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In recent years, new α-particle-, β⁻-particle-, and Auger electron- emitting radiometals-such as ⁶⁷Cu, ⁴⁷Sc, ¹⁶⁶Ho, ¹⁶¹Tb, ¹⁴⁹Tb, ²¹²Pb/²¹²Bi, ²²⁵Ac, and ²¹³Bi-have been produced and evaluated (pre)clinically for therapeutic purposes. In this short review article, the most important routes of production of these radiometals are critically discussed...
Contexts in source publication
Context 1
... b 2 -emitter 212 Pb has been proposed as an in vivo a-emitter generator because of its a-emitting daughter nuclide, 212 Bi (Fig. 2). 203 Pb was recently described as a diagnostic match that can be readily produced from nat Tl via the 203 Tl(p,n) 203 Pb nuclear reaction (46). The supply of 212 Pb is based on the availability of 228 Th extracted from spent nuclear fuel. Because 228 Th-based generators were affected by radiolytic damage, a generator based on 224 Ra (t ...
Context 2
... Bi is available from a 225 Ac/ 213 Bi generator (Table 1; Fig. 2). Successful a-therapy with 213 Bi has been demonstrated in many preclinical studies and several clinical trials (52). Clinically, 213 Bi- labeled substance P was used for local administration in patients with located gliomas (71). High retention of the activity at the target site and radiation-induced necrosis of tumors were observed, ...
Citations
... On the other hand, 47 Sc has potential as a βemitter, making it a viable option for therapeutic applications [11]. Furthermore, 47 Sc can be utilized for visualization through single photon emission computed tomography (SPECT) imaging due to its favorable γ-ray emission characteristics [12][13][14][15]. PET imaging with 44 Sc or 43 Sc is generally considered advantageous over the current use of 68 Ga (T ½ = 68 min) as both 44 Sc and 43 Sc possess half-lives approximately four times longer than that of 68 Ga allowing a longer acquisition time during imaging, which could potentially enhance the quality of images obtained [16]. ...
... Recently, targeted alpha therapy (TAT) demonstrated to be more effective than the standard PRRT, due to the high linear energy transfer (LET) offered by the alpha particles compared to beta emitters (80-100 vs. 0.1-1.0 keV/μm, respectively) (Müller et al. 2017;Navalkissoor and Grossman 2019;Brechbiel 2007). In fact, it was confirmed that alpha particles can induce more DNA damage compared to beta emitters, hence leading to more cell death (Feijtel et al. 2020;Miederer et al. 2008). ...
Background
The [¹⁷⁷Lu]Lu-DOTA-TATE mediated peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) is sometimes leading to treatment resistance and disease recurrence. An interesting alternative could be the somatostatin antagonist, [¹⁷⁷Lu]Lu-DOTA-JR11, that demonstrated better biodistribution profile and higher tumor uptake than [¹⁷⁷Lu]Lu-DOTA-TATE. Furthermore, treatment with alpha emitters showed improvement of the therapeutic index of PRRT due to the high LET offered by the alpha particles compared to beta emitters. Therefore, [²²⁵Ac]Ac-DOTA-JR11 can be a potential candidate to improve the treatment of NETs (Graphical abstract). DOTA-JR11 was radiolabeled with [²²⁵Ac]Ac(NO3)3 and [¹⁷⁷Lu]LuCl3. Stability studies were performed in phosphate buffered saline (PBS) and mouse serum. In vitro competitive binding assay has been carried out in U2OS-SSTR2 + cells for natLa-DOTA-JR11, natLu-DOTA-JR11 and DOTA-JR11. Ex vivo biodistribution studies were performed in mice inoculated with H69 cells at 4, 24, 48 and 72 h after injection of [²²⁵Ac]Ac-DOTA-JR11. A blocking group was included to verify uptake specificity. Dosimetry of selected organs was determined for [²²⁵Ac]Ac-DOTA-JR11 and [¹⁷⁷Lu]Lu-DOTA-JR11.
