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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5624_Библиотеки_им_академика_М_И_Перельмана.pdf
One would infer that if radioimmunotherapy refers to the use of mAbs, then radioligand
dd/
therapy would refer to non-mAb radiotherapeutics. Radiotherapeutics targeting peptide receptors specically are sometimes referred to as peptide receptor radionuclide
therapy (PRRT). As with positron emission tomography (PET) and single-photon emission
computed tomography (SPECT), PRRT, RIT, and RLT benet the most from exploiting a
specic target that is expressed solely on (or inside) cancerous cells in high concentrations (high B
) and is found in comparatively very low levels in healthy, non-cancerous
max
tissues. Such targeted radiotherapeutics are known as endoradiotherapies because they
are administered intravenously, as opposed to external beam radiation therapy.
RIT is a powerful tool in cancer treatment that expands on the ability to target specic
cells with antibodies. While immunotherapy uses epitope-specic antibodies to target
specic cells, the cytotoxic eect of the antibody is limited to the cell on which the antibody binds. When a radionuclide is bound (or chelated) to an antibody, the therapeutic
eect is greater[4]. RIT nds the most utility in cancers prone to radiosensitive tumors,
such as leukemia and lymphoma. Achieving a signicant response in solid tumors can
require much higher radiation doses. However, with the development of more specic
antibodies and the use of more powerful radionuclides, such as alpha emitters, the
benets of RIT are also having an impressive impact on the treatment of, for example,
pancreatic and prostate cancers[5]. Solid tumors are more eectively treated using
a pre-targeted RIT approach if injecting the treatment intravenously, or injecting the
treatment into the tumor itself (intratumoral injection) or the region/body cavity in which
the tumor resides (compartmental injection)[2].
The selection of a radionuclide determines the mode and energy of decay, and
therefore the range of eect and potency of a radiotherapeutic. Considerations when
selecting a radionuclide for use in radiotherapy include not only characteristics of the
radionuclide, but also the feasibility of chemistry with the nuclide, as well as its availability. Matching the half-life of the radionuclide to the physiological half-life of the
therapeutic is important to the success of the treatment. Linear energy transfer (LET) is
an important consideration when choosing a radionuclide. LET (LΔ) is a measure of how
much energy a radionuclide deposits into an area. It is calculated by dividing the amount
of energy that an ionizing particle emitted by the radionuclide transfers to the material
(dEΔ) by the range of the particle in tissue (dx) according to the following equation:
x
A higher LET indicates a more concentrated area of energy deposition and results in
less toxicity to neighboring healthy cells. In larger and/or heterogeneous tumors, a lower
LET may be more benecial as the radiation will travel deeper into the tumor[6]. Radionuclides with lower energy/longer range, and therefore lower LET (e.g. beta emitters),
are preferred for treating bulky/poorly vascularized tumors, while radionuclides with
higher-energy/shorter-range radionuclides, and therefore higher LET (e.g. alpha emitters), are better for treating small tumors and decreasing toxicity. Beta emitters are more
Chapter 2: Concepts andIssues forTherapeutic Radiopharmaceuticals 25
likely to cause single-strand DNA breaks, while alpha emitters, with higher energy and
LET, are more likely to cause double-strand DNA breaks, increasing their eectiveness.
Of the therapeutic particle-emitting radionuclides, beta emitters, such as lutetium-177
177
(
Lu) and yttrium-90 (90Y), appear to be the most commonly used, likely due to their
availability and straightforward labeling chemistry. A general comparison of the properties of therapeutic isotope classes can be seen in Table2.1, while example radionuclides
in each category are provided in Table2.2.
Alpha particles are more desirable for RIT of smaller malignancies, but until recently,
the availability of the isotopes and methods of incorporating them into radiopharmaceuticals have been somewhat lacking. This has shifted in recent years, as there has
been an increase in eorts toward incorporating alpha-emitting radioisotopes such as
bismuth-213 (
213
Bi), radium-223 (
223
Ra), and actinium-225 (
225
Ac) into bioactive molecules
because of the higher LET[7]. Use of alpha emitters can lead to a decrease in toxicity
and o-target eects compared to beta emitters, but as mentioned previously, alphaemitting radioisotopes lack the range to target large, heterogeneous, and/or poorly vascularized tumors. Often, alpha-emitting radionuclides decay through a chain of multiple
emissions. For example, actinium-225 has a decay chain that includes four alpha decays
(Figure2.2), allowing smaller doses to be administered to patients. Radionuclides that
decay through such a chain are sometimes referred to as nano or in vivo generators[8].
