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18 pages, 6001 KiB

Open AccessArticle

“Click-to-Clear”: A Strategy to Minimize Radioactivity from the Blood Pool Utilizing Staudinger Ligation

by Nisarg Soni, Swarbhanu Sarkar, Abhinav Bhise, Yeong Su Ha, Wonchoul Park, A-Ram Yu, Virendra Kumar, Jeong Eun Lim, Young-Ran Yoon and Jeongsoo Yoo

Pharmaceutics 2023, 15(3), 719; https://doi.org/10.3390/pharmaceutics15030719 - 21 Feb 2023

Cited by 2 | Viewed by 2566

Abstract

The availability of several bioorthogonal reactions that can proceed selectively and efficiently under physiologically relevant conditions has garnered the interest of biochemists and organic chemists alike. Bioorthogonal cleavage reactions represent the latest innovation in click chemistry. Here, we employed the Staudinger ligation reaction [...] Read more.

The availability of several bioorthogonal reactions that can proceed selectively and efficiently under physiologically relevant conditions has garnered the interest of biochemists and organic chemists alike. Bioorthogonal cleavage reactions represent the latest innovation in click chemistry. Here, we employed the Staudinger ligation reaction to release radioactivity from immunoconjugates, improving target-to-background ratios. In this proof-of-concept study, model systems, including the anti-HER2 antibody trastuzumab, radioisotope I-131, and a newly synthesized bifunctional phosphine, were used. Staudinger ligation occurred when biocompatible N-glycosyl azides reacted with this radiolabeled immunoconjugate, leading to cleavage of the radioactive label from the molecule. We demonstrated this click cleavage in vitro and in vivo. Biodistribution studies in tumor models showed that radioactivity was eliminated from the bloodstream, thereby improving tumor-to-blood ratios. SPECT imaging revealed that tumors could be visualized with enhanced clarity. Our simple approach represents a novel application of bioorthogonal click chemistry in the development of antibody-based theranostics. Full article

(This article belongs to the Special Issue Advances in the Development and Application of Targeted Radiopharmaceuticals for Cancer Management)

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16 pages, 4676 KiB

Open AccessArticle

A Theranostic Small-Molecule Prodrug Conjugate for Neuroendocrine Prostate Cancer

by Paulina Gonzalez, Sashi Debnath, Yu-An Chen, Elizabeth Hernandez, Preeti Jha, Marianna Dakanali, Jer-Tsong Hsieh and Xiankai Sun

Pharmaceutics 2023, 15(2), 481; https://doi.org/10.3390/pharmaceutics15020481 - 1 Feb 2023

Cited by 8 | Viewed by 3210

Abstract

After androgen deprivation therapy, a significant number of prostate cancer cases progress with a therapy-resistant neuroendocrine phenotype (NEPC). This represents a challenge for diagnosis and treatment. Based on our previously reported design of theranostic small-molecule prodrug conjugates (T-SMPDCs), herein we report a T-SMPDC [...] Read more.

