“liquid brachytherapy” direct administration of therapeutic radioisotopes into tumors
DESCRIPTION
“Liquid Brachytherapy” Direct Administration of Therapeutic Radioisotopes Into Tumors. Jim Simon,* 1 Stan Stearns, 2 Kenneth McMillan, 1 Max Loy, 2 and Keith Frank 1 IsoTherapeutics Group LLC, Angleton, Texas (1) & Valco Instruments Co. Inc., Houston, Texas (2). Brachytherapy - PowerPoint PPT PresentationTRANSCRIPT
“Liquid Brachytherapy”Direct Administration of Therapeutic
Radioisotopes Into Tumors
Jim Simon,*1 Stan Stearns,2 Kenneth McMillan,1 Max Loy,2 and Keith Frank1
IsoTherapeutics Group LLC, Angleton, Texas (1) & Valco Instruments Co. Inc., Houston, Texas (2)
2
Background
• Brachytherapy– Radioactive source placed
in or next to a tissue– Encapsulated to ensure
activity does not become systemic
– Usually gamma / X-Ray emitting radioisotopes due to the need to penetrate the capsule
– Range in tissue higher than desirable
– “Seeds” can migrate
• Radiopharmaceutical– Radioactive construct
usually administered systemically
– Targets tissue or organ• Metabolic (e.g. I-131)
• Bio-targeting (mAbs)
• Bone targeting (phosphonates)
– Uptake if non-target tissue
Therapy Using Isotopes
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OpportunityLiquid Brachytherapy
• “Brachyceutical” (brachytherapy + radiopharmaceutical)
• No encapsulation for radiation to penetrate
• Can use particle emitters (β or α)
• More precise placement of dose
• Fewer side effects
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Beta-Emitting Isotopes
Half Life BetaMax Tissue
PenetrationGamma
166Ho 26.83 hr 1.8 MeV 0.85 cm80.6 keV
(6%)
153Sm 46.3 hr 0.705 MeV0.32 cm 118 keV
(30%)
177Lu 6.7 days 0.498 MeV 0.17 cm208 keV
(11%)
90Y 64 hr 2.28 MeV 1.1 cm --
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Methods• 177Lu, 153Sm, and 166Ho were deposited in bone,
brain, prostate, and soft tissue tumors• Administration was accomplished under
anesthesia using custom micro syringes, micro drills and a micro pump.
• Gamma images and dissection data were used to determine the amount of isotope remaining as a function of time and form of the isotope.
• A clinical trial in canine osteosarcoma has been initiated
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Results• We have found microsyringes, miniature drills and low
volume pumps were easy to use and capable of delivering isotopes accurately even when penetrating bone.
• High pH formulations were retained at the sites of injection with little migration of the isotope for up to 14 days.
• Low pH formulations showed rapid redistribution of the isotope outside the injection site.
• In bone, stable chelates were less retained at the site of injection than weak chelates.
• HT-29 tumors-bearing mice injected with high pH formulations showed a reduction of tumor growth compared to controls.
• Initial results in canine OS show positive clinical effect.
