Targeted Radionuclide Therapy: Options and

Challenges

M.R.A. Pillai Ph.D.; D.Sc

Molecular Group of Companies, Cochin

pillai.mra@molecularglobal.com
https://independent.academia.edu/PillaiMRA
Theranostics with Iodine-131 since 1946
Best example for all the new terminologies
◦ Targeted therapy
◦ Targeted radionuclide therapy
◦ Theranostics
◦ Personalized medicine
◦ Molecular Imaging
◦ Molecular therapy
Targeted Radionuclide Therapies:
Current Status

Radioimmunotherapy
◦ 90Y/131I-labelled anti CD-20 antibodies
Peptide Receptor Radionuclide Therapy
◦ NETS with DOTA-TATE
Enzyme targeted therapy (Since 2014)
◦ PCa with PSMA analogs
Radioimmunotherapy
A modality where the NM community had
lots of hope; but the application was limited
RIT for Non-Hodgkin’s lymphoma
◦ 131I-tositumomab (Bexar)
◦ 90Y-Ibritumomab (Zavalin)
Abundant research everywhere with all sort
of antibodies
◦ 177
Lu-J591 for prostate cancer
Why RIT failed to live up to the
expectation?
The size of the antibody (150 K Da)
inhibited its movement through the biological
system resulting in slow targeting in tumor
Lingering in the blood stream for long time
and long biological half life
Difficulty in finding a suitable radioisotope
having half life compatible with the
biological half life of the MAb
Moving on to peptides
Peptides as Targeting agents

Krenning EP et al.

Localisation of endocrine-related
tumours with radioiodinated analogue
of somatostatin. 

Lancet. 1989;1(8632):242–244. 
“Disease as Dissonance”
Highlights Lecture by Prof. H.N. Wagner
at the SNM Annual Conference at Orlando,
1994
“The development of the somatostatin
analogue, 111In-octreoscan, recently
approved by the FDA in the United States,
illustrates how basic science advances are
translated into health care benefits”
“Peptides are the molecules for the future”
H.N. Wagner, 1994
Developments in PRRNT
Somotostatin analogs having higher
biological half life
Analogues with varying affinities to
different subtypes of receptors, SST1-5
◦ LANREOTIDE, DOTA-TOC, DOTA-TATE,
DOTA-NOC
Indium-111 to Yttrium-90 and Lutetium-
177.
Introduction of 177Lu in Nuclear Medicine
An isotope tried in early 1960s and left out
UMC patent on 153Sm-EDTMP covered
177
Lu but not pursued
177Lu-J591 by Vallabhajosula et al.
177Lu-phosphonate work from BARC
since1998
IAEA CRPs on 177Lu since 2004
Impact Factor: 47.928 in 2016
177 Lu-DOTATATE therapy
Startedin Europe, Netherlands and Italy
Latin American countries
◦ 2005 in Brazil
India
◦ 2006 at AIIMS
◦ Nearly 20 departments are doing therapy
◦ Ready to use 177Lu-DOTATATE from BRIT
Can we have more PRRNT?
Somatostatin

Oxytocin

Bombesin

Substance P

Neurotensin

CCK/gastrin

Integrin
Yes, Lots of R&D but none came to
the clinical stage
Enzyme-Targeted Therapy
Theranostics by targeting PSMA
Prostate Specific Membrane Antigen
(PSMA), a cell surface enzyme, is over
expressed in the case of prostate cancer
PSMA can be targeted using an enzyme
inhibitor
68Ga-PSMA and 177Lu-PSMA
Now routinely done in several hospitals
Theranostics with 68Ga-PSMA and 177Lu-PSMA

PSMA-11
Several Chemists have toiled to develop
ligands before finalizing PSMA-617!
Why Enzyme targeting using inhibitor is
successful?
Enzyme Inhibitors are small molecules
They move through blood stream very fast
Accumulation in the tumor is fast
Excretion from blood stream is fast and through
the renal route
 There is no redistribution of activity from tumor
The physical half life of the isotope determines
the biological half life of the
radiopharmaceutical
 Static images

Skull bone mets (red), Liver mets (green), penile mets (yellow), Pelvic bone mets (blue)
Radioisotopes for therapy
Options and Availability?
Are we happy with Lutetium for all therapy?