After androgen deprivation therapy, a significant number of prostate cancer cases progress with a therapy-resistant neuroendocrine phenotype (NEPC). This represents a challenge for diagnosis and treatment. Based on our previously reported design of theranostic small-molecule prodrug conjugates (T-SMPDCs), herein we report a T-SMPDC tailored for targeted positron emission tomography (PET) imaging and chemotherapy of NEPC. The T-SMPDC is built upon a triazine core (TZ) to present three functionalities: (1) a chelating moiety (DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) for PET imaging when labeled with ⁶⁸Ga (t_1/2 = 68 min) or other relevant radiometals; (2) an octreotide (Octr) that targets the somatostatin receptor 2 (SSTR2), which is overexpressed in the innervated tumor microenvironment (TME); and (3) fingolimod, FTY720—an antagonist of sphingosine kinase 1 that is an intracellular enzyme upregulated in NEPC. Polyethylene glycol (PEG) chains were incorporated via conventional conjugation methods or a click chemistry reaction forming a 1,4-disubstituted 1,2,3-triazole (Trz) linkage for the optimization of in vivo kinetics as necessary. The T-SMPDC, DOTA-PEG₃-TZ(PEG₄-Octr)-PEG₂-Trz-PEG₃-Val-Cit-pABOC-FTY720 (PEG_n: PEG with n repeating ethyleneoxy units (n = 2, 3, or 4); Val: valine; Cit: citrulline; pABOC: p-amino-benzyloxycarbonyl), showed selective SSTR2 binding and mediated internalization of the molecule in SSTR2 ^high cells. Release of FTY720 was observed when the T-SMPDC was exposed to cathepsin B, and the released FTY720 exerted cytotoxicity in cells. In vivo PET imaging showed significantly higher accumulation (2.1 ± 0.3 %ID/g; p = 0.02) of [⁶⁸Ga]Ga-DOTA-PEG₃-TZ(PEG₄-Octr)-PEG₂-Trz-PEG₃-Val-Cit-pABOC-FTY720 in SSTR2^high prostate cancer xenografts than in the SSTR2^low xenografts (1.5 ± 0.4 %ID/g) at 13 min post-injection (p.i.) with a rapid excretion through the kidneys. Taken together, these proof-of-concept results validate the design concept of the T-SMPDC, which may hold a great potential for targeted diagnosis and therapy of NEPC. Full article

(This article belongs to the Special Issue Advances in the Development and Application of Targeted Radiopharmaceuticals for Cancer Management)

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16 pages, 1798 KiB

Open AccessArticle

The Synthesis and Preclinical Investigation of Lactosamine-Based Radiopharmaceuticals for the Detection of Galectin-3-Expressing Melanoma Cells

by Barbara Gyuricza, Ágnes Szűcs, Judit P. Szabó, Viktória Arató, Zita Képes, Dániel Szücs, Dezső Szikra, György Trencsényi and Anikó Fekete

Pharmaceutics 2022, 14(11), 2504; https://doi.org/10.3390/pharmaceutics14112504 - 18 Nov 2022

Cited by 1 | Viewed by 1864

Abstract

Given that galectin-3 (Gal-3) is a β-galactoside-binding lectin promoting tumor growth and metastatis, it could be a valuable target for the treatment of Gal-3-expressing neoplasms. An aromatic group introduced to the C-3′ position of lactosamine increased its affinity for Gal-3. Herein, we aimed [...] Read more.

Given that galectin-3 (Gal-3) is a β-galactoside-binding lectin promoting tumor growth and metastatis, it could be a valuable target for the treatment of Gal-3-expressing neoplasms. An aromatic group introduced to the C-3′ position of lactosamine increased its affinity for Gal-3. Herein, we aimed at developing a radiopharmaceutical for the detection of Gal-3 positive malignancies. To enhance tumor specificity, a heterodimeric radiotracer capable of binding to both Gal-3 and αvβ3 integrin was also synthetized. Arginine-glycine-asparagine (RGD) peptide is the ligand of angiogenesis- and metastasis-associated αvβ3 integrin. Following the synthesis of the chelator-conjugated (2-naphthyl)methylated lactosamine, the obtained compound was applied as a precursor for radiolabeling and was conjugated to the RGD peptide by click reaction as well. Both synthetized precursors were radiolabeled with ⁶⁸Ga, resulting in high labeling yield (>97). The biological studies were carried out using B16F10 melanoma tumor-bearing C57BL6 mice. High tumor accumulation of both labeled lactosamine derivatives—detected by in vivo PET and ex vivo biodistribution studies—indicated their potential for melanoma detection. However, the heterodimer radiotracer showed high hepatic uptake, while low liver accumulation characterized chelator-conjugated lactosamine, resulting in PET images with excellent contrast. Therefore, this novel carbohydrate-based radiotracer is suitable for the highly selective determination of Gal-3-expressing melanoma cells. Full article

(This article belongs to the Special Issue Advances in the Development and Application of Targeted Radiopharmaceuticals for Cancer Management)

