2. Combination of two words:
Therapeutic + Diagnostic
Sometimes interchangably refered to as
Theragnostics
Use of radionuclide-labeled agents that
specifically permit us to diagnose disease in
individuals and then use identical or closely
related agents to treat these diseases
3.
4. Theranostics involves the administration of a
diagnostic agent:
To determine localization in the site or disease
state under study as a surrogate for a potential
therapeutic agent with similar chemical
properties;
To examine its biodistribution as predictive of off-target(
adverse) effects of the potential therapeutic
agent;
As an aid in determining the optimal therapeutic
dosage or activity to be administered, based on
the anticipated tumoricidal doses measured in the
tumor site;
To monitor the response to this treatment
5. Also…
Theranostics is a term that has been used in the
context of molecular targeting vectors (eg,
peptides)
labeled either with diagnostic or with therapeutic
radionuclides for the diagnosis and therapy of a
particular disease, targeted specifically by the
vector at its molecular level
6.
7.
8. —Diagram shows example of single-entity theranostic system that combines initial staging
with imaging (green sunburst as active moiety) followed by therapy with therapeutic version
of imaging (red lightning bolt).
9. Dual purpose radionuclides
Emissions suitable for both diagnostic and
therapeutic purposes
when molecularly (selectively) targeted using
appropriate carriers, would allow pretherapy low-dose
imaging as well as higher-dose therapy in
the same patient
10.
11.
12. Iodine isotopes
the first theranostic agent
the agent in orally administered seaweed and its
extracts, which had been shown to cure neck
swelling due to thyromegaly, was iodine, first
demonstrated to be a new element in 1813 by Sir
Humphrey Davy
Enrico Fermi produced the first radioiodine, 128I,
in 1934
13. 131I
First therapeutic application by Hertz and Roberts at
MGH for treating thyrotoxicosis (1941)
Albert Keston et al (1942) first showed that a child’s
thyroid cancer could concentrate radioiodine
Initial therapeutic efforts were performed without the benefit of
true imaging until the Cassen and Curtis 21 rectilinear scanner,
in 1949
In 1952, Anger’s first gamma camera, designed for thyroid
imaging appeared, enabling visualization of structure/function
as well as for therapy
17. 123I: advantages
More efficient interaction with sodium iodide crystals
than 131I, with a 159 keV photopeak
No beta emission, so the radiation dose to the thyroid
gland is a few percent of that from 131I
An adequate 13.3-hour half-life allowing commercial
shipping
More efficient collimation than 131I because of its
lower energy
A requirement for less expensive shielding
18. Superior images with fewer radiation safety
issues
Preference to 123I over 131I for most diagnostic
purposes
19. 124I
Once was considered as an unnecessary
contaminant of diagnostic and therapeutic iodine
radionuclides
Now considered as a potential theranostic agent
in management of thyroid cancer
20. 124I
cyclotron product
124Te[p,n]124I
Half life: 4.2days
permits functional imaging of many biological
processes employing PET/CT
Auger electron emitter
high energy of the positrons emitted + presence
of single photons might lead to loss of image
quality due to increased dead time
21. 125I
Reactor produced;
Applications: protein iodination, RIA kits,
brachytherapy (long t1/2)
Currently no theranostic applications as it has no
obvious benefits over the less expensive 131I
22. Radio-iodinated MIBG
worthy agent for both diagnosis and therapy of
endocrine tumors
Pheochromocytoma
Paraganglioma
Carcinoid
MTC
Neuroblastoma:
reduced tumor volumes
and lessened excretions of
symptom-inflicting
hormones
tumor remission and prolonged
survival of treated patients
24. Theranostics in NETs
Applications in NETs:
68Ga labeled somatostatin analogs(derivatives of
octreotide, lanreotide) for diagnosis
177Lu and 90Y labeled to identical/similar analog for
PRRNT
Advantages of peptide-based targeting:
Better pharmacokinetics
Minimal/no antigenicity
25. Tumor binding capacity of peptide
receptor radiopharmaceuticals
High specific radioactivity preparation
In vivo stability of radioligand
SSTR expression density in the tumor
SSTR subtype expression
Efficiency of internalization and recycling
Amount of radiopeptide administered
26. Clinical indications of peptide
receptor PET/CT
Diagnosis, staging & restaging
Detection of unknown primary
Therapy stratification
Evaluation of therapy response and Prognosis
30. 90Y
Owing to higher energy of the beta emissions (935
keV),
Beneficial in larger tumors
Allows irradiaton of tumor cells which are not directly
targeted by the radiopharmaceutical
However,
Longer range of action, hence high likelihood of
nephrotoxicity
31. 177Lu
Emits intermediate energy beta particles (133
keV)
Beneficial in small sized tumors (tissue range
2mm)
Concomitant gamma emission property enables
easier imaging with a gamma camera and post-therapy
dosimetry
32.
