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14 pages, 3388 KiB

Open AccessArticle

Synthesis and Evaluation of ^99mTc-Labelled 2-Nitroimidazole Derivatives with Different Linkers for Tumour Hypoxia Imaging

by Qing Ruan, Yitong Liu, Lihao Liao, Jinyu Hao, Yuhao Jiang, Jianyong Jiang and Junbo Zhang

Pharmaceuticals 2023, 16(9), 1276; https://doi.org/10.3390/ph16091276 - 09 Sep 2023

Viewed by 955

Abstract

When developing novel radiopharmaceuticals, a linker moiety between the chelator and targeting vector can have a crucial influence on adjusting the affinity of the tracer and its biodistribution in organisms. To develop novel ^99mTc-labelled hypoxia imaging radiotracers, in this study, five isocyanide-containing [...] Read more.

When developing novel radiopharmaceuticals, a linker moiety between the chelator and targeting vector can have a crucial influence on adjusting the affinity of the tracer and its biodistribution in organisms. To develop novel ^99mTc-labelled hypoxia imaging radiotracers, in this study, five isocyanide-containing 2-nitroimidazole derivatives with different linkers (L1, L2, L3, L4 and L5) were synthesised and radiolabelled with technetium-99m to obtain five stable ^99mTc-complexes ([^99mTc]Tc-L1, [^99mTc]Tc-L2, [^99mTc]Tc-L3, [^99mTc]Tc-L4 and [^99mTc]Tc-L5). Corresponding rhenium analogues of [^99mTc]Tc-L1 were synthesised and suggested the structures of these ^99mTc-complexes would be a monovalent cation with a technetium (I) core surrounded by six ligands. [^99mTc]Tc-L1 is hydrophilic, while the lipophilicities of [^99mTc]Tc-L2, [^99mTc]Tc-L3, [^99mTc]Tc-L4 and [^99mTc]Tc-L5 are close. In vitro cell experiments showed that all five novel ^99mTc-complexes had higher uptake in hypoxic cells compared with aerobic cells, which indicates the complexes have good hypoxia selectivity. The biodistribution of the five ^99mTc-complexes in S180 tumour-bearing mice showed that they all had certain uptake in the tumours. Among them, [^99mTc]Tc-L1 had the highest tumour-to-muscle (4.68 ± 0.44) and tumour-to-blood (3.81 ± 0.46) ratios. The introduction of polyethylene glycol (PEG) chains effectively reduced the lipophilicity and decreased uptake by the liver, intestine and blood but also increased clearance from the tumours. In vivo metabolic studies showed [^99mTc]Tc-L1 kept intact and remained stable in tumour, blood and urine at 2 h post-injection. The results of SPECT imaging showed that [^99mTc]Tc-L1 had significant tumour uptake at 2 h post-injection, but there was still high uptake in abdominal organs such as the liver and kidney, suggesting that this complex needs to be further optimised before being used for tumour hypoxia imaging. Full article

(This article belongs to the Special Issue Application of Radiolabeled Agents: Imaging, Therapy, Multimodal Approaches and Beyond)

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19 pages, 2367 KiB

Open AccessArticle

Synthesis and Evaluation of ePSMA-DM1: A New Theranostic Small-Molecule Drug Conjugate (T-SMDC) for Prostate Cancer

by Erika Murce, Evelien Spaan, Savanne Beekman, Lilian van den Brink, Maryana Handula, Debra Stuurman, Corrina de Ridder, Simone U. Dalm and Yann Seimbille

Pharmaceuticals 2023, 16(8), 1072; https://doi.org/10.3390/ph16081072 - 28 Jul 2023

Cited by 1 | Viewed by 1870

Abstract

Small-molecule drug conjugates (SMDCs) are compounds in which a therapeutic payload is conjugated to a targeting vector, for specific delivery to the tumor site. This promising approach can be translated to the treatment of prostate cancer by selecting a targeting vector which binds [...] Read more.