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16 pages, 3238 KiB

Open AccessArticle

Toward Optimized ⁸⁹Zr-Immuno-PET: Side-by-Side Comparison of [⁸⁹Zr]Zr-DFO-, [⁸⁹Zr]Zr-3,4,3-(LI-1,2-HOPO)- and [⁸⁹Zr]Zr-DFO*-Cetuximab for Tumor Imaging: Which Chelator Is the Most Suitable?

by Helen Damerow, Xia Cheng, Valeska von Kiedrowski, Ralf Schirrmacher, Björn Wängler, Gert Fricker and Carmen Wängler

Pharmaceutics 2022, 14(10), 2114; https://doi.org/10.3390/pharmaceutics14102114 - 4 Oct 2022

Cited by 9 | Viewed by 2373

Abstract

⁸⁹Zr represents a highly favorable positron emitter for application in immuno-PET (Positron Emission Tomography) imaging. Clinically, the ⁸⁹Zr⁴⁺ ion is introduced into antibodies by complexation with desferrioxamine B. However, producing complexes of limited kinetic inertness. Therefore, several new chelators for [...] Read more.

⁸⁹Zr represents a highly favorable positron emitter for application in immuno-PET (Positron Emission Tomography) imaging. Clinically, the ⁸⁹Zr⁴⁺ ion is introduced into antibodies by complexation with desferrioxamine B. However, producing complexes of limited kinetic inertness. Therefore, several new chelators for ⁸⁹Zr introduction have been developed over the last years. Of these, the direct comparison of the most relevant ones for clinical translation, DFO* and 3,4,3-(LI-1,2-HOPO), is still missing. Thus, we directly compared DFO with DFO* and 3,4,3-(LI-1,2-HOPO) immunoconjugates to identify the most suitable agent stable ⁸⁹Zr-complexation. The chelators were introduced into cetuximab, and an optical analysis method was developed, enabling the efficient quantification of derivatization sites per protein. The cetuximab conjugates were efficiently obtained and radiolabeled with ⁸⁹Zr at 37 °C within 30 min, giving the [⁸⁹Zr]Zr-cetuximab derivatives in high radiochemical yields and purities of >99% as well as specific activities of 50 MBq/mg. The immunoreactive fraction of all ⁸⁹Zr-labeled cetuximab derivatives was determined to be in the range of 86.5–88.1%. In vivo PET imaging and ex vivo biodistribution studies in tumor-bearing animals revealed a comparable and significantly higher kinetic inertness for both [⁸⁹Zr]Zr-3,4,3-(LI-1,2-HOPO)-cetuximab and [⁸⁹Zr]Zr-DFO*-cetuximab, compared to [⁸⁹Zr]Zr-DFO-cetuximab. Of these, [⁸⁹Zr]Zr-DFO*-cetuximab showed a considerably more favorable pharmacokinetic profile with significantly lower liver and spleen retention than [⁸⁹Zr]Zr-3,4,3-(LI-1,2-HOPO)-cetuximab. Since [⁸⁹Zr]Zr-DFO* demonstrates a very high kinetic inertness, paired with a highly favorable pharmacokinetic profile of the resulting antibody conjugate, DFO* currently represents the most suitable chelator candidate for stable ⁸⁹Zr-radiolabeling of antibodies and clinical translation. Full article

(This article belongs to the Special Issue Advances in the Development and Application of Targeted Radiopharmaceuticals for Cancer Management)

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18 pages, 11329 KiB

Open AccessArticle

Towards Complete Tumor Resection: Novel Dual-Modality Probes for Improved Image-Guided Surgery of GRPR-Expressing Prostate Cancer

by Maryana Handula, Marjolein Verhoeven, Kuo-Ting Chen, Joost Haeck, Marion de Jong, Simone U. Dalm and Yann Seimbille

Pharmaceutics 2022, 14(1), 195; https://doi.org/10.3390/pharmaceutics14010195 - 14 Jan 2022

Cited by 7 | Viewed by 2816

Abstract

Nuclear and optical dual-modality probes can be of great assistance in prostate cancer localization, providing the means for both preoperative nuclear imaging and intraoperative surgical guidance. We developed a series of probes based on the backbone of the established GRPR-targeting radiotracer NeoB. The [...] Read more.

