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GOOD MORNING, I'M ELIZABETH
JONES OF CHIEF OF RADIOLOGY AND
IMAGING SCIENCES AND I'M PLEASED
TO WELCOME YOU TO TODAY'S LIVE
VIRTUAL GRAND ROUNDS. WHICH IS
THE JOHN MEMORIAL LECTURE FOR
IMAGING SCIENCES. THE HOPKINS
CODE FOR TODAY IS 57876 TEXT
THIS CODE TO THE JOHNS HOPKINS
CME PHONE NUMBER ON THE SLIDE TO
RECEIVE CME CREDIT AND WE KINDLY
INVITE YOU TO PROVIDE FEEDBACK
ON TODAY'S LECTURE BY SCANNING
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SURVEY'S USED TO PROVIDE US WITH
IMPORTANT FEEDBACK ABOUT THE
PRESENTATION AND ALLOWS YOU TO
SUBMIT ANY SUGGESTIONS FOR
FUTURE TOPICS AT GRAND ROUNDS
FOLLOWING THE PRESENTATION,
QUESTIONS FOR THE SPEAKER WILL
BE TAKEN FROM THE MICROPHONES IN
THE AISLES, AADDITIONALLY VIDEO
CAST VIEWERS CAN ASK QUESTIONS
AT ANY TIME. QUESTIONS WILL BE
ANSWERED AS TIME PERMITS AT THE
CONCLUSION OF THE PRESENTATION.
DR. WOODARD CHAIRS THE
DEPARTMENT OF RADIOLOGY AND
DIRECTS THE INSTITUTE OF
RADIOLOGY IN ST. LOUIS WHERE SHE
ALSO SERVES AS THE ELIZABETH E
PROFESSOR OF RADIOLOGY AND A
PROFESSOR OF MEDICINE,
PEDIATRICS AND BIOMEDICAL
ENGINEERING, EARNED HER BACHELOR
OF ARTS AT DUKE UNIVERSITY AND
HER MEDICAL DEGREE AT DUKE
UNIVERSITY SCHOOL OF MEDICINE,
COMPLETED HER INTERNSHIP AT THE
UNIVERSITY OF NORTH CAROLINA AT
CHAPEL HILL AND A RESIDENCY?
DIAGNOSTIC RADIOLOGY AS DUKE
UNIVERSITY MEDICAL CENTER.
SHE THEN COMPLETED HER
FELLOWSHIP AT THE INSTITUTE OF
RADIOLOGY AT THE WASHINGTON
SCHOOL OF MEDICINE AND WAS
APPOINTED TO THE FACULTY THERE
IN 1997. DR. WOODARD IS
WELL-KNOWN FOR HER IMPORTANT
CONTRIBUTIONS IN CARDIOVASCULAR
RESEARCH, PARTICULARLY IN
TRANSLATING NEW IMAGING
PROCEDURE TO CLINICAL CARE.
IN 1995, WHILE STILL A RESIDENT
AT DUKE, DR. WOODARD PUBLISHED
ONE OF THE FIRST PAPERS
DEMONSTRATING THAT PULMONARY
EMBOLI COULD BE DETECTED.
AND LATER SERVED AS PI ON AN NIH
FUNDING CLINICAL TRIAL THAT
RESULTED IN A LANDMARK NEW
ENGLAND JOURNAL OF MEDICINE
PAPER ESTABLISHING MULTIDETECTER
CT AS THE CENTER OF CARE FOR
FINDING PULMONARY EMBOLI. TODAY
HE SERVES ON GRANTS. ALL WITH A
FOCUS ON CARDIOVASCULAR IMAGING
IN ADDITION SHE SERVES AS THE
PROGRAM DIRECTOR FOR THE NIH,
NATIONAL INSTITUTE OF BIOMEDICAL
ENGINEERING AND FUNDED T32
CLINICIAN SCIENCE GRANT CALLED
TOP TIER AT WASHINGTON
UNIVERSITY. DR. WOODARD WAS
NAMED THE 2021 OUTSTANDING
RESEARCHER BY THE RSNA,
RADIOLOGIC SOCIETY OF AMERICA
AND IS A FELLOW OF THE AMERICAN
ASSOCIATION FOR THE ADVANCEMENT
OF SCIENCE. SHE IS CURRENTLY
VICE PRESIDENT OF THE ACADEMY OF
RADIOLOGY AND BIOMEDICAL IMAGING
RESEARCH AND THE CURRENT
PRESIDENT OF THE AMERICAN
COLLEGE OF RADIOLOGY.
THE TITLE OF TODAY'S
PRESENTATION IS PRECISION PET,
TRANSLATIONAL IMAGING AND
BUILDING THE NEXT GENERATION OF
CLINICIAN SCIENTISTS PLEASE
WELCOME ME IN JOINING OUR
SPEAKER, DR. WOODARD.
>> WELL, ELIZABETH, THANK YOU
VERY MUCH FOR THAT EXCELLENT
PRESENTATION OR ANNOUNCEMENT. I
REALLY, YOU KNOW, FEEL HONORED
TO BE HERE AND I'M REALLY
DELIGHTED TO BE SPEAKING TO YOU
ALL. IT'S VERY EXCITING. I WAS
ABLE TO SEE A LOT OF INTERESTING
RESEARCH AND EXCITING CUTTING
EDGE LOW FIELD STRENGTH MMRI
RESEARCH THIS MORNING. WE ARE
HERE TODAY TO HONOR JOHN, BY ALL
ACCOUNTS WAS A REMARKABLE
RADIOLOGIST AND INTERVENTIONAL
RADIOLOGIST AND HERE ARE MY
DISCLOSURES. DR. DEVELOP MAN
PASSED AWAY IN 2000 BUT WAS HERE
AT THE NIH FOR 26 YEARS.
AS THE DIRECTOR OF THE WARREN
GRANT MAGNUSON CLINICAL CENTER
MORE INSTITUTES OF HEALTH.
ARRIVED AT NIH THE YEAR I WAS
BORN AND BECAME CHIEF OF
RADIOLOGY IN 1972.
AND BROUGHT NEW TECHNOLOGY TO
THE DEPARTMENT. CT AND MRI
SCANNERS WHICH AT THE TIME WERE
THE CUTTING EDGE, YOU KNOW, JUST
THE VERY FIRST SCANNERS COMING
IN IN THE 70S AND THEN IN THE
80S WITH MRI. AS AN
INTERVENTIONAL RADIOLOGIST HE
WAS A PIONEER, HE INVENTED AND
PERFORMED MANY DIAGNOSTIC
PROCEDURES, MANY THERAPEUTIC
PROCEDURES SPECIFICALLY IN
LOCALIZATION AND TREATMENT OF
ENDOCRINE TUMORS. THIS IS HIS
ARTICLE THAT CAME OUT IN
RADIOLOGY IN 1970S. AND ALSO,
WAS INSTRUMENTAL IN STUDYING AND
IMAGING AND TREATING AVMS AND
FISTULAS OF THE SPINE AND SPINAL
CORD. HE LOVED RADIOLOGY, HE
HAD 516 PAPERS. AND 38 BOOK
CHAPTERS. HAD GOLD MEDALS FROM
THE RANKIN RAY AND SUIVR, EDITOR
AND CONSULTING EDITOR OF
NUMEROUS JOURNALS. YOU KNOW,
NOT JUST ONE OR TWO. AND HE WAS
CALLED A TRIPLE THREAT. A
SUPERB TEACHER, AND AN ASTUTE
CLINICIAN, SO I'M DELIGHTED TO
BE HELPING YOU REMEMBER HIS
LEGACY TODAY. I'M GOING TO TALK
TO YOU ABOUT PRECISION PET
TRANSLATIONAL IMAGING AND
BUILDING THE NEXT GENERATION OF
SCIENTISTS I'M GOING TO TALK
ABOUT MY OWN RESEARCH. AND THE
NEXT STEP WHICH IS KIND OF, YOU
KNOW, ENCOURAGING RADIOLOGISTS
AND IMAGEERS TO CONTINUE ON WITH
RESEARCH.
ESPECIALLY IN THIS CURRENT
ENVIRONMENT WHERE RADIOLOGIST
CONSIST GO OUT. IT'S LUCRATIVE
TO MAKE MONEY.
YOU CAN READ IMAGES IN YOUR
BUNNY SLEEPERS IN YOUR BASEMENT
AND, YOU KNOW, MAKE HUNDREDS OF
THOUSANDS OF DOLLARS AND PEOPLE
WHO MIGHT OTHERWISE HAVE THE
DRIVE TO DO RESEARCH FEEL LIKE
MAYBE THEY'RE BEING LEFT OUT IF
THEY MAKE THIS CHOICE. AND SO
SOME OF OUR TRAINING GRANTS THAT
INVIGORATE RESEARCH AND TO
SUPPORT THE DESIRES OF OUR
RESIDENTS AND FELLOW WHO IS ARE
INTERESTED IN PURSUING RESEARCH
AND HELPING THEM ACHIEVE THEIR
DREAM.
BEFORE I BEGIN I JUST WANT TO
TALK ABOUT MY COLLABORATORS. WE
USUALLY PUT THESE SLIDES AT THE
END AND SOMETIMES EVERYBODY
STARTS ASKING QUESTIONS AND I
FORGET TO THANK THEM. SO I WANT
TO THANK THEM UP FRONT BECAUSE
THIS IS REALLY A MULTIMODALITY,
YOU KNOW, COMBINED APPROACH FOR
RESEARCH.
