hydrogels that we've delivered in
• 05:40the middle of the myocardium
• 05:41and in three d imaging,
• 05:43we can see them distributed
• 05:44and we can see them
• 05:45within the infarct area.
• 05:48So now we've been for
• 05:49many years evaluating,
• 05:51agents that, look at matrix
• 05:53metalloproteinase.
• 05:54These are macrocyclic
• 05:55pepto mimetics that are radio
• 05:56labeled that bind to the
• 05:57catalytic site of MMPs
• 05:59and look at in vivo
• 06:01balance of temp,
• 06:03m MMP
• 06:05sort of balance. And they're
• 06:06nonspecific
• 06:07and they target a host
• 06:09of MMPs that are known
• 06:10to be involved in post
• 06:11infarctal modeling.
• 06:12We have an STTR grant
• 06:15to develop,
• 06:16GMP grade compound, and and
• 06:19now we've done the final
• 06:20validation runs, and we're hoping
• 06:22to submit the final documents
• 06:23to the FDA for first
• 06:25in human studies.
• 06:27So the the early work
• 06:28we did was in collaboration
• 06:30with the group in the
• 06:31University of South Carolina where
• 06:33we were delivering bioresponsive
• 06:35hydrogels. These are hydrogels that
• 06:37break down in the presence
• 06:38of MMPs
• 06:39and locally release recombinant TINP
• 06:41three.
• 06:42So these early studies were
• 06:45surgical infarcts, acute delivery
• 06:47in pigs, the pigs were
• 06:48shipped to us, and then
• 06:50we did the imaging with
• 06:51our MMP targeted agent as
• 06:53well as perfusion imaging.
• 06:56And shown here are sort
• 06:58of the early
• 06:59or the initial results here.
• 07:00So shown on top
• 07:02are
• 07:03hearts, control hearts, control hearts,
• 07:05post myocardial infarction
• 07:07and you can see the
• 07:08decreased perfusion area, hearts that
• 07:10were delivered in a hydrogel,
• 07:12and hearts that were delivered
• 07:13a hydrogel that released recombinant
• 07:15TINP three. And below are
• 07:17the MMP maps. You can
• 07:18see at baseline there isn't
• 07:19a lot of MMP activation
• 07:21in the heart. Post MI
• 07:22there's activation in the infarct
• 07:24area, peri infarct area and
• 07:25the atria due to a
• 07:27pressure and volume overload.
• 07:29And the hydrogels themselves have
• 07:30an effect, but local release
• 07:32of an MMP inhibitor totally
• 07:34suppressed MMP activation.
• 07:36And so,
• 07:37shown here
• 07:39is, what we, we demonstrated
• 07:41that we significantly
• 07:43inhibited,
• 07:45the uptake of a compound
• 07:46with the local release and
• 07:48that there was a relationship
• 07:49between
• 07:50suppression of MMPs and changes
• 07:53in regional myocardial function.
• 07:57So now,
• 07:58the next step was to
• 08:00take these hydrogels
• 08:01and we wanna deliver therapies,
• 08:03but we wanted to radio
• 08:04label the drugs so that
• 08:06we not only could track
• 08:07the initial delivery
• 08:08of these hydrogels into the
• 08:10heart, but then we could
• 08:11track the,
• 08:13the, the dispersion and retention
• 08:14of these drugs from the
• 08:16hydrogels
• 08:17and then use molecular imaging
• 08:19to track the therapeutic effects.
• 08:21So again, doxycycline
• 08:23has been shown as a
• 08:24weak MMP inhibitor in clinical
• 08:26trials to have a benefit
• 08:27prevent post infarct remodeling,
• 08:30but we wanted to give
• 08:31high doses locally by this
• 08:33hydrogel approach.
• 08:36So in a small number
• 08:37of animals post MI and
• 08:39control, we delivered these drug
• 08:41delivering hydrogels and demonstrated
• 08:43as shown here in color
• 08:45code the the, delivery and
• 08:48retention over time of the
• 08:50radio labeled,
• 08:52MMP inhibitor on top of
• 08:54a cine CT and we
• 08:55can sort of watch that
• 08:56disperse over time.
• 08:59So then we wanted to
• 09:01what were the long term
• 09:02effects of these drugs, so
• 09:03we performed chronic animals. Our
• 09:05initial studies were done in
• 09:06permanent occlusions,
• 09:08but now we're doing a
• 09:09percutaneous
• 09:10ninety minute balloon occlusion more
• 09:12akin to what happens into
• 09:13pit in in patients.