Radiotherapy used in the clinic typically employs powerful alpha- or beta-emitting
radionuclides, but recent studies have found that Auger electron-emitting radionuclides
also have therapeutic potential[9]. Auger electrons are negatively charged particles produced by radionuclides that decay via electron capture (EC). With comparably low energy
(Table2.1), and therefore short range within tissue, these particles were not initially
Table 2.1
Comparison
oftherapeutic
atomic particles.
Particle Energy Range LET (linear energy transfer)
Beta (β) 50–2300 keV 0.0 5– 12 mm 0. 2 ke V mm
Auger electron eV keV 2– 50 0 n m 4–26 keV mm
Alpha (α) 5 – 9 M eV 40 –100 μm 80 ke V mm
Table 2.2 Prop-
erties of select
therapeutic isotopes (properties
Primary decay mode Isotope
α
of other radioisotopes can be found
in Chapters3–5
on the produc-
β
tion of therapeutic
radionuclides).
Electron capture (Auger emission)
26 Handbook of Radiopharmaceuticals
−1
−1
−1
Mean particle energy
(MeV ) Half-life
225
Ac 6 1 0 d
223
Ra 5.7 11. 4 d
211
At 5.9 7. 2 h
213
Bi 6 45.6 min
89
Sr 1.492 8 d
90
Y 2.28 6 4 h
177
Lu 0.149 6. 6 d
111
In 0.86 2 . 8 d
α (2%)
209
TI
β
2.2 min
10 d
225
Ac
221
α
Figure 2.2 Decay chain of
4.8
min
Fr
α
225
Ac.
217
0.032
s
At
α
213
Bi
46 min
β (98%)
213
α
4.2 μs
Po
thought to be good candidates for RLT. However, when an Auger electron is emitted, the
atom from which it is emitted is left positively charged. It is thought that the neutralization of this atom is compounded with the eect of the Auger electron, resulting in more
signicant biological eects than just an Auger emission by itself[9]. The challenge with
all radiotherapeutics is the ability to position the radionuclide within range of the tumor
DNA so that the emitted particles are able to inict damage and induce cell death. This
challenge is especially important for isotopes that emit either alpha particles or Auger
electrons due to the short range of the particles.
The majority of commonly used therapeutic radionuclides (except iodine and astatine)
are radioactive metal ions that require chelation to a mAb, peptide, or other targeting
molecule. In such cases, a chelating moiety is bound to the antibody, peptide, or molecule, and the metal is chelated (examples of chelators are shown in Figure2.3). The
chelating group is determined by the molecule it will be bound to, and both the size and
charge of the radionuclide to be chelated. Continual eorts have expanded the library
of chelators available with the goal of improving the incorporation of dierent radionuclides into radiotherapeutics[10, 11].
209
Pb
3.3 h
β
209
Bi
2.2 THERANOSTICS
Theranostics (therape ut ic + di a gnostic) is a term used to describe pairs of radiolabeled
molecules that can be used for both treatment and imaging of disease. There are two
main ways that a radiopharmaceutical can be considered a theranostic. First, a radiopharmaceutical can be chelated to two dierent isotopes with dierent decay mechanisms
and, therefore, dierent uses. To achieve both excellent images and eective treatment,
the same drug/antibody can be bound to either an imaging isotope or a radiotherapy
Chapter 2: Concepts andIssues forTherapeutic Radiopharmaceuticals 27
HO
HO
OH
AN
HEHA-NCS
Figure 2.3 Exam-
ples of chelators
used in radiotherapeutics.