NOT JUST RADIOLOGY BUT WE HAVE
CARDIOLOGISTS HELPING US DO SITE
SEEK TO HELP US UNDERSTAND SOME
OF THE TARGETS THAT WE'RE
IMAGING, PATHOLOGY AND
IMMUNOLOGY, WE HAVE PARTNERS AT
SEEDER SINAI WHERE WE'RE TRYING
TO DEMONSTRATE THAT NOT ONLY CAN
WE TRANSLATE INTO HUMANS BUT WE
CAN TRANSLATE ACROSS THE DUN
COUNTRY SO YOU DON'T HAVE JUST
TO COME TO WASH U YOU CAN COME
ACROSS THE COUNTRY. I WANT TO
HIGHLIGHT THE YANG LU LAB. NOW
HE IS IS FULL PROFESSOR AND
WORKING WITH ME AND ALSO WITH
MICHAEL WELL VP AND IS NOW TAKEN
UP THE MANTEL IN DEVELOPING SOME
OF THESE NOVEL RADIO TRACERS
AND, YOU KNOW, COULDN'T BE
MOVING THIS FORWARD WITHOUT HIM.
HIS GROUP IS THE ONE STILL RADIO
LABELS OUR TRACER THE DAY BEFORE
THE IMAGING SO WE INJECT AND
VERY IMPORTANT TO THE SUCCESS OF
THIS RESEARCH AND THEN ALSO TO
THE CENTER FOR CLINICAL IMAGING
RESEARCH WHICH I LED INTO LAST
YEAR WHEN I BECAME CHAIR AND
THIS TEAM IS REALLY EXPERTS IN
GETTING THESE NOVEL TRACERS,
INJECTING THEM INTO PEOPLE AND
MAKING SURE THE EXAM MOVES
FORWARD. SO I THINK WE CAN ALL
AGREE AND THE NIH HAS PROMOTED
THIS THAT PRECISION IMAGING IS
KEY TO BRINGING PRECISION
MEDICINE TO THE PATIENT. AND
ONE OF THE KEYS IS MOLECULAR
IMAGING THE FACT THAT WE CANNOT
ONLY IMAGE AT THE ANATOMIC LEVEL
BUT WE CAN IMAGE AT THE CELLULAR
LEVEL AND EVEN THE SUB CELLULAR
LEVEL AND LEARN WHAT'S GOING ON
IN PATIENTS. THROUGH MOLECULAR
IMAGING SO UNDERSTANDING THE
IMMUNOLOGY. PARTICULARLY
THROUGH ARTERY ROW SCLEROSIS.
THERE WAS A POINT IN MY CAREER
WHERE I WAS INTERESTED IN
LOOKING AT A SPECIFIC RECEPTOR.
AND I WENT TO MIKE WELCH AND
SAID I WOULD LIKE TO MAKE AN MR
AGENT AND HE SAID WE STARTED
LOOKING AT THE RECEPTOR DENSITY
AND IT TURNED OUT WE DIDN'T HAVE
ENOUGH SIGNAL TO SEE IT SO HE
SAID LET'S PUT COOPER 64 ON IT
AND THAT'S WHERE MY I SHOULD SAY
MY VENTURE INTO PET BEGAN.
BECAUSE MY POSTDOC IF YOU WANT
TO SAY I DID A POSTDOC I WAS
HALF ATTENDING, HALF FELLOW WITH
MARK WAS ALL MRI. SO, YOU KNOW,
WE STARTED LOOKING AT
ARTHROSCLEROSIS AND
ARTHROSCLEROSIS IS A SYSTEMIC
PROCESS OF INFLAMMATION,
RUPTURE, REPAIR, AND IN ORDER TO
TREAT THESE PARENTS WITH
PRECISION MEDICINE UNDERSTANDING
SPECIFIC -- PATIENT SPECIFIC
BIOMARKERS IS NEEDED AND SO, YOU
KNOW, IT'S NOT JUST IMAGING BUT
ONCE WE UNDERSTAND WHAT SOME OF
THESE RECEPTORS ARE, CAN WE
MODIFY THE PHYSIOLOGIC PROCESS
THROUGH TARGETING RECEPTORS NOT
JUST WITH IMAGING BUT ALSO WITH
THERAPEUTICS. AND SO, YOU KNOW,
ONE OF THE QUESTIONS MIGHT BE
WHY DO WE CARE? I DON'T KNOW
HOW MANY OF YOU, SOME OF YOU ARE
OLD ENOUGH TO REMEMBER WHO THIS
MAN IS. AND THIS IS TIM R. WITH
MEET THE PRESS AND I REMEMBER, I
WAS ACTUALLY ON VACATION ON CAPE
COD AND HAVING DINNER WITH MY
HUSBAND AND TIM ARE YOUS CERT
WAS SUPPOSED TO DO THE NEWS AND
INSTEAD SOMEBODY ELSE CAME ON
AND SAID, EXCUSE ME, SAID THAT
HI HAD PASSED AWAY AND WOULD NOT
BE DOING THE NEWS THAT NIGHT.
AND WHAT WAS SHOCKING WAS THAT
HE HAD PREVIOUSLY HAD A STRESS
TEST JUST LIKE ABOUT MONTH
EARLIER, A MONTH AND A HALF
EARLIER WITH NORMAL RESULTS. HE
HAD NO SIGNS OF ISCHEMIA, HE WAS
SIGNED YOU HAVE AS BEING HEALTHY
AND HE WAS ASYMPTOMATIC. SO ONE
OF THE, THIS IS SORT OF AN
OBVIOUS INCIDENT THAT HIGHLIGHTS
THAT NEARLY ONE-HALF OF PATIENTS
WITH SUDDEN DEATH OR STROKES ARE
ASYMPTOMATIC PATIENTS AND DIE
FROM LESIONS THAT AREN'T FLOW
LIMITING. THAT RUPTURE AND THEY
CAUSE MI OR STROKE. SO ONE
QUESTION IS, HOW DO WE IDENTIFY
THESE PATIENTS AND JUST ON A
VERY BASIC LEVEL, THERE ARE TWO
ARTERY ROW SLER ROTTIC TYPES OF
LEGIONS.
AND THIS IS VERY SIMPLISTIC.
THERE ARE THOSE THAT ARE STEN
NOTTIC AND THOSE THAT ARE NOT
STEN NOTTIC. AND THE STEN
NOTTIC ONES ARE FEW, THEY MAY BE
CALCIFIED.
THEY MAY CAUSE ANGIE KNOW WHEN
YOU WALK TO THE MAILBOX BUT NOT
THE ONES THAT ARE GOING TO
RUPTURE AND KILL YOU THE ONES
THAT WILL KILL YOU AND GIVE YOU
A MYOCARDIAL INFARCTION ARE THE
ONES THAT ARE NOT STABLE. THEY
ARE LIPID RICH, THEY ARE
INFLAMED AND THEY MAY LOOK LIKE
THIS. SO THIS IS A PATIENT WITH
TWO LESIONS AND THE FIRST IS A
VERY STABLE CALCIFIED LESION YOU
KNOW AT THE JUNCTION OF THE LEFT
MAIN AND LAD BUT THE SECOND W IS
THIS PLAQUE WHERE THERE'S NO
CALCIUM, YOU CAN SEE THERE'S A
LOT OF SOFT TISSUE, A LOT OF
NON-CALCIUM FEWED PLAQUE AND IF
YOU LOOK AT THE TRANSVERSE
IMAGE.
LIKE RIGHT THROUGH HERE, THIS
BLUE BOX MATCHES THIS BLUE LINE,
YOU CAN SEE THAT THIS IS PLAQUE
THAT HAS RUPTURED THE LUMEN IS
VERY SMALL. HERE IT LOOKS
COMPLETELY GONE AND THIS IS THE
ONE THAT IS THE CULPRIT LESION
THAT IS GIVEN THE PATIENT AN
EVENT. SO WHEN WE LOOK AT
HISTOPATHOLOGY AND REASONS FOR
PLAQUE AND STABILITY, WE LOOK
FOR INFILTRATION WITH
MACROPHAGES, WE LOOK FOR LARGE
LIPID NECROTIC CORE AND THIN
FI
FIBROUS CAP AND THESE ARE
WELL-KNOWN FEATURES. ANYONE
THAT LOOKS AT ARTERY ROW
SCLEROSIS KNOWS THESE. I AM
GOING TO FOCUS ON THREE CELL
TYPES.
THERE'S THE MACROPHAGES AND THE
MO
MONOCYTES AND THERE ARE ALSO
SMOOTH MUSCLE CELLS AND WHAT'S
VERY INTERESTING IS THAT THE
SMOOTH MUSCLE CELLS START TO
MIGRATE THROUGH THE, YOU KNOW,
THROUGH THE INTIMA UP TO THE
SURFACE AND IF YOU'VE TALKED TO
A FEW FOLKS, I DON'T KNOW HOW
MANY OF YOU KNOW GARY OWENS BUT
HE'S AT THE UNIVERSITY OF
VIRGINIA AND IS A VASCULAR
BIOLOGIST AND ONE OF THE THINGS,
HE AND I HAVE HAD A LOT OF
DISCUSSION ABOUT THE RECEPTORS
THAT WE END UP SEEING ON ALL
THREE CELL TYPES IS THAT THERE'S
VASCULAR CELL MIGRATION AND WITH
THAT, SEVERAL ARTICLES BELIEVE
THAT THERE'S PHENOTYPE CHANGE
AND SO YOU HAVE VASCULAR SMOOTH
MUSCLE CELLS THAT BECOME
MACROPHAGE-LIKE AND A FEW THAT
MIGRATE UP TO THE SURFACE AND
BECOME LIKE ENDOTHELIAL CELLS.