• 09:15So we have an infarct,
• 09:16and then three days later,
• 09:17we do targeted MMP imaging,
• 09:20and then we do rest
• 09:21and low dose
• 09:22echo,
• 09:23imaging, stress echo imaging.
• 09:26And then,
• 09:27five days later, four days
• 09:28later, we deliver the hydrogels
• 09:30through a more, a small
• 09:32surgical incision and then we
• 09:33reevaluate
• 09:35the animals at two and
• 09:36four weeks. And
• 09:38so shown here are cine
• 09:40CT images of a control,
• 09:42pig, a pig that got
• 09:43the hydrogel and the pig
• 09:45that got the hydrogel
• 09:46that locally released doxycycline.
• 09:48And shown are the bullseye
• 09:50map showing that in the
• 09:51MI controls, there's a significant
• 09:54regional activation of MMPs.
• 09:56The delivery of these hydrogels
• 09:58modulated that activation, but the
• 09:59local release of an MMP
• 10:01inhibitor significantly
• 10:03suppressed MMP activation.
• 10:05And then this was associated
• 10:07with
• 10:08decreases in left ventricular dilatation,
• 10:10decreases in left ventricular filling
• 10:12pressures,
• 10:14and suppression
• 10:15of the uptake of our
• 10:16MMP targeted radiotracer.
• 10:20So we've also explored another,
• 10:22targeted agent and that
• 10:25is maracyclotide,
• 10:26which is an RGT peptide
• 10:27that binds to the alpha
• 10:28V beta three integrin, which
• 10:30is expressed on proliferating endothelial
• 10:33cells,
• 10:34and also in inflammatory cells.
• 10:36And so it's, it's thought
• 10:37to be early post amide
• 10:39to be marker of angiogenesis.
• 10:40And these agents were developed
• 10:42as oncological imaging agents and
• 10:44we've sort of adapted,
• 10:46adapted them for cardiac imaging.
• 10:48So again, we created our
• 10:50infarct model. We assessed the
• 10:51area at risk.
• 10:53And then at five days
• 10:54we performed
• 10:55flow imaging with thalene or
• 10:57perfusion imaging and then targeted
• 10:58imaging of angiogenesis.
• 11:00And immediately thereafter through a
• 11:02small surgical window delivered the
• 11:04hydrogels
• 11:05and then looked a week
• 11:06later at angiogenesis
• 11:08and perfusion.
• 11:11And shown here are the
• 11:12three d maps of the
• 11:14perfusion defect in the lateral
• 11:16wall and the focal uptake
• 11:17of this compound that targets
• 11:19angiogenesis.
• 11:21And we showed that giving
• 11:22the hydrogels
• 11:23actually stimulated angiogenesis
• 11:26resulted in less LV dilatation
• 11:28and resulted in improvements in
• 11:30left ventricular function.
• 11:33So when we verified histologically
• 11:35that those changes that we
• 11:36preserved with the imaging were
• 11:38confirmed
• 11:39with markers of angiogenesis
• 11:41and integrin activation with very
• 11:43little inflammatory response around the
• 11:45hydrogels.
• 11:48So now I've showed you
• 11:50surgical delivery, but we want
• 11:51to deliver this in a
• 11:52non invasive way, and so
• 11:54we initially started to use
• 11:56superimposed
• 11:57three d ECHO on our
• 11:59fluoro suite. And then under
• 12:00fluoroscopic guidance,
• 12:02you can see,
• 12:04here
• 12:05a needle being passed, through
• 12:07the chest wall into the
• 12:08myocardium
• 12:09for the delivery of these
• 12:10hydrogels.
• 12:11And then,
• 12:12if we look at the
• 12:13gated images, this is a
• 12:15transesophageal
• 12:16echo at baseline
• 12:18following hydrogel delivery, and you
• 12:20can see the hydrogel within
• 12:21the wall of the heart
• 12:23and then, an hour post
• 12:25delivery.
• 12:26But we found that that
• 12:27was not the best way,
• 12:28so now we wanna do
• 12:29multimodality
• 12:30delivery of these agents and,
• 12:32and what we made the
• 12:33observation that early post
• 12:35MI, there's calcium deposition and
• 12:37that calcium can be detected
• 12:38on the CT
• 12:40within three to five days
• 12:41post MI. And it appears
• 12:43that a hyperdensity on non
• 12:45contrast studies and an increased
• 12:46density on on late hyper
• 12:48enhanced studies.
• 12:49So we use that to
• 12:50guide the delivery. So we
• 12:52took a sixty four slice
• 12:54CT scanner.