Slide from Dr. R. Baum

No, we need Y-90 having longer
range!
Lutetium-177

◦ T1/2 6.73 days, 0.497 MeV bmax,

◦ 0.7 mm mean tissue penetration
Yttirum-90

◦ T1/2 64 hours, 2.282 MeV bmax,

◦ 3.9 mm mean tissue penetration
There is a sea of Strontium-90 present in the world;
but willingness to separate Yttrium-90 is lacking
Targeted Alpha Therapy (TAT)
We need to break the DNA!
An alpha particle can do it!

3
5
Alpha
particles

Beta
particles

3.4nm
Conversion
electrons **
******
*
**
*****
******
Auger
electrons
0.34nm

5
3
2nm
Why TAT is so effective?

250

8.375 MeV
200 5.750 MeV range = 85 µm
range = 47 µm Init. LET = 61 keV/µm

LET (keV/µm)
Init. LET = 80 keV/µm

150

100

50

0
0 20 40 60 80 100
Path Lenght [µm]
Beta and Alpha particles
Range
2 MeV b- particle will deposit the energy within 3.9
mm of tissue
5 MeV a particle will deposit energy within 0.047 mm

Linear Energy Transfer

Beta particles
◦ 2 MeV: 0.5 keV/mm
Alpha particles
◦ 5750 keV: 80 keV/mm
 Isotopes for Alpha therapy
Isotope Half life Alpha Energy Gamma Energy
(MeV) (keV)

Astatine-211 7.21 h 5870 (41.7%) 77-92 (58%)

7450 (58.2%)
Terbium-149 4.12 h 2432 (31.5%) 853 (15.45%)
817 (11.6%)
Radium-223 11.43 d 6559 (100%) 269 (13.7)
Actinium-225 10.0 d 5935 (100%) 86 keV
Bismuth-213 45.6 min 5869 (93%) 440 (26.1%)
Actinium-225:
A nuclear bomb inside the cell
2 2 5 2 2 1 2 1 7 2 1 3
A c 1
F r 1
A t 1
B i
t 2 1 0 d t 2 4 . 9 m t 2 3 2 m s

2 1 3
_ P o

4 .2 µ S
_
2 1 3 9 8 %
B i 2 0 9 2 0 9
P b B i
4 6 m in _ 3 .3 h
2 %

2 .2 m in
2 0 9
T l
Actinium-225
Delivers 27.4 MeV per Bq

221
6297 keV ( Fr) 7065 keV (
217
At)
LET 75 keV/µm LET 69 keV/µm
250 Range 54 µm Range 64 µm

200 5750 keV (

225
Ac) 8375 keV (
213
Bi/
213
Po)
LET 80 keV/µm LET 61 keV/µm
Range 47 µm Range 85 µm
LET (keV/ µm)

150

100

50

0
0 20 40 60 80 100
Path Lenght [µm]
225
Ac-213Bi Generator
10 day half life for the parent 225Ac
46 min half life for the daughter 213Bi
213Bi can be eluted at multiple times 2-3
hour gap to get activity for treatment
 The generator can be used in vivo or in
vitro
Challenges
Isotope Availability (Short term)
◦ 90Y not available
◦ 177Lu available but low specific activity
Isotope Availability (long term)
◦ There is a single research reactor, Dhruva
◦ Nearly 35 years old
◦ No new reactor under construction
◦ What will happen when Dhruva is shut down?
Radiopharmaceuticals research is like
solving Rubix Cube

•It took 25 years to develop 68Ga-PSMA and the

solution came from multiple scientists
How did these PSMA ligands come into
Nuclear Medicine?
1987: Horoszewicz et al. discovered PSMA
1990: Subasinghe et al. Synthesised the
inhibitor Ac-Asp-Glu-OH
2001: Kozikowski synthesized urea (NH-CO-
NH) based inhibitors
2002: Pomper et al. made 11C-PSMA
2008: MIP-1091 a 99mTc agent used in man
2012: Eder et al 68Ga-PSMA-11 followed by
177Lu-PSMA-617
Some solutions are fast while others keep on
solving
PRRNT with Lu-DOTATATE
The growth of Lutetium-177 in nuclear
medicine
Theranosis with 68Ga-PSMA-11 and 177Lu-
PSMA-617
May be several molecular structures are
evolving in the brain of chemists
Several break through might be happening in
laboratories
Exciting Days are ahead

Thank you