THERE'S ONE RECEPTOR, THE
PEPTIDE RECEPTOR THAT WE'VE BEEN
IMAGING THAT WE SEE MOSTLY IN
THE DEEP INTIMA ON MACROPHAGES
BUT WE ALSO SEE IN SOME OF THE
SMOOTH MUSCLE CELLS AND ALSO SEE
IN A FEW OF THE ENDOTHELIAL
CELLS AND SO I'M GOING TO TALK A
LITTLE BIT ABOUT THAT RECEPTOR
WHEN WE STARTED IMAGING THIS,
YOU KNOW, ALL WE KNOW WAS
THAT -- WE KNEW IT WAS ON
MACROPHAGES AND WE ALSO SEE IT
ON SOME OF THE HISTOCHEMISTRY IN
THE VASCULAR SMOOTH MUSCLE CELLS
AND A FEW IN THE ENDOTHELIAL
CELLS, WHAT'S GOING ON HERE?
THERE'S -- LINCOLN POTTER IS A
PEPTIDE EXPERT. AND WHEN WE
TALK ABOUT PEPTIDES, B, WITH
HEART FAILURE, PEPTIDE C IS
RESPONSIBLE FOR THE STATUS.
THAT'S HOW THE SNAKE KILLS YOU
BY GIVING YOU CMP AND CAUSING
YOU TO VASODILATE AND YOU DIE.
BUT WHAT WAS VERY INTERESTING
WAS I ASKED HIM, I SAID, WHY --
WHAT IS -- THIS IS WHERE YOU
HAVE SMOOTH MUSCLE CELLS. WHAT
IS IT DOING? THIS WAS WAY BACK
IN 2003-04. HE SAID PAM, GOD
PUT IT THERE FOR YOU TO IMAGE.
I'M SITTING THERE GOING, WELL,
FIRST OF ALL, GOD, HE'S THINKING
ABOUT MY RESEARCH CAREER. YOU
KNOW, I'M SITTING THERE GOING
THAT DOESN'T QUITE MAKE SENSE.
BUT THERE ARE A LOT OF DIFFERENT
TARGETS THAT PEOPLE HAVE IMAGED
IN ARTHROSCLEROSIS, AND REALLY
THIS IS A MICROCOSM OF COMPLEX
ACTIVITY, YOU KNOW, THERE ARE
VASCULAR ADHESION MODULES, THERE
ARE CHEMOKINES AND WE ARE
IMAGING A LOT OF THIS IN OUR
LABORATORIES AT WASHINGTON
UNIVERSITY CC R 2, THERE'S AN MP
I'M ON WITH LEE YOU AND THERE
ARE MMPS A NUMBER OF FOLKS ARE
LOOKING AT THIS, MMPS IN IN
ANEURYSMS.
ALPHA V BETA 3, PEOPLE LOOK AT
ANGIOGENESIS. AND ALPHA V BETA
3 AND ENDOTHELIAL CELLS AND
PEOPLE HAVE ALSO LOOKED AT
HYPOXIC PLAQUE. THERE ARE RADIO
TRACERS THAT LOOK AT PLAQUE
HYPOXIA OR CELLS AND WE HAVE
USED THEM LIKE WE CAN LOOK AT
TUMORS. I THINK PETER, YOU'RE
PROBABLY FAMILIAR WITH PEOPLE
LOOKING AT HYPOXIC CELLS IN
TUMORS BUT WE'VE BEEN ABLE TO
SEE HYPOXIC CELLS IN
ARTHROSCLEROSIS USING SOME OF
THE SAME AGENTS AND THEN OF
COURSE THERE'S THIS TARGET, THE
NATRIUR
NATRIURETIC C THAT HAVE GOTTEN
INTO HUMANS. SO AWHILE AGO
THERE WAS A GRANT, THE PROGRAM
OF EXCELLENCE IN NAN TECHNOLOGY
THAT ELLIE PIONEERED WHEN HE WAS
THE DIRECTOR OF THE NIH AND WE
WERE FORTUNATE ENOUGH TO HAVE
ONE OF THOSE GRANTS AND THE
AGENT THAT WE GOT INTO HUMAN
SUBJECTS WAS THE RADIO TRACER
THAT TARGETED MPRC AND IT WAS
FUNDED THROUGH THAT GRANT AND IT
WAS THE PROGRAM OF EXCELLENCE IN
NANOTECHNOLOGY WE STARTED TO
LOOK AT NANO IMAGING USING THIS
PEPTIDE AND ONE QUESTION WAS,
YOU KNOW, BEYOND JUST DIAGNOSIS.
CAN THESE AGENTS PREDICT
OUTCOME? CAN THEY INCREASE OUR
UNDERSTANDING OF MECHANISM? AND
THEN REALLY THE HOLY GRAIL IS
CAN WE USE THEM ALSO FOR
THERAPY? AND I MENTIONED THE
MULTIPLE DIFFERENT TARGETS THAT
COULD BE USED. FOR THESE RADIO
TRACERS OR FUNCTIONALIZED
NANOPARTICLES AND CERTAINLY WITH
ARTHROSCLEROSIS A LOT THAT ARE
PRESENT ON MACROPHAGES OR
MONOCYTES WE HAVE A RADIO TRACER
THAT TARGETS KETO CAME RECEPTOR,
PEOPLE HAVE LOOKED AT CD 68.
P32. ACTIVATED CELLS. AND
HYPOXIA AND MPRC THAT WE'RE
LOOKING AT AND THEN, YOU KNOW,
MANY PEOPLE HAVE LOOKED AT
ENDOTHELIAL CELLS LIKE VEGF AND
THE INTE GRANTS. AND SO, YOU
KNOW, WHEN WE TALK ABOUT IMAGING
AGENTS PEOPLE TALK ABOUT SMALL
MOLECULES VERSUS PROTEINS VERSUS
NAN PARTICLES AND THE SMALL
MOLECULES ARE REALLY THE MOST
COMMON.
THESE ARE AGENTS BELOW TWO
THOUSAND KILO DALTONS. AND LESS
THAN -- THAN ONE NANO MOLE BUT
FDG FOR INSTANCE IS ONE OF THE
MOST COMMON THAT WE USE AND
THAT'S FOR PET.
ION CONTRAST FOR CT AND THEN
PROTEINS, WE HAVE RADIO LABELED
MONOCLONAL ANTIBODIES THEY CAN
OFFER PRECISE INFORMATION AND
THEN NANOPARTICLES. NOW
NANOPARTICLES ARE VERY SMALL AND
ONE OF THE NICE THINGS ABOUT
THEM TOO IS THAT WE'VE
DISCOVERED THAT WHEN YOU USE
THEM, YOU COULD CONCEIVABLY
INJECT LESS THAN 100 MICRO GRAMS
INTO THE HUMAN SUBJECT.
AND SO COULD QUALIFY FOR AN EIND
SO REALLY EASILY TRANSLATED INTO
HUMAN SUBJECTS OR AT LEAST NOW
EASILY TRANSLATE TO THE TIME
WHEN WE FIRST STARTED DOING THIS
WE WERE CONCERNED THAT THE FDA
WOULD NOT WANT TO APPROVE A
NANOPARTICLE FOR INJECTION INTO
A HUMAN SUBJECT.
THAT WASN'T, YOU KNOW, THAT
WOULD CONTINUE TO LIVE. I THINK
THERE HAVE BEEN A FEW THAT HAD
BEEN EIN -- OR INDS HAD BEEN
APPROVED FOR PATIENTS WHO WERE
TERMINAL. SO MOST OF YOU ARE
FAMILIAR WITH THE SMALL
MOLECULES LIKE THE NANOPARTICLES
AND ALSO NANOPARTICLES THAT ARE
CURRENTLY USED IN HUMAN
ARTHROSCLEROSIS SO LIKE FARRAH A
HOME ANOTHER US PIOS AND THESE
IRON BASED AGENCIES ARE COMMONLY
USED, HAVE HAD A LONG HISTORY
WHERE YOU INJECT AND THEN THEY
ARE TAKEN UP BY MACROPHAGES AND
THEY START TO MAKE THE PLAQUE.
LOOK DARK AND YOU CAN SEE THIS
IS A PATIENT, THIS IS NOT MY
RESEARCH, IT'S FROM THE
LITERATURE. BUT YOU CAN SEE
THAT THE -- THIS IS WITH NO
THERAPY. IT IS TAKEN UP AND THE
PLAQUE STARTS TO BECOME DARK AND
AS YOU START TO TREAT THIS
PATIENT THIS PATIENT IS BEING
TREATED WITH ATORVASTATIN AND
THIS GRADUALLY DECREASES AND
MAPS HAVE BEEN USED TO KIND OF
HIGHLIGHT THE CHANGE. SO, FDG
AS WELL, IS ANOTHER AGENT. AND
EVERYBODY'S FAMILIAR WITH FDG,
IT'S A GLUCOSE ANALOG AND THERE
YOU'RE ESSENTIALLY LOOKING AT
METABOLIC ACTIVITY. SO
IDENTIFIES METABOLLICALLY ACTIVE
CAROTID PLAQUE BUT NECESSARILY
DOESN'T REALLY TELL YOU EXACTLY
WHY. SO, SOME OF THE PET
TRACERS THAT TARGET SPECIFIC
RECEPTORS AND CELLS THAT CAN BE
USED IN HUMAN SUBJECTS ARE THIS
COPPER 64 CNF AND THIS HAS BEEN
NIH FUNDED NOW STARTING BACK, IT
WAS BACK IN 2010-11 WITH THE PEN
GRANT AND WE'RE NOW IN OUR
SECOND CYCLE OF COMPETITIVE
FUNDING WITH AN RO 1. I SHOULD
SAY, SO WE'VE HAD TWO RO 1S
SINCE THE PEN GRANT AND THIS
TARGETS THE RECEPTOR IN DEEP
MACROPHAGES AND THE VASCULAR
SMOOTH MUSCLE CELLS WE'VE ALSO
LOOKED AT COPPER ATSM AND
HYPOXIC PLAQUE AND YAWNING GIN
LOU HAS DEVELOPED AN AGENT IN
MONOCYTES. SO IT'S REALLY A
TARGETING MONOCYTES AND I WILL
SHOW YOU SOME INTERESTING WORK
THAT'S BEEN DONE WITH THAT.