• 12:55We outlined the area of
• 12:57the hyper density
• 12:59and then registered that with
• 13:01a cone beam CT in
• 13:02the fluoro unit. So we
• 13:04have a a
• 13:05low resolution
• 13:06CT
• 13:07in the fluoro space. Now
• 13:09we're in fluoro, we're moving
• 13:10in three d CT space.
• 13:12And so
• 13:13under that fluoroscopic guidance, we
• 13:15placed guide needles, parasternal directed
• 13:18into the target into the
• 13:20infarct area.
• 13:21And then
• 13:23as before,
• 13:25we did
• 13:27transesophageal,
• 13:28echo
• 13:29to verify
• 13:30that a steerable meter needle
• 13:32passed through these guides was
• 13:34placed mid myocardial before
• 13:36we delivered the hydrogel. So
• 13:38now we've developed a percutaneous
• 13:40non invasive way to deliver
• 13:42these therapeutic hydrogels to the
• 13:44central infarct area.
• 13:47And this just shows our,
• 13:49ability to effectively
• 13:51deliver these iodinated hydrogels into
• 13:53the central infarct area. And
• 13:55then, of course, we're evaluating
• 13:57that with a number of
• 13:58targeted molecular probes, looking at
• 14:00MMP activation, looking at fibroblast
• 14:03activation,
• 14:04and other markers of inflammation.
• 14:08So
• 14:09we also have been working
• 14:11to develop a novel catheter
• 14:13based approach to do molecular
• 14:15guided therapy. So in cardiology,
• 14:17a standard approach is to
• 14:18do electro anatomical mapping that
• 14:20is passing a catheter
• 14:22and mapping electrical voltages on
• 14:24the surface of the heart.
• 14:25So in collaboration with a
• 14:27company in in California,
• 14:29we replaced that electrical sensor
• 14:31with a plastic scintillator to
• 14:33detect local radiation.
• 14:35So radio tracers that emit
• 14:36betas will will travel one
• 14:38or two millimeters. So on
• 14:39the tip of the catheter,
• 14:40we can detect
• 14:41a targeted molecular signal. Now
• 14:44many of the probes, as
• 14:45you know, deliver an imageable
• 14:46gamma as well as a
• 14:48low energy beta. So we
• 14:49can have a three d
• 14:50map of the of the
• 14:52radio tracer by gamma imaging
• 14:54and then local detection,
• 14:56with this beta detector. And
• 14:58we have a number of
• 14:59versions of that, and this
• 15:00is sort of a patented
• 15:01technology.
• 15:03And the last thing we
• 15:04wanna talk about is the
• 15:05use of this approach in
• 15:07lung injury models. And so
• 15:08again, we apply the same
• 15:10approach where we take, a
• 15:12CT scan, we define the
• 15:13airways,
• 15:14and then we register that
• 15:16with a cone beam CT
• 15:17and then under fluoroscopic
• 15:19guidance with a balloon catheter,
• 15:21we deliver bleomycin,
• 15:22a lung toxic agent. So
• 15:24we can create a lung
• 15:26injury model, and then we
• 15:28perform serial imaging with a
• 15:29number of molecular probes.
• 15:31And shown is here is
• 15:33just
• 15:34SPECT imaging of our our
• 15:36tech labeled agent looks at
• 15:38fiberglass activation protein to look
• 15:40at the early markers of
• 15:41fibrosis.
• 15:42And clearly, there was increased
• 15:44uptake relative to
• 15:46remote areas.
• 15:48So to summarize,
• 15:50molecular imaging
• 15:51is critical for the early
• 15:53detection of the disease,
• 15:55and that we're exploring
• 15:57the, the use of these
• 15:58thyranostic hydrogels that allow us
• 16:00to deliver concentrated drugs
• 16:03or cells or gene therapy
• 16:05to the heart to modulate
• 16:06post infarct prepare
• 16:08or other cardio, cardiovascular
• 16:10processes.
• 16:11And we're exploring these therapies
• 16:13also in the setting of
• 16:14lung entry.
• 16:15But you need to have
• 16:17molecular imaging to evaluate the
• 16:19therapeutic efficacy of these therapies.
• 16:21And so it's the integration
• 16:23of the theranostics and molecular
• 16:25imaging.
• 16:26And so none of this
• 16:27work would be accomplished without
• 16:28a long list of collaborators
• 16:31here at Yale
• 16:32and within the the YTREC,
• 16:35center as well as other
• 16:37members in cardiology and pathology
• 16:40and radiology,
• 16:41and particularly Stephanie Thorn who's
• 16:43the associate director in the
• 16:44lab and Jim Duncan and
• 16:45Chi Lu. So thank you
• 16:47for your
• 16:51attention.