“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)
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“Liquid Brachytherapy” Direct Administration of Therapeutic Radioisotopes Into Tumors
“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 Presentation
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“Liquid Brachytherapy”Direct Administration of Therapeutic
Radioisotopes Into Tumors
Jim Simon,*1 Stan Stearns,2 Kenneth McMillan,1 Max Loy,2 and Keith Frank1
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
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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.