AND THERE ARE OTHER COMMON
AGENCI
AGENCY -- AGENTS THAT PEOPLE
HAVE USED.
ONE IS SODIUM FLUORIDE AND THIS
IS AN AGENT THAT PEOPLE HAVE
USED MORE BONE IMAGING AND FOR
PROSTATE, TO ASSESS PROSTATE
MEDICINE BUT IT HAS BEEN SHOWN
TO BE A MARKER OF PLAQUE RUPTURE
AND ACTIVE CALCIFICATION AND
POSITIVE REMODELLING. F 18 GA
LACK TO RDG THAT IS ANOTHER
AGENT THAT IS AVAILABLE FOR
HUMANS. HUMAN SUGGESTS.
TARGETS ALPHA BETA 3 AND THEN
GAL YUM, IT TARGETS THE
SOMATOSTATIN RECEPTOR IN
PROINFLAMMATORY MACROPHAGES AND
ONE OF THE INTERESTING THINGS
ABOUT THAT IS IT WAS DESIGNED
FOR ASSESSING ENDOCRINE TUMORS
AND WAS CO-OPTED. SO A COUPLE
OF THESE THINGS WERE DESIGNED
FOR TUMOR IMAGING AND HAVE KIND
OF BEEN CO-OPTED TO LOOK AT
ARTHROSCLEROSIS, YOU KNOW, MOVED
FOR OTHER USES. AND THIS IS A
SLIDE FROM THE FOLKS AT EMBER
WHO HAVE BEEN -- HAD PIONEERED
THIS F 18 SODIUM FLUORIDE. THIS
IS F DASDA BUT NOT FOR THIS.
THERE'S A LESION RIGHT HERE AND
IF YOU HOOK AT CT, THIS IS A CT
CORONARY CTA, PET CT WITH THIS
AGENT AND THIS -- YOU CAN SEE
WHERE'S THERE A CULPRIT LESION
SO IT TAKES UP THE CULPRIT
LESION AND THEY LOOKED AT SOME
PATIENTS AND NOTED THAT THE
HIGHEST UPTAKE WAS SEEN IN THESE
PATIENTS SO AS THE -- AS THE
PLAQUE HAS RUPTURED AND IS
STARTING TO LAY DOWN NEW BONE OR
HYDROXY APPETITE. SO, GAL YUM
68 IS VERY INTERESTING BECAUSE
IT WAS FDA APPROVED FOR
NEUROENDOCRINE TUMORS AND
TARGETS THE SOMATOSTATIN. AND
IN ORDER TO LOOK AT THE
INFLAMMATION IN THE CORONARY
ARTERY YOU HAVE TO SUPPRESS ALL
THE MET BOLLIC ACTIVITY IN THE
HEART YOU HAVE TO PUT PATIENTS
ON SPECIAL DIETS AND IF YOU
CAN'T GET THE MYOCARDIUM
SUPPRESSED. YOU MIGHT SEE THE
TINY DOT UP THERE IN THE PLAQUE
HOWEVER RIGHT ADJACENT TO IT IS
THE UPTAKE TO THE HEART AND IF
YOU USE GAL YUM 68 DO TO AT A
TIME YOU SEE THE ACTIVITY IN THE
PLAQUE ITSELF.
YOU DON'T HAVE IT IN --
EXTENSIVELY IN THE MYOCARDIUM.
IT COULD BE MUCH MORE SPECIFIC
SO AS I MENTIONED, THERE ARE
SOME BENEFITS TO NANOPARTICLES
AND IMAGING USING THEM IN
IMAGING THE ARTHROSCLEROSIS.
THEIR SMALL SIZE ALLOWS A HIGH
SURFACE AREA TO VOLUME. IF
YOU'RE TRYING FUNCTIONALIZE IT,
IT CAN BE VERY USEFUL. THERE
ARE MULTIPLE TARGETING
STRATEGIES.
YOU CAN HAVE PASSIVE TARGETING
BY THE MACROPHAGE PHAGOCYTOSIS,
YOU CAN HAVE THE AARON AGENTS,
YOU CAN ACTIVELY TARGET THE
LIGANDS WHICH IS WHAT WE'VE BEEN
DOING AND AS I MENTIONED PUT
POTENTIALLY MULTIPLE LIGANDS PER
PARTICLE AND POTENTIALLY, MAY
HAVE THEY ARE RAN ZEROSIC
CAPABILITIES. I WILL SHOW YOU
WHERE A SINGLE AGENT IS USED TO
BOTH DIAGNOSE AND DELIVER A DRUG
PAYLOA
IN OUR LAB WITH THE DOCTOR WE'VE
BEEN FOCUSING ON DENDRITES AND
COMBS. USING A METAL BACKBONE
AND ARMS WE HAVE THIS COMB
STRUCTURE BUT HE IS ALSO LOOKED
AT GOLD CLUSTERS. AND QUANTUM
AND C DOTS AND SOME OF THIS, THE
GOLD CLUSTERS ARE NICE BECAUSE
YOU CAN COOK THEM UP IN YOUR OWN
LAB WITH THE CNF COMB. WE HAVE
A SYNTHESIS CHEMIST MAKING AND
THE SYNTHESIS CHEMIST IS WORLD
RENOWNED AND HAS INVENTED
SOMETHING CALLED O LOW PLEXUS.
I DON'T KNOW IF ANY OF YOU KNOW
WHAT THAT IS.
NO. IF YOU ARE AN ACTOR OR AN
ACTRESS OR A WOMAN WHO GETS HER
HAIR DONE OR COLORED OR
PERMANPERMED
MANY TIMES. SO REVLON BOUGHT
THAT AND IN THE MIDDLE OF OUR
RESEARCH PROJECT SO AS I SAID
I'M SURPRISE ME TAKES MY PHONE
CALLS WHEN I'M TELLING HIM I
NEED THAT COMB TYPE STUFF BUT
THAT'S A LITTLE SIDE BAR. BUT
IN ANY CASE, YOU KNOW, GOLD
CLUSTERS ARE NICE BECAUSE YOU
CAN MAKE, WE'VE BEEN LOOKING AT
ALTERNATIVES IN CASE HE DECIDES
HE WANT TO GO LIVE ON A BEACH
SOMEWHERE WHERE WE COULD USE
GOLD CLUSTERS INSTEAD TO
FUNCTIONALIZE THEM WITH OUR
PEPTIDE. BUT THIS IS THE AGENT,
AND IT'S THIS IS THE, YOU KNOW,
IT FORMULATES INTO A COMB. WE
FUNCTIONALIZE THIS WITH CANF AND
THIS IS THE METHYL BACKBONE,
PALLY ETHYLENE ARMS AND WE USE
DOTA AND HERE'S COPPER 64.
THESE GREEN DOTS ARE THE CANF.
AND THIS IS THE NAN PARTICLE AND
IT BECOMES KIND OF LIKE A
MICELLE IN WATER. ON THE
OUTSIDE. AND THEN THE CNF ON
THE ARMS.
AND SO, YOU KNOW, AND THEN WE
PUT COPPER 64 ON THIS. SO THIS
IS THE SIZE. AND THEN ROUGHLY
ABOUT 35 CNF PEPTIDES PER
PARTICLE AND, YOU KNOW, ONE OF
THE QUESTIONS WAS HOW DID WE
DECIDE WHAT WE ENDED UP
DETERMINING WAS THAT 25% OF THE
ARMS WE HAVE FUNCTIONALIZED 25%
OF THE ARMS WITH CANF AND WE
TRIED MULTIPLE DIFFERENT
APPROACHES WE TRIED 5%, 10% AND,
YOU KNOW, WE ACTUALLY WENT AT
ONE POINT UP TO 50% AND IT JUST
DIDN'T FIND IT AT ALL. BUT
LOOKED AT BINDING CAPACITY AND
DID BLOCK AND SO IF YOU LOOK AT
THE 25% CNF ON THE COMB, AND THE
BLOCKING MUCH MORE SIGNIFICANT
THAN 10% CNF COMB WITH BLOCKING.
SO I ENDED UP WITH THIS
PARTICULAR AGENT IN -- THROUGH
THAT PROGRAM OF EXCELLENCE AND
THE AMOUNT OF NANO TECHNOLOGY
THAT WE BROUGHT INTO HUMANS.