Results
[²²⁵Ac]Ac-DOTA-JR11 has been successfully prepared and obtained in high radiochemical yield (RCY; 95%) and radiochemical purity (RCP; 94%). [²²⁵Ac]Ac-DOTA-JR11 showed reasonably good stability in PBS (77% intact radiopeptide at 24 h after incubation) and in mouse serum (~ 81% intact radiopeptide 24 h after incubation). [¹⁷⁷Lu]Lu-DOTA-JR11 demonstrated excellent stability in both media (> 93%) up to 24 h post incubation. Competitive binding assay revealed that complexation of DOTA-JR11 with natLa and natLu did not affect its binding affinity to SSTR2. Similar biodistribution profiles were observed for both radiopeptides, however, higher uptake was noticed in the kidneys, liver and bone for [²²⁵Ac]Ac-DOTA-JR11 than [¹⁷⁷Lu]Lu-DOTA-JR11.
Conclusion
[²²⁵Ac]Ac-DOTA-JR11 showed a higher absorbed dose in the kidneys compared to [¹⁷⁷Lu]Lu-DOTA-JR11, which may limit further studies with this radiopeptide. However, several strategies can be explored to reduce nephrotoxicity and offer opportunities for future clinical investigations with [²²⁵Ac]Ac-DOTA-JR11.
... In the case of α-emitters, 213 Bi, 223 Ra, 211 At, and 225 Ac have been investigated for the treatment of cancer metastases due to their apoptotic effects [39]. Various theragnostic strategies involving them have been studied, and some radioisotopes, such as 225 Ac, have been utilised for cancer therapy in preclinical and clinical trials [40][41][42][43]. ...
Radiopharmaceutical therapy, which can detect and treat tumours simultaneously, was introduced more than 80 years ago, and it has changed medical strategies with respect to cancer. Many radioactive radionuclides have been developed, and functional, molecularly modified radiolabelled peptides have been used to produce biomolecules and therapeutics that are vastly utilised in the field of radio medicine. Since the 1990s, they have smoothly transitioned into clinical application, and as of today, a wide variety of radiolabelled radionuclide derivatives have been examined and evaluated in various studies. Advanced technologies, such as conjugation of functional peptides or incorporation of radionuclides into chelating ligands, have been developed for advanced radiopharmaceutical cancer therapy. New radiolabelled conjugates for targeted radiotherapy have been designed to deliver radiation directly to cancer cells with improved specificity and minimal damage to the surrounding normal tissue. The development of new theragnostic radionuclides, which can be used for both imaging and therapy purposes, allows for more precise targeting and monitoring of the treatment response. The increased use of peptide receptor radionuclide therapy (PRRT) is also important in the targeting of specific receptors which are overexpressed in cancer cells. In this review, we provide insights into the development of radionuclides and functional radiolabelled peptides, give a brief background, and describe their transition into clinical application.
... Unfortunately, for the most common pattern of end-stage metastases (numerous lung IGF-1R expression in osteosarcoma: An opportunity for anti-IGF-1R antibody-actinium-225 alpha particle therapy Sarcomas, particularly Ewing sarcoma and osteosarcoma have overexpression of IGF1R (69). Although cold antibody was only modestly effective in Ewing sarcoma and not in osteosarcoma (69), chelation of the alpha emitter 225 Ac can arm the anti-IGF1R antibody to become a potent alpha emitter (70,71). Table 1 compares 223 Ra, which targets areas of bone turnover, with anti-IGF1R-Actinium-225. Currently, the clinical trial NCT0374631 is open at MD Anderson Cancer Center, City of Hope, Memorial Sloan Kettering, University of Minnesota, Dana Farber Cancer Institute, University of Pennsylvania, Juravinski/Hamilton Health, CHU-Montreal, Princess Margaret (Toronto), and CHU Quebec. ...
