Page 26 - ARNM-1-2

Advances in Radiotherapy
& Nuclear Medicine FAP-targeted RLT in cancer

Table 2. Summary of fibroblast activation protein enhancing the antitumor effect [36,37] . Moon et al. took a
(FAP)‑targeting radiopharmaceuticals different approach by transforming FAPI-04 into a dimeric
system, resulting in DOTA (SA.FAPI) and DOTAGA (SA.
2
FAP-targeting radiopharmaceuticals in imaging studies FAPI) . In addition to these developments, a cyclic peptide
[38]
68 Ga-tracers 68 Ga-FAPI-04 known as FAP-2286 has been designed specifically for FAP-
68 Ga-FAPI-46 based radionuclide therapy. This peptide has demonstrated
68 Ga-FAPI-74 higher tumor uptake, lower background signal, prolonged
68 Ga-DOTA-2P (FAPI) tumor retention time, and remarkable antitumor
2
[39]
68 Ga-OncoFAP-DOTAGA effects . Furthermore, albumin binder-truncated Evans
177
68 Ga-FAPI NOS blue ( Lu-EB-FAPI-B1) has demonstrated favorable
[40]
68 Ga-FAPI-02 pharmacokinetics and significant antitumor effects . The
68 Ga-DOTA-SA-FAPi introduction of albumin-binding FAPIs has contributed to
increased blood drug concentrations, delayed excretion,
68 Ga-DATA5m-SA-FAPi stability in physiological saline and plasma, high FAP-
68 Ga-FAP-2286 binding affinity, and minimal physiological uptake .
[41]
18 F-tracers 18 F-AlF-NOTA-FAPI
Another crucial aspect of TRT is the selection of the
18 F-FAPI-74 appropriate radionuclide. The radiation dose delivered to
18 F-FAPI-NOS a target relies on the type, range, half-life, and energy of
18 F-FAPI-42 the particles emitted. α-particle-based treatments have
18 F-AlF-P-FAPI demonstrated effectiveness in targeting CAFs, although
99m Tc-tracers 99m Tc-FAPI-34 their direct impact on tumor cells may be limited. In
FAP-targeting radiopharmaceuticals in radionuclide therapy studies a pre-clinical study, a single dose of 225 Ac-FAPI-04
177 Lu-radionuclides 177 Lu-FAPI-46 resulted in tumor growth retardation in mice bearing
177 Lu-FAPI-04 PANC-1 xenografts, with no significant changes in body
weight . Tranel et al. conducted a study comparing
[30]
177 Lu-DOTA-SA-FAPi absorbed dose estimates in a three-dimensional cell model
177 Lu-FAPI-2286 consisting of a mixture of CAFs and tumor cells . Their
[42]
225
90 Y-radionuclides 90 Y-FAPI-46 findings revealed that the efficacy of Ac decreased with
177
90 Y-FAPI-04 increasing tumor cluster size. In such cases, Lu, which
153 Sm-radionuclides 153 Sm-FAPI-04 emits β-emitters with a more extended range, might be
a more effective option due to crossfire effects. However,
177
the efficacy of Lu is also limited when dealing with large
with FAPI-02 and FAPI-04, Loktev et al. embarked cluster sizes (0.6–0.7 mm) . In addition, the use of other
[42]
on the development of several other derivatives . radionuclides, such as Y and I, for labeling FAPIs could
[31]
90
131
Their investigation led to the discovery that FAPI-46 provide additional treatment options for tumors.
exhibited superior pharmacokinetics when compared to
FAPI-04. Notably, FAPI-46 displayed higher 24-h tumor 5. Initial findings from clinical studies on
retention and lower physiological uptake. While FAPI-21 FAP-targeted RLT
demonstrated the highest tumor retention after 24 h,
unfortunately, it also exhibited high physiological uptake in At present, our knowledge of human FAP-targeted RLT
the oral mucosa, thyroid, and salivary glands . Moreover, is primarily derived from case reports, case series, and
[31]
the incorporation of the 1,4,7,10-tetraazacyclododecane- small-scale prospective studies (Table 3) [11-13,32-34,43-50] .
1,4,7,10-tetraacetic acid (DOTA) ligand as a chelator for These investigations employed various FAPI agents,
FAPI-46 made it compatible with the labeling Y, Lu, and including FAPI-04, FAPI-46, FAP-2286, 3BP-3940, and
177
90
153 Sm radionuclides, rendering it suitable for TRT [12,32-34] . (SA.FAPi) in combinations with radionuclides such as
2
Researchers have leveraged the multimerization effect to 90 Y, 177 Lu, 153 Sm, and 225 Sc. While most studies included
design and synthesize radiopharmaceuticals with improved patients with various malignancies, Ballal et al. specifically
properties. Zhao et al. linked two FAPI-46 monomer motifs focused on patients with thyroid cancer . Early studies
[51]
to create DOTA-2P(FAPI) 2 [35] , while Pang et al. synthesized reported disease progression or stable disease [32,44,45] ,
[36]
DOTA-4P(FAPI) using four FAPI-46 monomers . The while recent studies have revealed partial responses by
4
application of multimerization techniques has been shown patients to new therapies [12,49] . The first documented case
to increase tumor uptake and retention, consequently of FAP-targeted RLT was reported by Lindner et al. ,
[11]
Volume 1 Issue 2 (2023) 5 https://doi.org/10.36922/arnm.1667