“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 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

3

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

4

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 --

5

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

6

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.

7

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

8

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

9

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

10

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

11

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

12

High pH formulation (Mouse 459)

• Two 5 µL injections 177Lu (0.8 mCi total) into tumor

tumor

14 days

13

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

15

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

16

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

17

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

18

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

19

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)

20

Possible Applications of Technology

• Primary Bone Cancer – can replace amputation

• Brain Cancer

• Prostate Cancer– Replacing seeds

• Lung cancers

• Many Inoperable Cancers

21

Canine Osteosarcoma Trial• University of Missouri – Columbia

– Dept of Veterinary Medicine and Surgery

22

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

23

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

24

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