Radionuclides and Radiation :

Aiding Better Health Care

M.R.A. PillaiRadiopharmaceuticals Division, BARC

Radionuclides Unstable nuclides of elements. Emission of energetic rays in the process of becoming more stable nuclide.

Alpha or α particles – 4He+2 nucleus, particulate

Beta or β particles – electrons or positrons, particulate

Gamma or γ rays – electromagnetic radiation

Auger electrons X rays

Principles of Applications in Healthcare

Energetic rays Easy detection

• Tracer – Diagnostic applications

Energy deposition in matter• Destruction of diseased tissue/cells– Therapeutic applications

• Destruction of microorganisms- Radiation sterilization

• Polymerization –New materials/products with better properties

Radioisotope Production• Reactor:

– (n,,),(n,p),(n,α),Szilard-Chalmers (SC) process or - emitters : 60 Co, 131I, 3H

– Fission reaction : 137Cs,89Sr, 99Mo,131I

• Cyclotron/Accelerator: – Proton, Deuteron, α particles for isotope production

+ emitters : 11C, 13N, 15O,18FEC: 67Ga,111In,123I, 201Tl

• Radioisotope generators99Mo/99mTc generator90Sr/90Y, 188W/188Re generator

Radioisotope Production• Production and Supply of Radioisotopes to users in

the country through BRITAbout 50 radioisotopes regularly produced and supplied– Revenue equivalent ~ Rs. 10-13 Crore p.a.

Medically useful isotopesDiagnostic applications : emitters: 99mTc(99Mo), 125I(Reactor produced).+ emitter for PET : 18F ( Cyclotron produced)Therapeutic applications:-emitters 32P, 89Sr, 153Sm,166Ho,186Re, 131I & 177Lu (Reactor produced). 90Y ( Generator)• Irradiation service to users (NAA etc.)

Year Activity produced (GBq)

Activity supplied( GBq)

No of batches

No of consignments

2010 128242 122155 136 1161

Radionuclide GeneratorsA closed system housing parent (relatively long t1/2) and daughter radionuclides in a state of radioactive equilibrium.The daughter is repeatedly separated from the parent by taking advantage of their difference in chemical properties.

Diagnostic isotope:99Mo/99mTc generatorRepeated use; “Cow”. supply to remote places, utility in hospitals by milking 99mTc daily

Therapeutic isotope:90Sr/90Y, 188W/188Re generators

Kamdhenu ITD Novel strategy : Electrochemical method developed at RPhD; amenable to scaling up and automation; Automated by a German Company

Radioisotopes in Healthcare

Diagnostic Therapeutic

Radiation processing

•In-vitro assays

RIA & IRMA

•In-vivo Radiopharmaceuticals

• Teletherapy• Brachytherapy

• Gamma knife

•Radiation Sterilization

•Sludge Hygienization

•Radiation Processing: Hydrogel

•Blood Irradiator

In-vitro Diagnostics

Radiommunoassay (RIA) & Immunoradiometric assay (IRMA): Techniques to measure trace amounts of relevant molecules

(< 10-9 gm per ml) in a complex matrix, using radiolabeled molecule as the tracer.

Very useful tool in diagnosing diseases related to hormones,tumor markers, viral antigens etc., indispensable in pathology laboratories.

Immunoassay Kits supplied by BRIT

RIA: T3, T4, LH, Testosterone, Insulin. IRMA: Prolactin, TSH, Ferritin, HCG and LH.

125I isotope for tracer preparation , produced, processed and supplied by RPhD , BARC.

RadiopharmaceuticalsSpecial drug formulations containing radioactivity of adequate purity and pharmaceutical safety suitable for oral or intravenous administration for diagnosis or treatment

Diagnostic Therapeutic

( or +emitters) ( or -emitters) emitters 99mTc,111In,123I,201Tl,67Ga,131I emitters 211At, 213Bi+ emitters for PET 11C, 13N, 15O,18F -emitters 125I,169Er, 67Cu, 124I, 32P, 89Sr,

90Y,153Sm,166Ho,186Re, 188Rs, 131I.