AND SO WE THEN GOT BACK TO WHAT
ACTUALLY DOES THIS DO? AND NPR
SEES THE RECEPTOR FOR THE CNP
FOR THE PEPTIDE AND SO THAT IS
WHAT TARGETS CNP TARGETS IN P
RSHR
C. THIS IS ACTIVE. SO WHAT WE
USE IS A 15 FRAGMENT. AND THE
CANF IS A NONACTIVE FRAGMENT
WHICH IS THE PEPTIDE THAT WE PUT
ON THESE PEG ARMS AND THAT IS
WHAT TARGETS NPRC. AND US THE
OTHER THING I SHOULD MENTION IS
IT IS RESPONSIBLE FOR SMOOTH
MUSCLE CELL MIGRATION WHICH AS
WE DISCUSSED WITH OUR FINDINGS
WITH SOME OF OUR VASCULAR
BIOLOGISTS, SEEMS TO ACTUALLY
NOT ONLY CAUSE MIGRATION BUT
SOME PHENOTYPE CHANGE. SO, YOU
KNOW, EARLY ON, WE STARTED
LOOKING AT SOME OF THE PA THTHOY
OURSELVES. WE PUBLISHED IN A
PATHOLOGY JOURNAL. THERE WAS A
COUPLE OTHER GROUPS THAT HAD
NOTICED THAT NPRC IS PRESENT ON
MACROPHAGES AND ALSO IN PLAQUE
WITH VULNERABLE FEATURES. BUT
SINCE WE NOTICED THIS AS WELL,
WE DECIDED TO PUBLISH IT AND YOU
CAN SEE THAT THE RELATIVE NPRC
EXPRESSION WE LOOKED AT TISSUE
THAT WAS MINIMALLY DISEASED AND
MAXIMALLY DISEASED AND IT HAD A
GREATER PREVALENCE IN MAXIMAL
DISEASE AND ALSO MORE SO IN THE
DEEP INTIMA OR THE MEDIA IN
COMPARISON TO THE SUPERFICIAL
INTIMA AND MEDIA. AND THIS WAS
WHERE WE STARTED TO TALK TO GARY
OWENS WHO SUGGESTED THIS MAY BE
RESPONSIBLE NOT ONLY FOR
VASCULAR SMOOTH MUSCLE CELL
MIGRATION BUT EITHER A MARKER
THAT REMAINS ON THE CELLS AS IT
STARTS TO UNDERGO PHENOTYPE
CHANGE. SO, HOW DID WE GET THIS
INTO HUMANS? WE TOOK A LOT OF
PRECLINICAL VALIDATION. I
SHOWED YOU SOME OF THE BINDING
ASSAYS. THE CELL STUDIES. BUT
ALSO, YOU KNOW, WE DID ANIMAL
WORK. WE INJURED RABBITS AND
GAVE THEM A WESTERN FED DIET AND
DEMONSTRATED THAT THE RADIO
TRACER WAS TAKEN UP IN THESE
LESIONS. DID SOME KNOCKOUT
MOUSE AND SOME ANGIOGENESIS
STUDIES AS WELL LOOK AT THE
PRESENCE, THE -- IT IS PRESENT
IN SOME ENDOTHELIAL CELLS WHO
WERE ABLE TO SEE THE DIFFERENCE
BETWEEN A HIGH ISCHEMIA MOUSE
AND ALSO LOOKED AT SOME GENE
EXPRESSION AND THEN BIO
DISTRIBUTION. SO WHAT DO YOU
NEED TO GET AGENTS INTO THE FDA?
WELL YOU NEED A GMP FACILITY FOR
RADIO LABELING BECAUSE YOU'RE
GOING TO BE BRINGING THIS INTO
HUMANS.
YOU ALSO NEED TO ASSESS
SYMMETRY. TOXICITY ASSESSMENT.
IT HELPS IF YOU HAVE A LAB AND I
WILL TELL YOU ABOUT THAT IN A
MINUTE BUT YOU DON'T HAVE TO
HAVE A GOP LAB FOR TOX, FOR
ANIMALS. IF IT'S LESS THAN 100
MICROGRAMS IF WHAT YOU PLAN TO
INJECT INTO A HUMAN IS LESS THAN
100 MICRO PROGRAMS YOU CAN APPLY
FOR AN EIND AND THAT CAN HELP
YOU OUT A BIT THEN YOU DON'T
NEED A LARGE ANIMAL MODEL YOU
CAN GO WITH A SINGLE MODEL. I
WILL TELL YOU THE STORY, YOU
WILL HAVE A PRE-IND MEETING WITH
THE FDA BUT AT THE TIME WE WERE
WORKING WITH MIKE WELCH AND --
HOW MANY OF YOU KNEW MIKE WELCH?
YEAH, I'M SURE YOU DO AND MIKE
WAS ALWAYS VERY OPINIONATED.
AND SO IT WAS THE WEDNESDAY
BEFORE HE DIED. AND HE CALLS US
ALL INTO THE STEP DOWN UNIT
WHERE HE IS. HE HAS AN
OBJECTION FRACTION OF 20% AND
BLADDER CANCER AND A
CARDIODEFIBRILLATOR AND I THINK
HE BELIEVES THE END IS NEAR AND
HE CALLS US INTO THIS ROOM.
AND HE NEVER TOLD US HOW MUCH
MONEY WE HAD EVEN THOUGH WE WERE
PROGRAM PROJECT DIRECTORS.
HE -- HE WAS FINALLY TELLING US,
THIS IS WHAT YOU HAVE, THIS IS
WHAT YOU SHOULD DO AND ROB SAYS
WE WERE TALKING ABOUT THIS AND
I'M LIKE, ROB, ASK HIM, SHOULD
WE GET A PRE-IND MEETING AND
MIKE GOES, IN HIS BRITISH
ACCENT, NO, NO PRE-IND. NO. SO
OVER THE WEEKEND HE PASSED AWAY
AND THEN TWO YEARS LATER WE'RE
TALKING TO OUR PROJECT OFFICER,
PROGRAM OFFICER DENNIS BUXTON AT
THE NHLBI AND WE'RE ABOUT TO
SUBMIT THIS TO THE FDA AND HE
SAYS I THINK YOU NEED A PRE-IND
MEETING AND ROB AND I JUST LOOK
AT EACH OTHER AND HE GOES WHAT?
WHAT'S WRONG? AND ROB GOES,
WELL MIKE TOLD US NOT TO GET
ONE. AND THERE'S SILENCE AND
THEN HE SAYS, HE GOES WHEN DID
YOU TALK TO MIKE? LIKE WE WERE
HOLDING THESE SEANCES AND TRYING
TO GET INFORMATION FROM MIKE AND
I THINK IT WAS JUST BECAUSE IT
WAS ON HIS DEATHBED THAT WE FELT
THIS WAS ONE OF HIS LAST DYING
WORDS THAT WE HAVE TO DO IT AND
WE JUST SUBMITTED IT AND WE WERE
VERY FORTUNATE WE HAD NOT GONE
TO SEVENTH WAVE WE DID IT ALL
IN-HOUSE. THEY DID AN EXCELLENT
JOB THE PAPERWORK WAS VERY
THOROUGH THEY DID SEND SOME
THINGS OUT TO CHARLES RIVER FOR
BLOOD, QUESTIONS ON BLOOD TOX.
BUT IT WENT THROUGH. THERE WERE
A LOT OF QUESTIONS. BUT REALLY
WENT THROUGH, YOU KNOW, MUCH
MORE EASILY THAN I THOUGHT WOULD
BE. EVEN THOUGH WE DIDN'T USE
THE GLP. I JUST WANT TO TALK
ABOUT THE DOSE SYMMETRY AND THE
BUY YOU DISTRIBUTION.
THIS IS IN MICE AND WHEN WE
FIRST DID THIS IN MICE THE
CRITICAL ORGAN WAS BONE SURFACE
THESE ARE YOUNG MICE AND YOU SEE
THE UPTAKE IN THE END PLATES OF
BONE. NPRC IS ALSO RESPONSIBLE
FOR DEPOSITING BONE WHICH MAKES
YOU WONDER IF THERE ARE OTHER
ROLES THAT IT PLAYS IN THE
ARTHROSCLEROSIS WHEN YOU DO
THESE CAROTID IMAGING IN PATIENT
WHO IS HAVE DEGENERATIVE CHANGE
IN THE SPAIN YOU -- SPINE YOU
SEE IT IN THE SPINE ITSELF.
IT'S AT THE END PLAITS AND SO --
BUT I HAVE TO SAY IN -- TOX
ACTUALLY IN THE OTHER ANIMALS
WAS FINE. I DON'T KNOW IF I
HAVE THE SLIDE BUT IF HUMANS YOU
DON'T HAVE -- BONE IS NOT A
TARGET ORGAN AND I THINK THIS IS
BECAUSE WE WERE LOOKING AT
ADULTS, IN OTHER WORDS, WE
WEREN'T LOOKING AT PEOPLE WHO
WERE LAYING DOWN NEW BONE AS
THEY START TO GROW. THE
KNOCKOUT MICE ACTUALLY HAVE
SKELETAL DEFORMITIES WHICH IS
VERY INTERESTING. SO ONE THING
YOU DO HAVE TO EXPECT, WHEN YOU
ARE SUBMITTING TO THE FDA IS
THAT YOU WILL BE WRITING A LOT
OF SOPS. YOU KNOW, UCSB HAD NOT
BEEN A GMP FACILITY BEFORE.
UCSB IS WHERE YOUR PHYSICIST
CHEMIST IS SO WE FLEW OUT AND
THERE'S AND HE -- AND HELPED TH
WITH THE FACILITY.