Small-molecule drug conjugates (SMDCs) are compounds in which a therapeutic payload is conjugated to a targeting vector, for specific delivery to the tumor site. This promising approach can be translated to the treatment of prostate cancer by selecting a targeting vector which binds to the prostate-specific membrane antigen (PSMA). Moreover, the addition of a bifunctional chelator to the molecule allows for the use of both diagnostic and therapeutic radionuclides. In this way, the distribution of the SMDC in the body can be monitored, and combination therapy regimes can be implemented. We combined a glutamate-urea-lysine vector to the cytotoxic agent DM1 and a DOTA chelator via an optimized linker to obtain the theranostic SMDC (T-SMDC) ePSMA-DM1. ePSMA-DM1 retained a high binding affinity to PSMA and demonstrated PSMA-specific uptake in cells. Glutathione stability assays showed that the half-life of the T-SMDC in a reducing environment was 2 h, and full drug release was obtained after 6 h. Moreover, 100 nM of ePSMA-DM1 reduced the cell viability of the human PSMA-positive LS174T cells by >85% after 72 h of incubation, which was comparable to a 10-fold higher dose of free DM1. [¹¹¹In]In-ePSMA-DM1 and [¹⁷⁷Lu]Lu-ePSMA-DM1 were both obtained in high radiochemical yields and purities (>95%), with >90% stability in PBS and >80% stability in mouse serum for up to 24 h post incubation at 37 °C. SPECT/CT imaging studies allowed for a faint tumor visualization of [¹¹¹In]In-ePSMA-DM1 at 1 h p.i., and the ex vivo biodistribution showed tumor uptake (2.39 ± 0.29% ID/g) at 1 h p.i., with the compound retained in the tumor for up to 24 h. Therefore, ePSMA-DM1 is a promising T-SMDC candidate for prostate cancer, and the data obtained so far warrant further investigations, such as therapeutic experiments, after further optimization. Full article

(This article belongs to the Special Issue Application of Radiolabeled Agents: Imaging, Therapy, Multimodal Approaches and Beyond)

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16 pages, 2684 KiB

Open AccessArticle

Identification of the Hepatic Metabolites of Flumazenil and their Kinetic Application in Neuroimaging

by Wei-Hsi Chen, Chuang-Hsin Chiu, Shiou-Shiow Farn, Kai-Hung Cheng, Yuan-Ruei Huang, Shih-Ying Lee, Yao-Ching Fang, Yu-Hua Lin and Kang-Wei Chang

Pharmaceuticals 2023, 16(5), 764; https://doi.org/10.3390/ph16050764 - 18 May 2023

Cited by 1 | Viewed by 1546

Abstract

Studies of the neurobiological causes of anxiety disorders have suggested that the γ-aminobutyric acid (GABA) system increases synaptic concentrations and enhances the affinity of GABA_A (type A) receptors for benzodiazepine ligands. Flumazenil antagonizes the benzodiazepine-binding site of the GABA/benzodiazepine receptor (BZR) complex [...] Read more.

Studies of the neurobiological causes of anxiety disorders have suggested that the γ-aminobutyric acid (GABA) system increases synaptic concentrations and enhances the affinity of GABA_A (type A) receptors for benzodiazepine ligands. Flumazenil antagonizes the benzodiazepine-binding site of the GABA/benzodiazepine receptor (BZR) complex in the central nervous system (CNS). The investigation of flumazenil metabolites using liquid chromatography (LC)-tandem mass spectrometry will provide a complete understanding of the in vivo metabolism of flumazenil and accelerate radiopharmaceutical inspection and registration. The main goal of this study was to investigate the use of reversed-phase high performance liquid chromatography (PR-HPLC), coupled with electrospray ionization triple-quadrupole tandem mass spectrometry (ESI-QqQ MS), to identify flumazenil and its metabolites in the hepatic matrix. Carrier-free nucleophilic fluorination with an automatic synthesizer for [¹⁸F]flumazenil, combined with nano-positron emission tomography (NanoPET)/computed tomography (CT) imaging, was used to predict the biodistribution in normal rats. The study showed that 50% of the flumazenil was biotransformed by the rat liver homogenate in 60 min, whereas one metabolite (M1) was a methyl transesterification product of flumazenil. In the rat liver microsomal system, two metabolites were identified (M2 and M3), as their carboxylic acid and hydroxylated ethyl ester forms between 10 and 120 min, respectively. A total of 10–30 min post-injection of [¹⁸F]flumazenil showed an immediate decreased in the distribution ratio observed in the plasma. Nevertheless, a higher ratio of the complete [¹⁸F]flumazenil compound could be used for subsequent animal studies. [¹⁸F] According to in vivo nanoPET/CT imaging and ex vivo biodistribution assays, flumazenil also showed significant effects on GABA_A receptor availability in the amygdala, prefrontal cortex, cortex, and hippocampus in the rat brain, indicating the formation of metabolites. We reported the completion of the biotransformation of flumazenil by the hepatic system, as well as [¹⁸F]flumazenil’s potential as an ideal ligand and PET agent for the determination of the GABA_A/BZR complex for multiplex neurological syndromes at the clinical stage. Full article