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Bone Experiments• Used miniature drill• Forms of the Isotope (166Ho):
– Acidic solution (0.1-0.05 M HCl)
– Chelated• EDTMP complex (labile
complex with high chelant concentration)
• DOTMP complex (inert complex with low chelant concentration)
– High pH (metal oxide/ hydroxide mixture)
• Results– Metals in acid migrated quickly
– EDTMP complexes showed higher retention than DOTMP complexes
– DOTMP complexes had less soft tissue activity and more bone activity
– High pH formulation remains at injection site
femur
Bone drill prototype
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Potential Mechanism
• HCl formulation– Metal is soluble long enough
to become systemic leading to soft tissue (liver) uptake
• Weak Chelate (EDTMP)– Free metal released from
complex has some tenacity for the bone after precipitation, but there is enough time available for migration
– Liver activity
• Strong Chelate (DOTMP)– Complex stays intact and
migrates from the injection site depositing in all bone
NN
PO3H2H2O3P
PO3H2H2O3P
N
N N
NPO3H2
PO3H2H2O3P
H2O3P
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Biodistribution after Bone injection% I.D. 2 Hours after Administration
10 µL of 166Ho solution, add 8 µL of water and 2 µL of 50% NaOH
Bone Injection
Site
Rest of skeleton
Liver
HCl 5 28 52
EDTMP 7 22 11
DOTMP 7 18 0
OH 92 1 1.7
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Human Xenograft Experiments
• Athymic nude mice with HT-29 human colon cancer cell• Tumor size ranged from 64-324 mm3
• 177Lu from MURR (1.09 Ci/mL) in 0.05 M HCl– Low pH formulation is 50:50 solution of 177Lu and 0.05 M HCl– High pH formulation was prepared using 10 µL of 177Lu, 8 µL
water, 2 µL of 50% NaOH
HT-29 xenograft
Direct injectionInto tumor
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Low pH Formulation (Mouse # 458)
• Injected with 1.08 mCi 177Lu in about 3 µL
• One injection in the center of the tumor
7 days
tumor
Note systemic activity
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High pH formulation (Mouse 459)
• Two 5 µL injections 177Lu (0.8 mCi total) into tumor
tumor
14 days
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Whole Body Retention (Mouse 459)
Whole Body Activity (decay corrected)
0
100200
300
400500
600
700800
900
0 2 4 6 8 10 12 14
Days post injection
uC
i le
ft in
mo
us
e
14
Body Weight
15
17
19
21
23
25
0 2 4 6 8 10 12 14 16
Days
Bo
dy
Wei
gh
t (g
)
459, pH 10+
458, pH<1
462, pH10+
466, Control
177Lu Injection on Day 1
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Tumor Size
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
1 2 3 6 7 8 9 10 11 12 13
Days
Tu
mo
r M
as
s
459, pH 10+
458, pH<1
462, pH10+
466, Control
Euthanized
Lu-177 Injection on Day 1
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Summary of Xenograft Data
Mouse Dose pH Volume Fractions Scan Tumor
458 1.08 mCi Low 3 µL 1 PoorGrowth
Stopped
459 0.8 mCi High 5 µL 2 GoodLate
Reduction
462 0.88 mCi High 15 µL 3Some
Migration
Growth
Stopped
466 Control - - - -Continued
Growth
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Summary of Laboratory Work
• Rat tissues showing long term retention of isotope:– Bone– Prostate– Brain– Lung
• Human tumor (HT-29) in mice– Long term retention– Indication of efficacy
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How Much Activity is Needed
Assume 10,000 rads to ablate tissue (rad = cGy)
µCi Ho-166 Gram Tissue Dose (rads)
50 1 2,860
100 1 5,720
200 1 11,400
500 1 28,600
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Dose Comparison
• Typical dose of Quadramet is 1 mCi/kg (palliative)
• For a 70 kg person that is 70 mCi of 153Sm• For a 1 gram tumor, the dose could be as low
as 200 µCi• 70/0.2 = 350 times the dose for new
brachyceuticals (resolve tumor)
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Possible Applications of Technology
• Primary Bone Cancer – can replace amputation
• Brain Cancer
• Prostate Cancer– Replacing seeds
• Lung cancers
• Many Inoperable Cancers
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Canine Osteosarcoma Trial• University of Missouri – Columbia
– Dept of Veterinary Medicine and Surgery
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Status of Canine OS Trial
• Trial currently in progress• Preliminary results positive
– Pain relief– Use of leg
Dog Breed Sex Wt Age Tumor location1 Pit Bull Mix F 65 lb 12 yr Distal Radius2 Golden Retriever M 75 lb 10 yr Distal Radius3 Bernese Mountain Dog F 85 lb 13 mo Proximal Tibia
First patient
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Summary• Direct administration of beta-emitting isotopes to
tumors and tissues• High pH formulation identified and is easy to
prepare• Efficacy demonstrated in mice (HT-29
xenografts)• Efficacy demonstrated in dogs (osteosarcoma)• System being developed includes:
– Drill to access bone tumors– Pump to deliver sub-microliter amounts
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Conclusions• Rare earth isotopes administered at high pH are
retained with minimal loss of isotope from the site of injection.
• Low amounts of isotope necessary to treat tumor• The system developed warrants further
investigation for use in treating cancers such as bone, brain, pancreatic, prostate, and inoperable tumors.
• PCT patent application filed