WE DID EVERYTHING BACK AT WASH U
BUT ESSENTIAL LYCETT UP ABOUT 70
SOPS FOR THEM AND CLOSE TO ONE
HUNDRED FOR US FOR THE GMP
LABELING AND THEN HAD THE EIND
SUBMISSION WHICH ALSO INCLUDES
AN IRB SUBMISSION AND THEN SET
UP THE RELEASE QC. ALL OF THIS
IS NOW FAIRLY ROUTINE THAT WE'VE
DONE IT. YOU KNOW, 60 OR 70
TIMES BUT THE FIRST TIME THAT WE
DID THIS, YOU KNOW, IT'S -- IT
WAS QUITE LABORIOUS AND THIS WAS
THE EIND FDA SUBMISSION FOR THE
AGENT AND THESE FIRST THREE, THE
SUBMISSION, EVERYTHING USED TO
BE DONE IN PAPER. NOW YOU CAN
ACTUALLY UPLOAD. THERE'S A
WEBSITE WHICH MAKES IT A LOT
EASIER. AND THEY HAD TO BE
COLOR-CODED, YOU KNOW, THE
BINDERS HAD TO BE LIKE IN RED,
ORANGE AND GREEN. AND THIS WAS
THE SUBMISSION. AND THESE ARE
THE ANSWERS TO THE QUERIES. SO
WE ANSWERED THE QUERIES. BUT IN
BETWEEN HERE AND HERE WAS VERY
INTERESTING. YOU KNOW, THE FDA
HAS 30 DAYS AND THEY USUALLY,
AFTER THE 30TH DAY IF YOU DON'T
HEAR BACK FROM THEM, YOU'RE HOME
FREE BUT WHAT USUALLY HAPPENS IS
ON DAY 29 YOU GET AN E-MAIL THAT
HAS 17 QUERIES AND THENTAIL
THEY'LL SAY CAN YOU MEET WITH US
TOMORROW AFTERNOON AT 2 O'CLOCK
ON FRIDAY.
AND ANSWER ALL OF THESE
QUESTIONS AND SO FOR THE LAST
HALF OF THE DAY YOU'RE
SCRAMBLING AROUND TRYING TO FIND
OUT WHY, YOU KNOW, THIS FPLC'S
PEAK WAS THIS WAY AND WHATNOT
AND SO, YOU KNOW, THERE ARE MANY
INDIVIDUALS WHO ARE VERY HELPFUL
WHO, I DON'T KNOW HOW MANY OF
YOU KNOW SALLY SCHWARZ WE KNOW
HER BECAUSE SHE WAS PRESIDENT OF
THE SNMMI BUT SHE'S A RADIO
PHARMACIST. BUT SHE WAS
INVALUABLE I HAVE HER SITTING
NEXT TO ME.
AND THIS IS THE DAYS BEFORE ZOOM
WE'D HAVE A POLY CON AND THE FDA
WOULD BE ASKING ME QUESTIONS AND
ILL -- I WOULD START TO SAY
SOMETHING AND SHE WOULD SAY SAY
THIS, SAY THIS. IT REALLY DOES
TAKE A TEAM TO GO THROUGH TO GET
THINGS INTO, THROUGH THE FDA AND
TO HUMANS. AND SO AFTER THAT
FIRST EIND WE WERE ABLE TO DO
NORMAL VOLUNTEERS FOR HUMAN
DISTRIBUTION AND DOSE SYMMETRY
AND WE DID EIGHT OF THESE AND
EMBARKED ON A SORT OF A PROOF OF
CONCEPT STUDY WITH 44 PATIENTS.
I THINK WE HAD PLANNED FOR 50
BUT WE GOT TO 44 BEFORE OUR RO 1
FUNDING RAN OUT FOR OUR PROJECT
AND THESE ARE PATIENTS WHO ARE
SCHEDULED FOR ENDOOR DIRECT MY
AND SOME OF THEM WOULD GO AND
SOME OF THEM WOULDN'T AND WE
WOULD -- THE.
ONES THAT WENT ONTO SURGERY WE
WOULD TAKE THE PLAQUE AND DO
CELL COUNTS AND IT HAD A VERY
NICE CORRELATION TO THE UPTAKE
IN THESE -- IN THE PLAQUE AND I
WILL SHOW YOU THAT BUT THEY ALSO
GOT AN MRI SO YOU COULD SEE THE
PLAQUE COMPOSITION BY MRI AND
THEN WHETHER OR NOT, WHAT THE
UPTAKE WAS USING THE RADIO
TRACER.
SO THIS IS WHERE I WAS GOING TO
SHOW YOU, IT'S KIND OF
INTERESTING THAT THE CRITICAL
ORGAN WAS THE LIVER WHICH IS NOT
SURPRISING BECAUSE OF ALL THAT
PEG BUT THE BONE DIDN'T SHOW
MUCH UPTAKE AND I THINK PART OF
THIS IS BECAUSE YOU HAVE HUMANS
WHO ARE FULLY DEVELOPED
SKELETALLY AND THE CRITICAL
ORGAN WAS THE LIVER. SO, AS I
MENTIONED, WE DID THIS STUDY TO,
SO WE NOW HAVE -- WE ARE ON OUR
SECOND STUDY. THE FIRST ONE WAS
JUST SORT OF A FEASIBILITY STUDY
BUT THE SECOND IS LOOKING AT
PATIENT OUTCOMES. AND THIS IS
WHAT WE'RE DOING WITH SEEDERS
WITH THE TWO OBJECTIVES ONE IS
TO DEMONSTRATE AND WE CAN SHIP
OUT TO CALIFORNIA AND HAVE A
SIMILAR PET MR EXAM THERE,
FEASIBILITY IN THAT WAY, BUT
THEN ALSO TO TAKE PATIENTS WHO
HAVE A STENOSIS OF 70% DIAMETER
AND TAKE PATIENTS WHO ARE EITHER
BEING TREATED MEDICALLY OR
SURGICALLY AND WITH THE SURGICAL
PATIENTS WE'RE LOOK AT THE
PLAQUE BUT WITH THE MEDICAL
PATIENTS WE IMAGE THEM BEFORE
OPTIMAL MEDICAL THERAPY AND THEN
18 MONTHS LATER AND CALL THEM
ALONG THE WAY, EVERY THREE
MONTHS TO MAKE SURE THAT THEY
ARE TAKING THEIR OPTIMAL MEDICAL
THERAPY, THEIR STATIN AND THEIR
OTHER, YOU KNOW,
ANTIHYPERTENSIVES AND THEIR
ANTIDIABETIC DRUGS TO MAKE SURE
THAT AND THEN LOOK AT THE
DIFFERENCE. SO THE RESULTS, ONE
OF THE RESULTS OF OUR FIRST
STUDIES WAS THAT OF THE
PATIENCES PATIENTS WHO WERE
ENROLLED.
WE HAD 19, I THINK 15 PATIENTS
WHO WENT ONTO SURGERY AND OF
THESE 15 PATIENTS THAT
UNDERSTOOD WENT THE PLAQUE
COLLECTION WITH THE STAINING AND
CELL COUNTING SHOWED A NICE
CORRELATION BETWEEN THE SUV AND
THE PRESENCE OF THE MPRC. AND
THEN RETROSPECTIVELY WE WENT
BACK AND WENT DOES THIS MAKE ANY
DIFFERENCES IS SUV ELEVATION
CORRELATE WITH ANYTHING AND THIS
WAS REALLY MORE OF A TREND. BUT
THE FIVE PATIENTS THAT HAD
EVENTS DID HAVE AN SUV THAT WAS
HIGHER THAN THE 22 WHO DID NOT
HAVE AN EVENT SO THAT PROMPTED
US TO EMBARK ON OUR SECOND STUDY
LOOKING AT OUTCOMES. WHAT DO
THESE IMAGES LOOK LIKE? YOU CAN
SEE UPTAKE IN ARTHROSCLEROSIS,
THIS IS A PATIENT, 86-YEAR-OLD
WHO WENT TO SURGERY AND THE
IMAGES BELOW BETWEEN THE
MAXIMALLY DISEASED CAROTID AND
THE MINIMALLY DISEASED YOU CAN
NICELY SEE WE HAVE CD 68 WHICH
IS A MARKER FOR MACROPHAGES AND
NPRC WHICH IS THE, YOU KNOW, WE
HAVE A MARKER FOR NPRC. AND
WHEN YOU COLOCALIZE, YOU KNOW,
LOOKS LIKE THEY'RE PRINCIPALLY
IN MACROPHAGES BUT YOU CAN -- WE
ALSO -- THERE'S -- THIS IS A
HIGH RESOLUTION OF NPRC WITH CD
68 AND YOU CAN ALSO SEE IN THE
PLAQUE, REALLY NOT MUCH THERE,
NOT MUCH NPRC, NOT MUCH CD 68
AND SO THE DIFFERENCE BETWEEN
THE DISEASE AND THE NONDISEASED
PORTIONS OF THIS WOMAN'S CAROTID
ARTERY. AND JUST, AND SOME
OTHER EXAMPLES, THIS IS A
REFUSED PET MR IMAGE WHERE YOU
CAN SEE THE UPTAKE IN THE
ARTHROSCLEROSIS AND IN A
SEPARATE PATIENT BUT SIMILAR
WHERE YOU CAN SEE THE
COLOCALIZATION OF THE
MACROPHAGES IN NPRC AND THEN WE
THE AUTORAID YOL RAH FEW AND YOU
CAN SEE IT'S BEING BLOCKED.
I'M GOING TO TALK TO YOU
BRIEFLY. WE'RE GETTING CLOSE TO
THE END OF THE TALK.
ABOUT MYOCARDIAL INFLAMMATION
AND CCR 2 AND CCR 2 IS
MONOCYTES: AND SO, IT PLAYS A
CRITICAL ROLE IN DEFENSIVE
MULTIPLE DISEASES AND WE'VE BEEN
USING IT TO LOOK AT
ARTHROSCLEROSIS BUT ALSO LOOKING
AT PATIENTS POST MYOCARDIAL
INFARCTION. AND THE TOP PATIENT
HERE IS A NORMAL CONTROL BOTH A
SPEC STUDY AND THEN THE CCR 2
PET STUDY AND YOU CAN SEE NO CCR
2 UPTAKE BECAUSE PRESUMABLY NO
INFLAMMATION AND THE SPEC SHOWS
MY OWE CARDIAL ACTIVITY IN THE
NORMAL MYOCARDIUM.