O
N
O
O
N
N
DOT
OH
N
O
O
OH
S
HO
C
N
NN
O
OH
N
O
OTA
O
OH
N
O
N
OHHO O
O
HO
O
HO
O
N
N
N
N
isotope. For example, new theranostic pairs targeting somatostatin receptors (SSTRs) on
NETs and prostate-specic membrane antigen (PSMA) expressed in PC have been widely
utilized in recent years. In each case, the diagnostic agents are (typically) labeled with
68
Ga for PET imaging. The same molecules can also be labeled with alpha (
90
beta emitters (
177
Y or
Lu) for radiotherapy (see the following discussion and Chapter18
for specic examples). Radionuclides that have isotopes with use in both therapy and
imaging are referred to as true theranostic pairs, and examples include scandium-44 and
44
-47 (
Sc/47Sc) as well as copper-64 and -67 (64Cu/67Cu). The use of such pairings is especially benecial in cases where even small changes to the radiotracer or therapeutic disturb its pharmacokinetics. The second theranostic approach involves the use of a single
radionuclide, which decays via both a therapeutic particle (alpha or beta) and mechanism
suitable for imaging (e.g. positron or gamma).
177
as it is a beta-emitting therapeutic isotope but also emits low-energy gamma photons
that can provide scintigraphic data. While isotopes such as
and imaging, it does remain benecial to have two separate isotopes for these functions
that behave similarly in all aspects besides decay. For example, pairing an isotope that is
47
largely a beta emitter (e.g.
emission (e.g.
44
Sc, 68Ga) can give better images and/or therapeutic results than using an
177
Sc,
Lu) with an isotope with a high percentage of positron
isotope with a split decay path.
OH
213
Bi or
225
Ac) or
Lu is one example of such a radionuclide,
177
Lu are used for both therapy
28 Handbook of Radiopharmaceuticals
2.3 EXAMPLES OFRADIOTHERAPEUTICS
2
NH
*I
2.3.1
At the beginning of the new millennium, applications of targeted radiotherapy were fairly
limited. Perhaps the best-known example was meta-iodobenzylguanidine (MIBG), a norepinephrine mimic developed at the University of Michigan in the 1970s[12] (Figure2.4).
The uptake of MIBG is either through norepinephrine transporters or through a nonsaturable, passive mechanism[13]. MIBG was originally labeled with either iodine-123 or
iodine-131, both for imaging purposes; however, the beta emission of iodine-131 was later
noted as being useful for radiotherapy[14].
Food and Drug Administration (FDA) for radiotherapy of certain cancers. Production of
131
131
to treatment, patients’ thyroid glands are protected against free radioiodine by pretreatment with, for example, potassium iodide. Hyperthyroidism can still develop in patients
after treatment, however, and should be accounted for.
uptake in low-grade/well-dierentiated tumors than higher-grade/poorly dierentiated
tumors. The most common toxicity with
more common in patients with metastasis in the bone marrow, and the risk increases as
the whole-body dose increases[13]. Results of treatment with
period can be seen in Figure2.5[15].
(Figure2.6), which decays via alpha particle emission, resulting in a more powerful
treatment for brain tumors, especially smaller tumors. The use of the alpha-emitting
astatine-211 has also resulted in less toxicity among patients, although further studies
are needed to fully characterize this treatment path[13].
131
I-MIBG
131
I-MIBG was approved in June 2018 by the
I-MIBG with no-carrier-added (n.c.a) iodine has shown better results than traditional
I-MIBG as there is less non-radioactive product in the higher-specic-activity dose. Prior
131
I-MIBG has shown better
131
I-MIBG treatment is hematotoxicity. This is
123
I-MIBG over a 14-month
Recently, the parent benzoguanidine molecule has been labeled with astatine-211
2.3.2 Radiotherapy ofBone Metastases
Radionuclide therapy is a common treatment for painful bone metastases in many types
of cancer. Radionuclides such as radium-223 and strontium-89 have a natural anity for
bone with increased metabolic activity, while other radionuclides require the formation
of a complex with bone-seeking cations such as phosphates. In the latter case, betaemitting radiophosphorus in the form of
the treatment of bone pain. The ease of oral administration and comparable aordability
make radiophosphorus a popular treatment option throughout the world[16].
Chapter 2: Concepts andIssues forTherapeutic Radiopharmaceuticals 29
32
P-sodium orthophosphate has been used in
NHNH
Figure 2.4
Meta-iodobenzylguanidine.