(This article belongs to the Special Issue Application of Radiolabeled Agents: Imaging, Therapy, Multimodal Approaches and Beyond)

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14 pages, 3413 KiB

Open AccessArticle

Clinical Confirmation of Pan-Amyloid Reactivity of Radioiodinated Peptide ¹²⁴I-p5+14 (AT-01) in Patients with Diverse Types of Systemic Amyloidosis Demonstrated by PET/CT Imaging

by Emily B. Martin, Alan Stuckey, Dustin Powell, Ronald Lands, Bryan Whittle, Craig Wooliver, Sallie Macy, James S. Foster, Spencer Guthrie, Stephen J. Kennel and Jonathan S. Wall

Pharmaceuticals 2023, 16(4), 629; https://doi.org/10.3390/ph16040629 - 21 Apr 2023

Cited by 8 | Viewed by 1574

Abstract

There are at least 20 distinct types of systemic amyloidosis, all of which result in the organ-compromising accumulation of extracellular amyloid deposits. Amyloidosis is challenging to diagnose due to the heterogeneity of the clinical presentation, yet early detection is critical for favorable patient [...] Read more.

There are at least 20 distinct types of systemic amyloidosis, all of which result in the organ-compromising accumulation of extracellular amyloid deposits. Amyloidosis is challenging to diagnose due to the heterogeneity of the clinical presentation, yet early detection is critical for favorable patient outcomes. The ability to non-invasively and quantitatively detect amyloid throughout the body, even in at-risk populations, before clinical manifestation would be invaluable. To this end, a pan-amyloid-reactive peptide, p5+14, has been developed that is capable of binding all types of amyloid. Herein, we demonstrate the ex vivo pan-amyloid reactivity of p5+14 by using peptide histochemistry on animal and human tissue sections containing various types of amyloid. Furthermore, we present clinical evidence of pan-amyloid binding using iodine-124-labeled p5+14 in a cohort of patients with eight (n = 8) different types of systemic amyloidosis. These patients underwent PET/CT imaging as part of the first-in-human Phase 1/2 clinical trial evaluating this radiotracer (NCT03678259). The uptake of ¹²⁴I-p5+14 was observed in abdominothoracic organs in patients with all types of amyloidosis evaluated and was consistent with the disease distribution described in the medical record and literature reports. On the other hand, the distribution in healthy subjects was consistent with radiotracer catabolism and clearance. The early and accurate diagnosis of amyloidosis remains challenging. These data support the utility of ¹²⁴I-p5+14 for the diagnosis of varied types of systemic amyloidosis by PET/CT imaging. Full article

(This article belongs to the Special Issue Application of Radiolabeled Agents: Imaging, Therapy, Multimodal Approaches and Beyond)

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15 pages, 3527 KiB

Open AccessArticle

Automated Synthesis of [¹⁸F]Flumazenil Application in GABA_A Receptor Neuroimaging Availability for Rat Model of Anxiety

by Shiou-Shiow Farn, Kai-Hung Cheng, Yuan-Ruei Huang, Shih-Ying Lee, Jenn-Tzong Chen and Kang-Wei Chang

Pharmaceuticals 2023, 16(3), 417; https://doi.org/10.3390/ph16030417 - 09 Mar 2023

Cited by 1 | Viewed by 1609

Abstract

Clinical studies have demonstrated that the γ-aminobutyric acid type A (GABA_A) receptor complex plays a central role in the modulation of anxiety. Conditioned fear and anxiety-like behaviors have many similarities at the neuroanatomical and pharmacological levels. The radioactive GABA/BZR receptor antagonist, [...] Read more.