AND THIS IS DAY 101 AND YOU CAN
SEE THIS IS THE AREA OF
MYOCARDIAL INFARCTION AND THIS
IS TAKEN UP IN THE AREA OF
MYOCARDIAL INFARCTION AND SO,
OUR HOPE IS THAT IT COULD TELL
US SOMETHING ABOUT MYOCARDIAL
INFARCTION EVOLUTION AND THIS
WAS PUBLISHED BY KORIE LEVINE
AND ROB IN NATURE CARDIOVASCULAR
RESEARCH JUST THIS PAST YEAR.
AND, YOU KNOW, YOU CAN LOOK AT
THE SUV DIFFERENCES BETWEEN THE
INFARCT AND THE REMOTE MY OWE
CARD I DIDN'T MEAN AND THEN THE
CONTROLS. AND THEN IN SKELETAL
MUSCLE.
SO ANOTHER INTERESTING AGENT.
AND, YOU KNOW, THIS WAS SORT OF
AN ACCIDENT ONE OF OUR RESEARCH
ASSISTANTS WAS STAINING, YOU
KNOW, FOR CCR 2 AND NPRC FOR
DIFFERENT PROJECTS AND USED
ADJACENT PROJECTS FROM A
BIOREPOSITORY. AND WHAT'S KIND
OF INTERESTING IS YOU CAN SEE
THAT CCR 2 IS PRESENT ON
DIFFERENT CELLS THAN NPRC AND WE
KNOW THIS, I MEAN, BY LITERATURE
CCR 2 IS PROTEESENT IN MONOCYTE
BUT THESE ARE THE STAINED CELLS
AND THE GREEN IS CCR 2. AND IS
THERE SOME UNEVENNESS IN THE
STAINING HERE AND ONCE YOU GET
TO THE ENDOTHELIUM THIS IS THE
PRESENCE IN THE CELLS. PRESENT
IN VASCULAR SMOOTH MUSCLE CELLS,
IN MACROPHAGES AND ALSO IN THE
ENDOTHELIUM. NOW, ULTIMATELY,
YOU KNOW, WHAT MIGHT BE -- IF I
LIVE LONG ENOUGH, WHAT WOULD BE
OUR ULTIMATE GOAL? COULD YOU
SUPPRESS NPRC AND SLOW DOWN
ARTHROSCLEROSIS? AND, YOU KNOW,
ONE QUESTION IS HOW WOULD YOU
USE A NANOPARTICLE THAT MIGHT
INVOLVE CARGO SWITCHING? THIS
WAS AN ARTICLE NOT WRITTEN BY US
BUT ONE THAT I THOUGHT WAS
INSPIRATIONAL. THEY HAVE A CORE
STRUCTURE AND THIS IS A COMPLEX.
AND THE SHELL IS PHOSPHOLIPIDS.
AND WHEN THE CSNP ENCOUNTERS
CHOLESTEROL THE STATINS RELEASE
AND THE STATIN AND CHOLESTEROL
SKA SKRENGED THROW THE
CARGO-SWITCHING.
SO ARE THERE THINGS THAT COULD
BE DONE, COULD BE PLACED ON A
NANOPARTICLE WITH THIS C TYPE,
THIS CNF THAT'S TARGETING THE
PEPTIDE RECEPTOR THAT MIGHT SLOW
DOWN THE ARTHROSCLEROSIS. SO
UNDERSTANDING PLAQUE BIOLOGY AND
IMAGING IT ON THE PATIENT LEVEL
AND BEING ABLE TO IMAGE IT CAN
HELP US UNDERSTAND, YOU KNOW,
WHICH PLAQUES RUPTURE, IT
MIGHT -- WHICH ONES MIGHT CAUSE
MAJOR AVERSE EVENT AND WHO YOU
MIGHT BE ABLE TO INTERVENE ON
AND WHAT WE'RE SEEING AT THE
MOLECULAR LEVEL. SO, YOU KNOW,
FURTHERING PRECISION MEDICINE
THERAPY. NOW I DID PROMISE YOU,
HOW AM I DOING ON TIME HERE?
I'VE GOT A FEW MORE MINUTES.
GOOD. WHAT DO YOU NEED GET ALL
THIS IN, THE AGENTS LIKE THIS
THROUGH THE FDA INTO HUMANS YOU
NEED A LOT OF PEOPLE IT'S
HELPFUL TO GET ADVICE. THIS IS
OUR SYNTHESIS CHEMISTS GROUP AND
HERE IS SALLY, AS I MENTIONED
WAS A RADIO PHARMACIST WHO
REALLY HAS A STRONG
UNDERSTANDING OF THE FDA, SHE'S
NOW EMERITUS, SHE'S NOW AN
EMERITUS PROFESSOR AND MIKE
NICKELS IS THE DIRECTOR OF OUR
CYCLOTRON CENTER AND THEN, YOU
KNOW, DESPITE WHAT I SAID I
THINK IT IS A GOOD IDEA TO GET
PRE-IND ADVICE. THEY'RE USUALLY
VERY FORTHCOMING. SOMETIMES
THEY'LL EVEN DO IT JUST BY
E-MAIL. YOU CAN ASK YOUR
QUESTION AND THEN THEY WILL
RESPOND. AND SINCE THAT FIRST,
THE BEGINNING, WE'VE DONE THAT
AND BEEN VERY SUCCESSFUL IN
GETTING ADVICE FROM THE NIH EVEN
JUST BY E-MAIL. SO THE LESSONS
LEARNED ARE, YOU KNOW, HAVE A
STRONG INFRASTRUCTURE, HAVE A
STRONG AND DIVERSE TEAM, YOU
WANT TO GET ADVICE, YOU WANT TO
HAVE A GOOD INDICATION AND A
MEANINGFUL TARGET. HAVE STRONG
PRELIMINARY DATA. BE PREPARED
TO WRITE A LOT OF SOPS AND THEN
GIVE YOURSELF TIME, YOU KNOW, IF
YOU'RE PLANNING TO PUT IN AN R
01, START THE YEAR BEFORE, DOING
A LOT OF THE STUFF. MAYBE EVEN
A YEAR AND A HALF BEFORE. AND
THEN HOW DO WE ENCOURAGE PEOPLE
WHO START OFF WITH INTERESTING
IDEAS AND ENTHUSIASM FOR
RESEARCH. ONE OF THE QUESTIONS
IS WHY AM I STILL HERE DOING
THIS INSTEAD OF OFF MAKING, YOU
KNOW, HUNDREDS OF THOUSANDS OF
DOLLARS? BUT THIS WAS ME IN
MEDICAL SCHOOL AND THIS WAS IN
THE 80S SO YOU NOTICE THE, WHAT
IS IT THE WINGED HAIR TYPE THING
AND THEN THIS IS ME ON THE NIH
CAMPUS AND THIS IS BUILDING 37 I
THINK. SO, AT DUKE WE HAD TO DO
A YEAR OF RESEARCH IN MEDICAL
SCHOOL AND I HAD A GRANT WITH --
A MEDICAL STUDENT GRANT AT WASH
U BUT I WAS DATING ANOTHER
FELLOW CLASSMATE WHO HAD A
GRANT -- A HOWARD HUGHES GRANT
AND WAS LIVING IN THE CLOISTER
SO, YOU KNOW, A LOT OF US AT THE
TIME WERE VERY INTERESTED IN THE
RESEARCH. THIS IS A PICTURE OF
KEENE AND THEN ANOTHER WHO
CONVINCED ME TO GO INTO
RADIOLOGY AND THEN I COULD DO
RESEARCH ANDOLOGY RADIOLOGY
TOGETHER. CHARLIE WAS IN
RADIOLOGY BUT ALSO DOUBLE
BOARDED IN INTERNAL MEDICINE AND
ONE WHO PREVAILED UPON HAROLD TO
ESTABLISH THE NIBIB.
SO AT WASHINGTON UNIVERSITY IN
OUR DEPARTMENT, WE HAVE THREE
NIH FUNDED T32 PROGRAMS THROUGH
THE NIV AND THEY'VE BEEN QUITE
INSTRUMENTAL I THINK IN, YOU
KNOW, KEEPING THE VISIBILITY OF
RESEARCH PRESENT TO OUR
CLINICIAN SCIENTISTS ESPECIALLY.
BUT ALSO THROUGHOUT THE
DEPARTMENT. AND THE FIRST ONE
IS OPPORTUNITIES AND
TRANSLATIONAL IMAGING, THESE ARE
FOR RESIDENTS AND FOR FELLOWS SO
HAVE AN M.D. SOME OF THEM MIGHT
HAVE A PH.D. AS WELL. BUT
REALLY ALLOWING OUR RESIDENTS
AND FELLOWS TO SEE RESEARCH,
THEY HAVE, ESPECIALLY IN THOSE
WHO ARE NOT IN THIS PROGRAM, YOU
KNOW, THESE RESIDENTS PRESENT
AND WE HAVE A SEMINAR RESEARCH
SEMINAR EVERY YEAR SO ALL OF OUR
RESIDENT GOES TO THAT, SO WE
HAVE PEOPLE DOING RESEARCH WHO
ARE ENTHUSIASTIC AND HAVE
MENTORS.
AND WE HAVE A SEMINAR SERIES
THAT KIND OF GOES ALONG WITH
THAT. I WILL SHOW YOU A LITTLE
BIT OF THAT. THE 21ST CENTURY
IMAGING SCIENCES PROGRAM IS A
PRECLINICAL -- A PRE-DOCTORAL
PROGRAM.