33. 64Cu/67Cu
64Cu
has become of great interest in the last few years
as a potential PET tracer
Short t1/2: 12.7 hr
Decays by EC (44) + positron (17) + beta (39)
decay modes
36. 64Cu: applications
64Cu-RGD analogs
to monitor changes in tumour vascularity following treatment
with anti-tumour therapies
Potential applications in gliomas, carcinoma breast,
carcinoma prostate
64Cu-DOTA-trastuzumab
Has been used in identifying Her2-positive lesions in cases
of primary and metastatic breast cancer
37. Cu-67
with a 2.6-day half-life, is the longest lived
radioisotope of Cu
Photon energy (keV) Abundance (%)
184 48.7
93 16
91 7
Eβmax = 0.6 MeV (avg = 141 keV)
38. Why Cu-67??
half-life is suitable for imaging slow in-vivo
pharmacokinetics with agents such as MAbs and
other carrier molecules
beta particle energy is appropriate for therapy
In vitro studies have proven equal effectiveness
to 64Cu in inhibiting cell growth and DNA
synthesis
39. ADVANTAGES:
184-keV gamma ray permits imaging of the uptake and
biodistribution of the agent both before and during therapy
administration
can also be paired with the positron emitter 64Cu to
perform pretherapy biodistribution determinations and
dosimetry by PET
DRAWBACKS:
lack of regular availability of sufficient quantities at a cost
that researchers can afford
Low specific activity comparable to what is acceptable for
antibody therapy
40.
41. Sn-117m
one of the best radionuclides for the development
of theragnostic radiopharmaceuticals, in
particular, for nuclear oncology
include palliation of bone pain from osseous
metastases, radiosynovectomy,
radioimmunotherapy and cardiovascular
applications
42. In contrast to most other therapeutic beta
emitters,117mSn decays via isomeric transition
emission of 3 major monoenergetic conversion
electrons
Energies (keV) Abundance (%)
127 65
129 12
152 26
T1/2: 14.0 days
43. very high LET; have short discrete penetration
ranges of between 0.22 (127 keV) and 0.29 mm
(152 keV) in water
effective for therapy of metastatic disease and for
certain other inflammatory conditions (eg,
atherosclerotic disease)
much reduced myelosuppression and greatly
reduced dose to normal organs
47. Sn-117m: applications
good therapeutic agent for cancer
noninvasive molecular imaging and treatment of
active atheromatous disease (vulnerable plaque,
thin-cap fibroatheroma) through use of
(i) coronary stents electroplated with 117mSn
(ii) 117mSn-labeled specific molecules systemically
targeted to VP components
48. 18F-FDG as a theranostic
agent??
Extensively used in diagnostic positron emission
tomography (PET) in oncology
18F emits energetic positrons with high
abundance (96%) and a path length in tissue of
0.1-0.2 cm
Theoretically, these positrons can kill cancer cells
in the same manner as electrons
Additional effects: by-stander/cross-fire
49. 18F-FDG theranosis: small
animals
Meyer et al (Soc Neurosci Abstr 1996;22:948):
tumor shrinkage after intratumoral injection of
FDG into glioma xenograft-bearing mice
Moadel et al (Breast Cancer Res 2003;5:199-
205)(Cancer Res 2005;65:698-702): therapeutic
benefit of FDG in mouse model of breast cancer
51. Caridad et al (Cancer Biother Radiopharm
2008;23:371-375): FDG has in vitro as well as in
vivo cytostatic effects on multiple cancer cell lines
(melanoma, colon ca, breast ca)
No toxicity upto 6 mCi/20g mouse
Dose escalation studies to be performed to
validate the therapeutic role of FDG
52. Hindrances in using 18F-FDG for Rx
High physiologic uptake in brain, skeletal muscles
High radiation delivery to the excretory pathway
(KUB)
53. To summarize…
Classical definition of theranostics implies the use
of same or similar radiopharmaceuticals for
management of diseases
However, the definition and the scope of
theranostics has broadened to involve various
novel, innovative and safer techniques
54. However, an increased and reliable availability at
reasonable cost of the theranostic radionuclides has
remained a major issue,
must be addressed before we successfully put into
routine clinical practice.
It is worth emphasizing that the various nuclear
medicine modalities optimally fulfil the requirements
to convenitently carry out the practices of
personalized medicine
This field is an exciting development that marks the
future of the field of nuclear medicine
—Diagram shows how theranostic systems combine diagnostic tests, in this case, imaging, to detect presence of molecular target in each patient. Patients who are found to be positive for molecular target are selected for therapeutic intervention.
—Diagram shows example of single-entity theranostic system that combines initial staging with imaging version of specific probe (green sunburst as active moiety) followed by therapy with therapeutic version of imaging probe (red lightning bolt). Restaging examinations at follow-up are performed with imaging probe. Patients with positive imaging results (red lesion) can be treated with therapeutic agent. Patients with negative results will not be treated with targeted agent. Organic molecule structure used in this example is that of metaiodobenzylguanidine with 123I for imaging and 131I for therapy-imaging.