Types of Radiopharmaceuticals

Simple Radiopharmaceuticals Na131I (thyroid), 201TlCl (heart)

Labeled compounds True / foreign labels : 11C-Methionine/ 123 I-

MoAb

Co-ordinate complexes Most widely-used: 99mTc-HMPAO, 111In-Oxine,177Lu-

DOTATATE

Particulate formations Colloids and Macro-aggregates : 99mTc-Sulfur

colloid , 99mTc-MAA

Mechanism of uptake of Radiopharmaceuticals

•Physiologic tracers: – Diffusion : 99mTc-HMPAO,99mTcO4- – Entrapment: 99mTc-Sulfur colloid , 99mTc-MAA– Electrostatic interactions : 201TlCl,82RbCl

•Molecular targeting:– Direct target imaging & therapy

• Receptor-Ligand: 177Lu-DOTATATE• Antigen-Antibody: 90Y-Anti CD20• Enzyme Substrate: 18F-FDG• Oligonucleotides-Antisense based targeting• Cell labeling : 111In-Oxine labelled Leukocytes

– Indirect imaging: Reporter gene approach

• SPECT & PET Radiopharmaceuticals: Pathway probes for Tumor, Angiogenesis, Hypoxia, Proliferation & Apoptosis targeting agents

Diagnostic Radiopharmaceuticals

Medical imaging (In- vivo technique)

Gamma ray emitters Absence of particulate emission Short half life Simple chemistry Kits available inexpensively

Isotopes • 99mTc (Reactor /Generator produced - ‘workhorse’)• 67 Ga,123I, 18F (Cyclotron produced )

99mTc : The Work Horse of Nuclear Medicine

99mTc• Half life 6 h, • Decay mode : IT; • E 140 keV, • Quick decay from body, ideal for scintigraphy.

Availability from reactor produced 99Mo ( T1/2 66 h), 99Mo-99mTc generator

Chemistry : versatile; +1 to +7 valency, capability of being complexed by a variety of ligands

Diagnostic Radiopharmaceuticals

Static Imaging– Organ size, shape, abnormalities etc.– Thyroid , Liver, Kidneys, Brain, Skeleton, Lung malignanciesPresence of nodules, tumors, metastatic lesions, goiter, abscess, shrinkage etc.

Dynamic Imaging– Functioning of the organ, rate, output, defects etc..

– Heart, Liver, KidneysInfracted myocardium, hole in the heart, filtration defects in the kidneys etc..

Cold Kits supplied by

BRIT

Other agents 131I NaI capsules

131I-MIBG inj 51Cr- Na2CrO4 inj

Setup of Medical Imaging Facility

Clinical Trials for 99mTc-HSA • Keen interest from Indian medical community to perform SLN detection using HSA nanocolloid based radiotracer

• HSA nanocolloid preparation optimized in-house and supplied in lyophilized “cold kit” form to Hospitals

• Clinical trials currently on at different medical centers

SLN imaging in a human patient using radiotracer prepared from indigenous HSA nanocolloid cold kit(Image courtesy Dr. Venkatesh Rangarajan, Bio-Imaging Unit, Tata Memorial Hospital, Mumbai, India)

Positron Emission Tomography (PET)

Advanced molecular imaging technology Use of positron emitters :11C,18F,13N,15O

High resolution and sensitivity compared to SPECT

18F-Fluoro deoxy glucose (18F-FDG) The molecule of the Millennium! 2-FDG, mimics glucose, enters the cell, phosphorylated like glucose, but not further metabolized; trapped.

High cell activity, population, proliferation :High FDG uptake

Applications: Oncology, neurology, Cardiology & Psychiatry

Fusion Imaging with SPECT-PET,PET-CT ..