2
NH
*At
I-123 MiBG
(a)
(b)
(c)
(d)
(e)
Baseline
I-131 MiBG
1st Rx
I-123 MiBG
Post Rx 2
I-123 MiBG
Post Rx 4
I-123 MiBG
Post Rx 4 and
surgery
Figure 2.5 Serial I-123 MIBG anterior whole-body images. (a) The patient had unresectable primary PHEO
of the right adrenal (upper thin arrow) and metastatic disease to retroperitoneal nodes (chevron), pelvis
(arrowhead), and ribs and bilateral lung (thick upper arrow). He received four treatments consisting of
204–243 mCi and cumulative 873 mCi of I-131 MIBG over a 14-month period. (b) The initial I-131 MIBG is
shown to illustrate tumor targeting post-rst treatment; because of higher counts, lesions are seen better
than on the diagnostic baseline scan. (c) MIBG imaging post-second treatment shows the disappearance
of bone and lung lesions and shrinkage of other lesions. (d) Images post-fourth treatment show continued
improvement that allowed for debulking surgery. (e) This panel shows images after the fourth I-131 MIBG
treatment and 14 months post-surgery. Source (a–e): Reproduced from Carrasquillo etal.[15] with the
permission of John Wiley and Sons. © 2012, Wiley Periodicals, Inc.
Figure 2.6 Meta-
astatoben-
NHNH
zylguanidine.
Another beta emitter, 89Sr, is paired with its true theranostic partner, the gamma-
emitting
85
Sr, for biodistribution studies. While 89SrCl2 localizes to metabolically active
bone, a study comparing it to palliative radiotherapy suggested that the associated
myelotoxicity, and decreased heme in the
rate versus local eld radiotherapy[17]. [
89
SrCl2-treated patients, lead to a lower survival
223
Ra]RaCl2 (Xogo) was the rst alpha emitter
to be approved by the FDA in May 2013 and is indicated as the rst-line treatment for castration-resistant PC with symptomatic bone metastases (Figure2.7)[18, 19]. Clinical trials
using Xogo alone or in combination with other treatments are ongoing in patients with
other cancers with skeletal metastases[19]. Like calcium, radium accumulates in areas of
bone with increased levels of metabolism. Owing to the short range of alpha particles,
223
[
Ra]RaCl2 is able to target bone metastases without high toxicity to the surrounding
30 Handbook of Radiopharmaceuticals
(a) (b) (c)
II-15
Naf
III-15 VIII-15
+6.3%
−63.5%
Figure 2.7 An old patient (83 years) with Gleason score 6. (a) The NaF-PET before the Ra-223 treatment
of six cycles is shown (II-15). Source: Imaged reproduced from Kairemo and Joensuu 2015[18] under
the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/
licenses/by/4.0). (b) No essential response to the treatment was seen after the rst cycle (+6.3% change,
III-15). Source: Imaged reproduced from Kairemo and Joensuu 2015[18] under the terms and conditions
of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0). (c) After six
cycles, a dramatic response was seen (−63.5% change, VIII-15). Many of the lesions have disappeared,
especially in the thoracic girdle. Source: Imaged reproduced from Kairemo and Joensuu 2015[18] under
the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/
licenses/by/4.0).
areas such as bone marrow[20]. Unfortunately, radium cannot be eectively chelated, so
its use in other tumor-targeting radiotherapeutics is currently limited[21].
2.3.3 Somatostatin Receptor-Targeted Ligands
The discovery that SSTRs are expressed on NET cells has opened up new possibilities
for diagnosing and treating patients with NETs. A number of radiopharmaceuticals
targeting SSTRs have been developed, based on peptides such as (Tyr
(TOC) and (Tyr
3
-Thr6)-octreotide (TATE) with an anity for SSTRs. These peptides
can be functionalized with a chelating group such as DOTA (Figure2.3) and labeled
with diagnostic or therapeutic radionuclides. From an imaging perspective, [
ATATE (Figure2.8) is FDA approved and marketed in the United States under the name
Chapter 2: Concepts andIssues forTherapeutic Radiopharmaceuticals 31
3
)-octreotide
68
Ga]DOT-
Figure 2.8
NETSPOT and
Lutathera.