Osteosarcoma is a high-grade sarcoma characterized by osteoid formation, nearly universal expression of IGF1R and with a subset expressing HER-2. These qualities provide opportunities for the use of the alpha particle-emitting isotopes to provide targeted radiation therapy via alpha particles precisely to bone-forming tumors in addition to IFG1R or Her-2 expressing metastases. This review will detail experience using the alpha emitter radium-223 (223Ra, tradename Xofigo), that targets bone formation, in osteosarcoma, specifically related to patient selection, use of gemcitabine for radio-sensitization, and using denosumab to increasing the osteoblastic phenotype of these cancers. A case of an inoperable left upper lobe vertebral-paraspinal-mediastinal osteoblastic lesion treated successfully with 223Ra combined with gemcitabine is described. Because not all areas of osteosarcoma lesions are osteoblastic, but nearly all osteosarcoma cells overexpress IGF1R, and some subsets expressing Her-2, the anti-IGF1R antibody FPI-1434 linked to actinium-225 (225Ac) or the Her-2 antibody linked to thorium-227 (227Th) may become other means to provide targeted alpha particle therapy against osteosarcoma (NCT03746431 and NCT04147819).
... A recent meta-analysis of 225 Ac-PSMA-TAT data found a PSA decline greater than 50% was seen in 83% of patients and complete molecular response in 17% of patients [8]. Except for 223 Ra and 225 Ac previously mentioned, other feasible radionuclide candidates for TAT include 227 Th, 213 Bi, 211 At, 212 Pb and 149 Tb [2,9]. ...
Background
The development of new targeted alpha therapies motivates improving alpha particle dosimetry. For alpha particles, microscopic targets must be considered to estimate dosimetric quantities that can predict the biological response. As double-strand breaks (DSB) on DNA are the main cause of cell death by ionizing radiation, cell nuclei are relevant volumes necessary to consider as targets. Since a large variance is expected of alpha particle hits in individual cell nuclei irradiated by an uncollimated alpha-emitting source, the damage induced should have a similar distribution. The induction of DSB can be measured by immunofluorescent γ-H2AX staining. The cell γ-H2AX foci distribution and alpha particle hits distribution should be comparable and thereby verify the necessity to consider the relevant dosimetric volumes.
Methods
A Monte Carlo simulation model of an ²⁴¹ Am source alpha particle irradiation setup was combined with two versions of realistic cell nuclei phantoms. These were generated from DAPI-stained PC3 cells imaged with fluorescent microscopy, one consisting of elliptical cylinders and the other of segmented mesh volumes. PC3 cells were irradiated with the ²⁴¹ Am source for 4, 8 and 12 min, and after 30 min fixated and stained with immunofluorescent γ-H2AX marker. The detected radiation-induced foci (RIF) were compared to simulated RIF.
Results
The mesh volume phantom detected a higher mean of alpha particle hits and energy imparted (MeV) per cell nuclei than the elliptical cylinder phantom, but the mean specific energy (Gy) was very similar. The mesh volume phantom detected a slightly larger variance between individual cells, stemming from the more extreme and less continuous distribution of cell nuclei sizes represented in this phantom. The simulated RIF distribution from both phantoms was in good agreement with the detected RIF, although the detected distribution had a zero-inflated shape not seen in the simulated distributions. An estimate of undetected foci was used to correct the detected RIF distribution and improved the agreement with the simulations.
Conclusion
Two methods to generate cell nuclei phantoms for Monte Carlo dosimetry simulations were tested and generated similar results. The simulated and detected RIF distributions from alpha particle-irradiated PC3 cells were in good agreement, proposing the necessity to consider microscopic targets in alpha particle dosimetry.
... Glu-Urea-Glu was selected as the PSMA targeting moiety to facilitate synthesis. 177 Lu, as a β-emitter with a half-life of 6.65 days, is an ideal radioisotope for RLT [31] and was chosen for our study. It can be efficiently and stably labeled by the metal chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) [32]. ...
Purpose
Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is emerging as an effective treatment option for metastatic castration-resistant prostate cancer (mCRPC). An imaging-based method to quantify early treatment responses can help to understand and optimize RLT.
Methods
We developed a self-triggered probe 2 targeting the colocalization of PSMA and caspase-3 for fluorescence imaging of RLT-induced apoptosis.
Results
The probe binds to PSMA potently with a Ki of 4.12 nM, and its fluorescence can be effectively switched on by caspase-3 with a Km of 67.62 μM. Cellular and in vivo studies demonstrated its specificity for imaging radiation-induced caspase-3 upregulation in prostate cancer. To identify the detection limit of our method, we showed that probe 2 could achieve 1.79 times fluorescence enhancement in response to ¹⁷⁷Lu-RLT in a medium PSMA-expressing 22Rv1 xenograft model.