Clinical studies have demonstrated that the γ-aminobutyric acid type A (GABA_A) receptor complex plays a central role in the modulation of anxiety. Conditioned fear and anxiety-like behaviors have many similarities at the neuroanatomical and pharmacological levels. The radioactive GABA/BZR receptor antagonist, fluorine-18-labeled flumazenil, [¹⁸F]flumazenil, behaves as a potential PET imaging agent for the evaluation of cortical damage of the brain in stroke, alcoholism, and for Alzheimer disease investigation. The main goal of our study was to investigate a fully automated nucleophilic fluorination system, with solid extraction purification, developed to replace traditional preparation methods, and to detect underlying expressions of contextual fear and characterize the distribution of GABA_A receptors in fear-conditioned rats by [¹⁸F]flumazenil. A carrier-free nucleophilic fluorination method using an automatic synthesizer with direct labeling of a nitro-flumazenil precursor was implemented. The semi-preparative high-performance liquid chromatography (HPLC) purification method (RCY = 15–20%) was applied to obtain high purity [¹⁸F]flumazenil. Nano-positron emission tomography (NanoPET)/computed tomography (CT) imaging and ex vivo autoradiography were used to analyze the fear conditioning of rats trained with 1–10 tone-foot-shock pairings. The anxiety rats had a significantly lower cerebral accumulation (in the amygdala, prefrontal cortex, cortex, and hippocampus) of fear conditioning. Our rat autoradiography results also supported the findings of PET imaging. Key findings were obtained by developing straightforward labeling and purification procedures that can be easily adapted to commercially available modules for the high radiochemical purity of [¹⁸F]flumazenil. The use of an automatic synthesizer with semi-preparative HPLC purification would be a suitable reference method for new drug studies of GABA_A/BZR receptors in the future. Full article

(This article belongs to the Special Issue Application of Radiolabeled Agents: Imaging, Therapy, Multimodal Approaches and Beyond)

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14 pages, 3676 KiB

Open AccessArticle

Efforts toward PET-Activatable Red-Shifted Silicon Rhodamines and Silicon Pyronine Dyes

by Carsten Sven Kramer, Thines Kanagasundaram, Jessica Matthias and Klaus Kopka

Pharmaceuticals 2023, 16(3), 401; https://doi.org/10.3390/ph16030401 - 07 Mar 2023

Cited by 1 | Viewed by 1539

Abstract

Tracers for bimodal optical imaging and positron emission tomography unite multiple advantages in a single molecule. Their tumor-specific uptake can be visualized after their PET activation by radiofluorination via PET/CT or PET/MRI allowing for staging or therapy planning, while their non-radioactive moiety additionally [...] Read more.

Tracers for bimodal optical imaging and positron emission tomography unite multiple advantages in a single molecule. Their tumor-specific uptake can be visualized after their PET activation by radiofluorination via PET/CT or PET/MRI allowing for staging or therapy planning, while their non-radioactive moiety additionally facilitates the visualization of malignant tissue during intraoperative fluorescence-guided surgery or in histological assessments. The silicon-bridged xanthene core offers the opportunity for radiofluorination with SiFA isotope exchange to obtain a small-molecule, PET-activatable NIR dye that can be linked to different target vectors. Herein, we demonstrate for the first time the PET-activation of a fluorinated silicon pyronine, belonging to a class of low-molecular-weight fluorescence dyes with a large Stokes shift (up to 129 nm) and solvent-dependent NIR dye properties, with a successful radiochemical conversion of 70%. The non-fluorinated pyronine precursor is easily accessible by a three-step sequence from commercially starting material with a 12% overall yield. Moreover, a library of seven unusually functionalized (by approximately 15 nm), red-shifted silicon rhodamines were synthesized in three- to four-step sequences and the optical properties of the novel dyes were characterized. It was also shown that the synthesized silicon rhodamine dyes can be easily conjugated by amide bond formation or ‘click-reaction’ approaches. Full article