NETSPOT. In Europe, [68Ga]DOTATOC is approved and marketed as SomaKit TOC. Substituting the radioisotope for the beta-emitting
177
Lu gives Lutathera (
177
Lu- DOTATATE ,
Figure2.8), a radiotherapeutic used for the treatment of SSTR-positive NETs, and the
rst approved PRRT[22]. Treatment of NETs with beta therapeutics such as Lutathera
has proven eective for treating NETs. In addition to the treatment of NETs, Lutathera and related therapies such as
90
Y-DOTATOC are nding use in the treatment of
other metastatic cancers that exhibit high expression of SSTRs, such as lung carcinoids
(Figure2.9)[23]. Prior to treatment with Lutathera, tumors are evaluated via imaging
with NETSPOT or SomaKit TOC (and sometimes biopsy) to conrm SSTR expression
and patient eligibility for therapy. Lutathera shows selectivity for SSTR2 over other
SSTRs[21] and is approved by the FDA, European Medicines Agency (EMA), and Health
Canada regulatory agencies.
In certain cases, tumors do not respond to beta therapy (with either Lutathera or
alternate treatments such as
90
Y-DOTATOC), so alternate versions labeled with alpha
emitters are also under development. For example, a clinical study of patients shown to
be refractory to DOTATOC or beta-emitter-labeled DOTATOC therapy showed that the
targeted alpha therapy (TAT) of
213
Bi-DOTATOC could halt the progression of the disease,
as well as eliminate some tumor burden. In this study, the radiotherapeutic was administered intra-arterially to better directly target the tumors[24].
32 Handbook of Radiopharmaceuticals
(a) (b)
Figure 2.9 Atypical carcinoid patient referred for restaging with Ga-68 DOTATOC PET/CT and treated
with three cycles of peptide receptor radionuclide therapy (PRRT; two cycles of Y-90 DOTATOC and one
cycle of Lu-177 DOTATATE) showing excellent response. (a) Ga-68 DOTATOC maximum-intensity projection
images before PRRT. Source: Reproduced From Prasad etal. 2015[23], under a Creative Commons License
(https://creativecommons.org/licenses/by/2.0). (b) Ga-68 DOTATOC maximum-intensity projection images
22 months after rst PRRT. Source: Reproduced From Prasad etal. 2015[23], under a Creative Commons
License (https://creativecommons.org/licenses/by/2.0).
2.3.4 Prostate-Specic Membrane Antigen
Levels of prostate-specic antigen (PSA) are used in the evaluation and detection of PC.
The development of peptide-based inhibitors of this antigen has resulted in both imaging
and therapeutic agents with unparalleled results. Small molecule PSMA-targeting ligands
are urea-based molecules that are internalized by PSMA (see[25] and Figure2.10, for
example). PSMA is signicantly upregulated in PC, and this upregulation, in conjunction
with the internalization of exogenous PSMA ligands, provides ideal conditions for RLT of
PC and associated metastases. This treatment typically utilizes PSMA-617[26, 27] but can
also use PSMA-I&T (imaging and therapy)[28] and has shown promise in multiple human
studies. For example, phase III clinical trials of
177
Lu-PSMA-617 is not yet approved, the studies have demonstrated that the agent is an
eective treatment for PC (Figure2.11). Side eects may include dry mouth syndrome as
a result of o-target binding to PSMA expressed in salivary glands. Multiple techniques
have been used to prevent/relieve these symptoms, including the use of Botox injections,
or external cooling in the salivary/parotid glands, to block uptake of the radiotherapeutic
and prevent the decrease in saliva production[29, 30].
Concomitant with the development of PSMA beta therapy, PSMA alpha therapy
with
225
Ac or
211
At for the treatment of metastatic castration-resistant prostate cancer
177
Lu-PSMA-617 are underway and, while
Chapter 2: Concepts andIssues forTherapeutic Radiopharmaceuticals 33
HO
O
O
OH
O
O
OH
O
PSMA-11
OH
PSMA-11
HO
N
N
OH
O
PSMA binding motif
HO
N
O
OHN
HO
N
N
O
HOOC
O
O
O
HN
HO
NH
NH
NH
O
NH
HN
O
HN
HOOC COOH
O
N
N
N
O
HO
O
H
N
O COOH
N
H
H
N
PSMA I&T
H
N
O COOH O
O
N
H
I
HO
O
PSMA binding motif
HN
HOOC
34 Handbook of Radiopharmaceuticals
HN
HOOC COOH
PSMA binding motif
HOOC
HN
O
HN
HOOC COOH
Figure 2.10 Chemical structures of small-molecule PSMA inhibitors PSMA-11, PSMA-617, and PSMA I&T. Source: Chatalic, K.L.S.,
Heskamp, S., Konijnenberg, M. et al. [25]. Licensed under CC BY 4.0.