Conclusion
Probe 2 can potently bind to PSMA, and the fluorescence signal can be sensitively switched on by caspase-3 both in vitro and in vivo. This method may provide an effective tool to investigate and optimize PSMA-RLT.
... Indeed, these two radioisotopes have lower β À particle emission energies (E β À (average) ¼ 153 and 134 keV, respectively) and tissue penetration (0.15 and 0.28 mm, respectively) than 90-Y (E β À (average) ¼ 936 keV; 2.76 mm) [51]. Although their longer half-lives (about 7 days [50]) require isolating the patient in a specialized area for longer times, 177-Lu and 161-Tb are more effective than 90-Y for the treatment of tumors, which allows reducing the administered doses [52,53]. 177-Lu and 161-Tb are therefore ideal for radiotherapeutic treatment of small tumors, while 90-Y is more suitable for radiotherapy of medium-sized tumors [54]. ...
In this chapter, we analyze ligand structural features necessary for the design of stable and inert lanthanide complexes for use in biomedical applications. In the first sections of the chapter we provide a brief introduction to the coordination chemistry of the lanthanides and some general complex design principles. We then discuss the main synthetic strategies available for the preparation of macrocycles for lanthanide complexation, paying particular attention to the regioselective functionalization of selected macrocycles. Subsequently, we review the thermodynamic stability of lanthanide complexes and the different stability trends observed across the lanthanide series. In the last part of the review, we present the main mechanisms responsible for the dissociation of lanthanide complexes and ligand characteristics that result in particularly inert complexes.
... Recently, targeted alpha therapy (TAT) demonstrated to be more effective than the standard PRRT, due to the high linear energy transfer (LET) offered by the alpha particles compared to beta emitters (80-100 vs. 0.1-1.0 keV/μm, respectively) (Müller et al. 2017;Navalkissoor and Grossman 2019;Brechbiel 2007). In fact, it was confirmed that alpha particles can induce more DNA damage compared to beta emitters, hence leading to more cell death (Feijtel et al. 2020;Miederer et al. 2008). ...
... Its low-energy beta particles (mean energy of 134 keV; maximum energy of 498 keV (79%)) have a mean range of 0.7 mm and a maximum of 2.1 mm in soft tissue (Ahmadzadehfar et al. 2020). Furthermore, its emitted photons of 113 keV (6.2%) and 208 keV (10.4%) are useful for 177 Lu SPECT dosimetry (Müller et al. 2017;Alnaaimi et al. 2021). Moreover, 177 Lu has a half-life of 6.65 days, which is suitable for radionuclide therapy. ...
... Its low-energy beta particles (mean energy of 134 keV; maximum energy of 498 keV (79%)) have a mean range of 0.7 mm and a maximum of 2.1 mm in soft tissue (Ahmadzadehfar et al. 2020). Furthermore, its emitted photons of 113 keV (6.2%) and 208 keV (10.4%) are useful for 177 Lu SPECT dosimetry (Müller et al. 2017;Alnaaimi et al. 2021). Moreover, 177 Lu has a half-life of 6.65 days, which is suitable for radionuclide therapy. ...
Background
Recent advances in nanotechnology have offered new hope for cancer detection, prevention, and treatment. Nanomedicine, a term for the application of nanotechnology in medical and health fields, uses nanoparticles for several applications such as imaging, diagnostic, targeted cancer therapy, drug and gene delivery, tissue engineering, and theranostics.
Results
Here, we overview the current state-of-the-art of radiolabeled nanoparticles for molecular imaging and radionuclide therapy. Nanostructured radiopharmaceuticals of technetium-99m, copper-64, lutetium-177, and radium-223 are discussed within the scope of this review article.
Conclusion
Nanoradiopharmaceuticals may lead to better development of theranostics inspired by ingenious delivery and imaging systems. Cancer nano-theranostics have the potential to lead the way to more specific and individualized cancer treatment.
Graphical abstract