(This article belongs to the Special Issue Application of Radiolabeled Agents: Imaging, Therapy, Multimodal Approaches and Beyond)

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19 pages, 1532 KiB

Open AccessArticle

Towards Radiolabeled EGFR-Specific Peptides: Alternatives to GE11

by Benedikt Judmann, Björn Wängler, Ralf Schirrmacher, Gert Fricker and Carmen Wängler

Pharmaceuticals 2023, 16(2), 273; https://doi.org/10.3390/ph16020273 - 11 Feb 2023

Viewed by 1749

Abstract

The human epidermal growth factor receptor (EGFR) is closely related to several cancer-promoting processes and overexpressed on a variety of tumor types, rendering it an important target structure for the imaging and therapy of several malignancies. To date, approaches to develop peptidic radioligands [...] Read more.

The human epidermal growth factor receptor (EGFR) is closely related to several cancer-promoting processes and overexpressed on a variety of tumor types, rendering it an important target structure for the imaging and therapy of several malignancies. To date, approaches to develop peptidic radioligands able to specifically address and visualize EGFR-positive tumors have been of limited success. Most of the attempts were based on the lead GE11, as this peptide was previously described to be a highly potent EGFR-specific agent. However, since it has recently been shown that GE11 exhibits an insufficient affinity to the EGFR in monomeric form to be suitable as a basis for the development of tracers based on it, in the present work we investigated which other peptides might be suitable as lead structures for the development of EGFR-specific peptidic radiotracers. For this purpose, we developed ⁶⁸Ga-labeled radioligands based on the peptides D4, P1, P2, CPP, QRH, EGBP and Pep11, having been described before as EGFR-specific. In addition, we also tested three truncated versions of the endogenous EGFR ligand hEGF (human epidermal growth factor) with respect to their ability to specifically target the EGFR with high affinity. Therefore, chelator-modified labeling precursors of the mentioned peptides were synthesized, radiolabeled with ⁶⁸Ga and the obtained radioligands were evaluated for their hydrophilicity/lipophilicity, stability against degradation by human serum peptidases, in vitro tumor cell uptake, and receptor affinity in competitive displacement experiments on EGFR-positive A431 cells. Although all NODA-GA-modified (NODA-GA: (1,4,7-triazacyclononane-4,7-diyl)diacetic acid-1-glutaric acid) labeling precursors could be obtained more or less efficient in yields between 5 and 74%, the ⁶⁸Ga-radiolabeling proved to be unsuccessful for two of the three truncated versions of hEGF ([⁶⁸Ga]Ga-8 and [⁶⁸Ga]Ga-9), producing several side-products. For the other agents [⁶⁸Ga]Ga-1–[⁶⁸Ga]Ga-7, [⁶⁸Ga]Ga-10 and [⁶⁸Ga]Ga-11, high radiochemical yields and purities of ≥98% and molar activities of up to 114 GBq/µmol were obtained. In the assay investigating the radiopeptide susceptibilities against serum peptidase degradation, the EGBP-based agent demonstrated a limited stability with a half-life of only 66.4 ± 3.0 min, whereas the other tracers showed considerably higher stabilities of up to an 8000 min half-life. Finally, all radiotracer candidates were evaluated in terms of tumor cell internalization and receptor binding potential on EGFR-positive A431 cell. In these experiments, all developed agents failed to show an EGFR-specific tumor cell uptake or a relevant EGFR-affinity. By contrast, the positive controls tested under identical conditions, [¹²⁵I]I-hEGF and hEGF demonstrated the expected high EGFR-specific tumor cell uptake (33.6% after 1 h, being reduced to 1.9% under blocking conditions) and affinity (IC₅₀ value of 15.2 ± 3.3 nM). Thus, these results indicate that none of the previously described peptidic agents developed for EGFR targeting appears to be a reasonable choice as a lead structure for the development of radiopeptides for targeting of EGFR-positive tumors. Likewise, the tested truncated variants of the endogenous hEGF do not seem to be promising alternatives for this purpose. Full article