Medical Cyclotron Medical Cyclotron at RMC, Parel ,Mumbai started

in 2002 2Ci/day of 18F-FDG (35-40 patient doses)is being

produced and supplied to hospitals for PET imaging.

RMC,TMH, Hinduja, Jaslok, Bombay Hospital

PET Imaging

Therapeutic Radiopharmaceuticals

Destruction of diseased tissue/cells– Therapeutic applications

Particulate emissions mainly or -emitters High energy emissions Relatively short half life Primarily Cancers; others : Hyperthyroidism, Radiation synoviorthesis etc.

Therapeutic Radiopharmaceuticals

Palliative treatment of pain due to skeletal metastasis in terminally ill cancer patients89Sr Chloride, 32P-phosphate, 153Sm-EDTMP,

177Lu-EDTMP etc. Radiation Synoviorthesis

Colloids/particulates : Intra articular injections166Ho-HA Hydroxyapaptite, 153Sm-HA

Treatment of thyroid cancer & hyperthyroidism : 131I

Treatment of cancers with target specific radiopharmaceuticals :177Lu-DOTA-TATE

177Lu-DOTA-TATE for Neuroendocrine Tumors

Target Vehicle Linker BFCA with radionuclide (Receptor) (Peptide)

•An effective treatment for neuroendcrine tumors and presently available in a limited number of countries with exceptionally high cost•Radiolabeling of DOTA-TATE with 177Lu in adequate specific activity optimized & study carried out in nude mice bearing HT 29 tumors •Human clinical investigation is presently underway at six different nuclear medicine centers across the country•More than 100 patients suffering from different types of neuroendocrine tumors have been treated so far•Preliminary clinical investigations revealed symptomatic relief for majority of patients

(Thr)

(Thr)

(Lys)

(Trp)

(Tyr)

(C ys)

(C ys)

(D-pheala)

HH OHH 3C O

HN

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ONH

H 3CH H H

NH2

HN

O

H

HOHN

N OH

O

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HN

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NHS H

H

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NN

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HOOC

HOOC

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COOH

Extensive metastatic pheochromocytoma

Ga-68 DOTA-NOC scan

Lu-177 DOTA-TATE post therapy scan

177Lu-EDTMP for Bone Pain Palliation

•EDTMP localize at the lesion site due to skeletal metastasis•Synthesis of 177Lu-EDTMP standardized•Biological behavior of the agent studied in animal models•Showed excellent accumulation and retention in the skeleton with negligible uptake in the non-target organs •Human clinical investigation is presently underway in patients suffering from bone metastases due to prostate carcinoma in collaboration with AIIMS, New Delhi• All the patients treated with this agent shown excellent pain relief

EDTM P

N

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HO

HO

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OH

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OOH

RadiotherapyTreatment of disease using radiations emitted from radioisotope source, X rays machines or using high energy electrons

Teletherapy Brachytherapy Gamma Knife

Teletherapy :External Beam Radiation Therapy

External source High intensity radiation; 60Co – most widely used A machine is used to direct the radiation to the tumor (cancer) through the skin.

BrachytherapyTherapy achieved by implantation of small sealed radioactive needles,tubes, seeds,wires for specific duration in close proximity to the tumors.

Surface therapy: Application of one or more sources on or near the area to be treated.

Treatment of eye , skin Intercavitary therapy: Placing one or more sources with an applicator within a natural body cavity wherein the tissue adjacent to the walls are to be treated

Treatment of cancer of cervix Interstitial therapy: Implanting one or more sources into the tissue to be treated

Treatment of breast, prostrate cancer

Radioactive Plaque Therapy for Treatment of

Ocular Melonoma : Surface Therapy

Tiny rice-sized {0.8mm(OD)x4.75mm(l)} radioactive(125I ) seeds (15-25 no.) are glued into the gold eye-plaque or seed carrier.

Plaque is sewn covering the tumor and removed after stipulated dose delivery.