AND THIS SUPPORTS OUR -- WE HAVE
MULTIPLE DIFFERENT DEPARTMENTS
THAT WE PARTNER WITH, SO
ENGINEERING, THE SCHOOL OF
ENGINEERING, THERE'S AN IMAGING
SCIENCES PATHWAY, MANY OF THE
STUDENTS COME IN FROM THAT, SOME
COME IN FROM DBBS, IT'S A
DEVELOPMENTAL BIOLOGY PH.D.
PROGRAM. AND THEN THIRDLY, MOST
RECENTLY, THIS WAS A T32
OBTAINED A COUPLE OF YEARS AGO.
THIS ONE'S ACTUALLY THROUGH THE
NCI AND IT'S A TRANSLATIONAL
IMAGING AND PHARMACEUTICAL
SCIENCES T32 AND IT TRAINS M.D.S
AND PH.D.S TO BE RADIO CHEMISTS
AND REALLY TO TRANSLATE SOME OF
THE RADIO TRACERS THAT I'VE
TALKED ABOUT.
SO THE T 32 PROGRAM TOP TIER,
THE CLINICIAN SCIENTIST PROGRAM
IS ONE OF SIX CLINICIAN
SCIENTIST PROGRAMS IN THE
COUNTRY.
JOHNS HON HOPKINS, SOUTHWESTERN
ALL HAVE THESE.
AND I FEEL LIKE THERE ARE PLACES
TO HAVE THE CAPABILITY TO
PROVIDE TRAINEES WITH RESEARCH
AND TEACH THEM TO BECOME
INDEPENDENT RESEARCHERS. HERE
ARE OUR PROGRAM DIRECTORS, I'M
ONE OF THE PROGRAM DIRECTORS I'M
THE PRINCIPLE DIRECTOR AND THEN
A COUPLE OF CO-PIS AND I THINK
AS WE GO INTO OUR NEXT
SUBMISSION, I WILL PROBABLY
SWITCH OUT TO DR. LONG YOU ANN
AND MAYBE STAY ON AS A CORKS PI,
RICHARD WAUL WAS OUR PREVIOUS
CHAIR.
AND THEN WE HAVE, THE PREVIOUS
CHAIR OF THE DEPARTMENT. WHICH
I SHOULD SAY BECAUSE HE WAS THE
ONE WHO SAID PAM, YOU SHOULD
SUBMIT A T-32 SO HE WAS THE
INSPIRATION BUT I SUBMITTED THE
GRANT. AND THEN WE HAVE
RESEARCH RESIDENCY PROGRAM
DIRECTORS DR. UP POE LEE TO,
DR. RAH GEE, BOTH OF THESE
INDIVIDUALS RUN THE RESEARCH
RESIDENT PROGRAM AND WE'VE HAD A
SEPARATE NRMP NUMBER FOR OUR
RESEARCH RESIDENT TRACK GOING
BACK TO 1989 EVEN BEFORE THE
LOCALMAN PATHWAY IF PEOPLE KNOW
WHAT THAT IS WITH THE ABR.
THE T32 PROGRAMS HAVE ELEVATED
THE RESEARCH BECAUSE, YOU KNOW,
IT -- THEY INSIST UPON THE
INSTRUCTION OF THE RESEARCH
RIGOR AND REPRODUCIBILITY AND
THE ETHICS AND, YOU KNOW, AND
THE DIDACTIC WHICH JUST I THINK,
YOU KNOW, ELEVATE THE VISIBILITY
AND THEN ALSO THE, YOU KNOW, THE
RIGOR OF THE RESEARCH SO THESE
ARE THE PIS OF THE PROGRAM
DIRECTORS FOR OUR TRANSLATIONAL
IMAGING AND RADIO PHARMACEUTICAL
SCIENCES. TAMMY BEN ZINGER, AND
WILL TU AND WE HAD THIS SUMMER
STUDENT PROGRAM WHICH CAN BE AN
ENTREE INTO SOME OF THESE T32S.
WE HAVE PEOPLE WHO COME OVER THE
SUMMER. WE GIVE THEM A STIPEND
AND BRING IN, YOU KNOW, FIFTEEN
OR SO STUDENTS. MEDICAL
STUDENTS. FROM THROUGHOUT THE
UNITED STATES IN TO DO RESEARCH
WITH US. HERE ARE SOME OF OUR
CURRENT RESIDENTS AND FELLOWS.
THIS YEAR WE HAD THREE OF THEM
WHO RECEIVED, THESE ARE THREE
RESIDENTS. THEY'VE RECEIVED
RSNA GRANTS. AND THEN DAVID
BALLARD IS A FORMER TRAINEE WHO
IS NOW FACULTY WHO HAS RECEIVE
AN RSNA RESEARCH SCHOLAR GRANT.
SO YOU KNOW I THINK I WILL GO
AHEAD AND STOP THERE. IT'S BEEN
VERY EXCITING TO BE ABLE TO
PROVIDE THIS EDUCATION TO OUR
RESIDENTS AND TO OUR FELLOWS.
AND I AM KIND OF HOPING THAT
THERE'S A FUTURE FOR RESEARCH IN
IMAGING THAT NOT EVERYBODY GOES
OFF INTO PRIVATE PRACTICE AND
WANTS THOSE BUNNY SLIPPERS AND
READING FOR HIGH REIMBURSEMENT
IN THEIR HOMES. SO, THANKS.
>> AUDIENCE: (APPLAUSE).
>> THANK YOU. MUCH APPRECIATED.
I HAD ASKED SOME OF THESE EXACT
QUESTIONS AND THANK YOU SO MUCH
FOR TELLING US WHAT YOU'RE DOING
THERE. I REALLY WANTED TO
UNDERSTAND HOW TO KEEP PEOPLE IN
THE RESEARCH FIELD AND NOT GOING
TO THE BASEMENT IN BUNNY
SLIPPERS. WE CAN TAKE SOME
QUESTIONS AND THEN THERE MAY BE
SOME ONLINE AS WELL.
>> THANK YOU, PAM. THAT WAS
REALLY GREAT. AND NEXT TIME YOU
HAVE A SEANCE WITH MIKE, PLEASE
INVITE US. I'D LOVE TO BE
THERE.
>> WE WILL. I KNOW, WONDER WITH
HIS ONLY IN THIS CASE SENSE IN
THE AFTERLIFE WHAT HE WOULD BE
ABLE TO TELL US E.
>> EXACTLY. I WAS THINKING HOW
I WOULD APPROACH THIS PROBLEM
AND I AM SO HAPPY I DON'T HAVE
THE PROBLEM OF TRYING TO FIND A
MILL MEET IR SIZED ARTERY ROW
PLAQUE WHAT IS YOUR THINKING OF
LOOKING FOR A LARGE PARTICLE.
22 NANOMETERS WHICH WOULD HAVE A
RELATIVELY LONG CLEARANCE TIME
FROM THE LUMEN? I WOULD THINK
YOU WOULD WANT TO GET IT OUT OF
THE LUMEN AS QUICKLY AS
POSSIBLE. SO I'M CURIOUS ABOUT
THAT AND THAT MUST HAVE DRIVEN
THE CHOICE OF COPPER TO BE
SLIGHTLY LONGER LIVED. AND THEN
SO WHEN DO YOU ACTUALLY IMAGE
THE PATIENT AFTER INJECTION?
>> SO THAT'S TRUE, WITH THE
NANOPARTICLE, THIS PARTICULAR
NANOPARTICLE AS I MENTIONED HAS
THE PEG ARMS AND THAT KEEPS,
DOES GIVE IT A LONG
INTRAVASCULAR HALF LIFE AND, YOU
KNOW, EARLY ON WE DID LOOK AT
JUST COPPER 64 AND THE PEPTIDE
ITSELF. THE NANOPARTICLE HAD
TWO REASONS, ONE WAS THE LONGER
INTRAVASCULAR HALF LIFE. THE
SECOND REASON WAS THE GRANT WE
WERE APPLYING FOR WAS A NANO
IMAGING GRANT. AND SO WE WERE
LIKE WE BETTER PUT A
NANOPARTICLE ON THIS. BUT, YOU
KNOW, THE DISADVANTAGE IS THAT
YOU HAVE TO INJECT AND THEN YOU
IMAGE TWELVE HOURS LATER. 12-18
SO BASICALLY WE BRING THE
PATIENTS IN IN THE AFTERNOON, WE
INJECT AROUND 3 O'CLOCK AND THEN
WE PUT THEM UP IN, YOU KNOW, A
HOTEL RIGHT NEXT DOOR AND THEN
THEY COME BACK IN AT 7:00 IN THE
MORNING AND WE IMAGE THEM. IF
YOU'RE DOING THIS, NOWADAYS,
PATIENTS WANT THINGS THAT ARE
REALLY EFFICIENT. AND SO,
ANOTHER REASON FOR LOOKING AT
OTHER NANOPARTICLES LIKE GOLD OR
MAYBE WE WERE CONSIDERING WITH
THE DIFFERENT CONJUGATE DO I
WANT TO GO WITH CNF AND COPPER
64 AGAIN. AND TRY TO SEE IF WE
CAN SHORTEN THAT WINDOW. SO
THAT YOU KNOW, YOU COULD IMAGE
AND HAVE A SHORTER UPTAKE TIME.
AND, YOU KNOW, SO THAT IS A
DISADVANTAGE. AND I THINK IT'S
ACTUALLY HINDERED SOME OF THE --
WE'VE HAD SOME VENTURE
CAPITALISTS WHO HAVE BEEN
INTERESTED IN THEIR KIND OF
LIKE, YOU HAVE TO COME BACK THE
NEXT MORNING. SO THAT IS A
DISADVANTAGE. THANK YOU VERY
MUCH. DELIGHTED TO BE HERE.