(This article belongs to the Special Issue Application of Radiolabeled Agents: Imaging, Therapy, Multimodal Approaches and Beyond)

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19 pages, 4773 KiB

Open AccessArticle

Antibody-Based In Vivo Imaging of Central Nervous System Targets—Evaluation of a Pretargeting Approach Utilizing a TCO-Conjugated Brain Shuttle Antibody and Radiolabeled Tetrazines

by Christoph Bredack, Martin R. Edelmann, Edilio Borroni, Luca C. Gobbi and Michael Honer

Pharmaceuticals 2022, 15(12), 1445; https://doi.org/10.3390/ph15121445 - 22 Nov 2022

Cited by 6 | Viewed by 2136

Abstract

Bioorthogonal pretargeted imaging using the inverse-electron-demand Diels–Alder (IEDDA) reaction between a tetrazine (Tz) and a trans-cyclooctene (TCO) represents an attractive strategy for molecular imaging via antibodies. The advantages of using a pretargeted imaging approach are on the one hand the possibility to [...] Read more.

Bioorthogonal pretargeted imaging using the inverse-electron-demand Diels–Alder (IEDDA) reaction between a tetrazine (Tz) and a trans-cyclooctene (TCO) represents an attractive strategy for molecular imaging via antibodies. The advantages of using a pretargeted imaging approach are on the one hand the possibility to achieve a high signal-to-noise ratio and imaging contrast; on the other hand, the method allows the uncoupling of the biological half-life of antibodies from the physical half-life of short-lived radionuclides. A brain-penetrating antibody (mAb) specific for β-amyloid (Aβ) plaques was functionalized with TCO moieties for pretargeted labeling of Aβ plaques in vitro, ex vivo, and in vivo by a tritium-labeled Tz. The overall aim was to explore the applicability of mAbs for brain imaging, using a preclinical model system. In vitro clicked mAb–TCO–Tz was able to pass the blood–brain barrier of transgenic PS2APP mice and specifically visualize Aβ plaques ex vivo. Further experiments showed that click reactivity of the mAb–TCO construct in vivo persisted up to 3 days after injection by labeling Aβ plaques ex vivo after incubation of brain sections with the Tz in vitro. An attempted in vivo click reaction between injected mAb–TCO and Tz did not lead to significant labeling of Aβ plaques, most probably due to unfavorable in vivo properties of the used Tz and a long half-life of the mAb–TCO in the blood stream. This study clearly demonstrates that pretargeted imaging of CNS targets via antibody-based click chemistry is a viable approach. Further experiments are warranted to optimize the balance between stability and reactivity of all reactants, particularly the Tz. Full article

(This article belongs to the Special Issue Application of Radiolabeled Agents: Imaging, Therapy, Multimodal Approaches and Beyond)

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11 pages, 2622 KiB

Open AccessEditor’s ChoiceArticle

Efficient Production of the PET Radionuclide ¹³³La for Theranostic Purposes in Targeted Alpha Therapy Using the ¹³⁴Ba(p,2n)¹³³La Reaction

by Santiago Andrés Brühlmann, Martin Kreller, Hans-Jürgen Pietzsch, Klaus Kopka, Constantin Mamat, Martin Walther and Falco Reissig

Pharmaceuticals 2022, 15(10), 1167; https://doi.org/10.3390/ph15101167 - 21 Sep 2022

Cited by 11 | Viewed by 2590

Abstract

Targeted Alpha Therapy is a research field of highest interest in specialized radionuclide therapy. Over the last decades, several alpha-emitting radionuclides have entered and left research topics towards their clinical translation. Especially, ²²⁵Ac provides all necessary physical and chemical properties for a [...] Read more.