Development of ‘BARC I-125 OcuProsta seeds’ for Eye and

Prostrate cancer Source development, characterization, quality

assurance and clinical deployment : Radiopharmaceuticals Division

Multicentric clinical trials with BARC I-125 OcuProsta seeds at various hospitals.

• Till June 2011, 681 sources have been given to the hospitals. (Sankara Nethralaya, chennai- 40 P.D. hinduja Hospital & medical research centre, Mumbai- 7 Sriramkrishna Hospital, in collaboration with Aravind eye

Hospital, Coimbatore - 14 Nos. 61 Eye cancer patients have been treated and

results are promising.

Seed implantation with I-125/Pd-103 seeds (Brachytherapy) is a highly effective treatment for men with Prostate cancer.

Cs-137 sources for the treatment of Gyneacologic cancers: Intercavitary Therapy

Source core: 1.5mm( ) x5mm(l) platinum sheathed vitrified glass rods,137Cs: 40-42mCi,encapsulated in stainless steel capsules sealed by Laser

More than 1500 sources (75 source kits) have been supplied through BRIT and are in use in cancer hospitals across the country.

32P Mould Brachytherapy sources • 32P incorporated mould brachytherapy sources

for treatment of superficial tumors – Pre-Clinical trials (AIIMS) Custom made 32P sources

• SNM Newsline: June 10, 2009,New Skin Cancer Patch: Possible Alternative to Surgery– Nontoxic radioactive patch successfully treats skin cancer,

say researchers at SNM's 56th Annual Meeting

Patient 1: Basal cell carcinomaPre treatment Treatment with 32P Mould

Brachytherapy source

1 wk post treatment 3 months post-treatment

Patient 2 : Basal cell carcinoma

Pre treatment Treatment with 32P Mould Brachytherapy source

1 wk post treatment 3 months post-treatment

Breast Cancer: Interstitial Brachytherapy

Gamma Knife Stereo-tactic surgery of deep-seated tumors

Multiple targeting (up to 201 60Co sources; 1 TBq each; circular array) to achieve better dose delivery and low damage to surrounding tissues.

Radiation can be X ray or rays

Gamma Knife Facility at VIMHANS, New Delhi

Radiation Processing Radiation Sterilization of Medical Products

Sludge /Biohazard Hygienization

New Products for Medical Applications: Hydrogel

Blood Irradiator

Radiation Sterilization of Medical Products

Gamma radiation used for sterilization of healthcare products on an industrial scale

Used for sterilization of :Surgical DressingsOintments Latex glovesAyurvedic medicinesOrthopedic implants

Pharmaceutical raw materials ISOMED plant at BARC

Advantages of Radiation Sterilization

• Highly reliable technique• Room temperature process, thermosensitive materials can be sterilized

• End product in the packaged form can be sterilized

• No toxic residues• Easy control as radiation sterilization depends only on radiation dose

• Can be carried out both as batch and continuous process

• Wide choice of packaging materials

Radiation Sterilization of Life Saving Equipments

Sludge /Biohazard Hygienization

Typical pathogens present in sludge and their concentrations

Microorganism Concentration per 100 ml

Coliforms 107 – 109

Fecal Coliforms 106 – 108

Fecal Streptococci 106 – 107

Salmonella 1-100Anaerobic spore forming bacteriaParasites and viruses

Sludge:Derivable benefits and associated problems

• Sludge is a rich source of many macro (N,P,K) and micro nutrients essential for soil

• Sludge is a rich source of Organic Carbon for soil conditioning

• Sludge carries a heavy microbial load and therefore its disposal or utilization poses a challenge to urban development authorities

Sludge Hygienization Facility ( SHRI), Vadodara

• Set up in 1992 in collaboration with State Government of Gujarat

• Vadodara Municipal Corporation• BARC

IANCAS-Vadodar-2010 48

Water soluble polymer

Hydrogel

Polyvinylalcohol

Thank You