Targeted Alpha Therapy is a research field of highest interest in specialized radionuclide therapy. Over the last decades, several alpha-emitting radionuclides have entered and left research topics towards their clinical translation. Especially, ²²⁵Ac provides all necessary physical and chemical properties for a successful clinical application, which has already been shown by [²²⁵Ac]Ac-PSMA-617. While PSMA-617 carries the DOTA moiety as the complexing agent, the chelator macropa as a macrocyclic alternative provides even more beneficial properties regarding labeling and complex stability in vivo. Lanthanum-133 is an excellent positron-emitting diagnostic lanthanide to radiolabel macropa-functionalized therapeutics since ¹³³La forms a perfectly matched theranostic pair of radionuclides with the therapeutic radionuclide ²²⁵Ac, which itself can optimally be complexed by macropa as well. ¹³³La was thus produced by cyclotron-based proton irradiation of an enriched ¹³⁴Ba target. The target (30 mg of [¹³⁴Ba]BaCO₃) was irradiated for 60 min at 22 MeV and 10–15 µA beam current. Irradiation side products in the raw target solution were identified and quantified: ¹³⁵La (0.4%), ^135mBa (0.03%), ^133mBa (0.01%), and ¹³³Ba (0.0004%). The subsequent workup and anion-exchange-based product purification process took approx. 30 min and led to a total amount of (1.2–1.8) GBq (decay-corrected to end of bombardment) of ¹³³La, formulated as [¹³³La]LaCl₃. After the complete decay of ¹³³La, a remainder of ca. 4 kBq of long-lived ¹³³Ba per 100 MBq of ¹³³La was detected and rated as uncritical regarding personal dose and waste management. Subsequent radiolabeling was successfully performed with previously published macropa-derived PSMA inhibitors at a micromolar range (quantitative labeling at 1 µM) and evaluated by radio-TLC and radio-HPLC analyses. The scale-up to radioactivity amounts that are needed for clinical application purposes would be easy to achieve by increasing target mass, beam current, and irradiation time to produce ¹³³La of high radionuclide purity (>99.5%) regarding labeling properties and side products. Full article

(This article belongs to the Special Issue Application of Radiolabeled Agents: Imaging, Therapy, Multimodal Approaches and Beyond)

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Review

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26 pages, 9226 KiB

Open AccessReview

PSMA-Targeted Nanotheranostics for Imaging and Radiotherapy of Prostate Cancer

by Niranjan Meher, Henry F. VanBrocklin, David M. Wilson and Robert R. Flavell

Pharmaceuticals 2023, 16(2), 315; https://doi.org/10.3390/ph16020315 - 17 Feb 2023

Cited by 6 | Viewed by 3029

Abstract

Targeted nanotheranostic systems offer significant benefits due to the integration of diagnostic and therapeutic functionality, promoting personalized medicine. In recent years, prostate-specific membrane antigen (PSMA) has emerged as an ideal theranostic target, fueling multiple new drug approvals and changing the standard of care [...] Read more.

Targeted nanotheranostic systems offer significant benefits due to the integration of diagnostic and therapeutic functionality, promoting personalized medicine. In recent years, prostate-specific membrane antigen (PSMA) has emerged as an ideal theranostic target, fueling multiple new drug approvals and changing the standard of care in prostate cancer (PCa). PSMA-targeted nanosystems such as self-assembled nanoparticles (NPs), liposomal structures, water-soluble polymers, dendrimers, and other macromolecules are under development for PCa theranostics due to their multifunctional sensing and therapeutic capabilities. Herein, we discuss the significance and up-to-date development of “PSMA-targeted nanocarrier systems for radioligand imaging and therapy of PCa”. The review also highlights critical parameters for designing nanostructured radiopharmaceuticals for PCa, including radionuclides and their chelators, PSMA-targeting ligands, and the EPR effect. Finally, prospects and potential for clinical translation is discussed. Full article

(This article belongs to the Special Issue Application of Radiolabeled Agents: Imaging, Therapy, Multimodal Approaches and Beyond)

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