Nuclear and optical dual-modality probes can be of great assistance in prostate cancer localization, providing the means for both preoperative nuclear imaging and intraoperative surgical guidance. We developed a series of probes based on the backbone of the established GRPR-targeting radiotracer NeoB. The inverse electron demand of the Diels–Alder reaction was used to integrate the sulfo-cyanine 5 dye. Indium-111 radiolabeling, stability studies and a competition binding assay were carried out. Pilot biodistribution and imaging studies were performed in PC-3 tumor-bearing mice, using the best two dual-labeled probes. The dual-modality probes were radiolabeled with a high yield (>92%), were proven to be hydrophilic and demonstrated high stability in mouse serum (>94% intact labeled ligand at 4 h). The binding affinity for the GRPR was in the nanomolar range (21.9–118.7 nM). SPECT/CT images at 2 h p.i. clearly visualized the tumor xenograft and biodistribution studies, after scanning confirmed the high tumor uptake (8.47 ± 0.46%ID/g and 6.90 ± 0.81%ID/g for probe [¹¹¹In]In-12 and [¹¹¹In]In-15, respectively). Receptor specificity was illustrated with blocking studies, and co-localization of the radioactive and fluorescent signal was verified by ex vivo fluorescent imaging. Although optimal tumor-to-blood and tumor-to-kidney ratios might not yet have been reached due to the prolonged blood circulation, our probes are promising candidates for the preoperative and intraoperative visualization of GRPR-positive prostate cancer. Full article

(This article belongs to the Special Issue Advances in the Development and Application of Targeted Radiopharmaceuticals for Cancer Management)

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14 pages, 6254 KiB

Open AccessArticle

The Effect of VPA Treatment on Radiolabeled DOTATATE Uptake: Differences Observed In Vitro and In Vivo

by Maria J. Klomp, Leo J. Hofland, Lilian van den Brink, Peter M. van Koetsveld, Fadime Dogan, Corrina M. A. de Ridder, Debra C. Stuurman, Marian C. Clahsen-van Groningen, Marion de Jong and Simone U. Dalm

Pharmaceutics 2022, 14(1), 173; https://doi.org/10.3390/pharmaceutics14010173 - 12 Jan 2022

Cited by 4 | Viewed by 1966

Abstract

Background: To improve peptide receptor radionuclide therapy (PRRT), we aimed to enhance the expression of somatostatin type-2 receptors (SSTR2) in vitro and in vivo, using valproic acid (VPA). Methods: Human NCI-H69 small-cell lung carcinoma cells were treated with VPA, followed by [¹¹¹ [...] Read more.

Background: To improve peptide receptor radionuclide therapy (PRRT), we aimed to enhance the expression of somatostatin type-2 receptors (SSTR2) in vitro and in vivo, using valproic acid (VPA). Methods: Human NCI-H69 small-cell lung carcinoma cells were treated with VPA, followed by [¹¹¹In]In-DOTATATE uptake studies, RT-qPCR and immunohistochemistry analysis. Furthermore, NCI-H69 xenografted mice were treated with VPA or vehicle, followed by [¹⁷⁷Lu]Lu-DOTATATE injection. Biodistribution studies were performed, and tissues were collected for further analysis. Results: VPA significantly increased SSTR2 expression in vitro. In animals, a statistically significant increased [¹⁷⁷Lu]Lu-DOTATATE tumoral uptake was observed when VPA was administered eight hours before [¹⁷⁷Lu]Lu-DOTATATE administration, but increased tumor SSTR2 expression levels were lacking. The animals also presented significantly higher [¹⁷⁷Lu]Lu-DOTATATE blood levels, as well as an elevated renal tubular damage score. This suggests that the enhanced tumor uptake was presumably a consequence of the increased radiotracer circulation and the induced kidney damage. Conclusions: VPA increases SSTR2 expression in vitro. In vivo, the observed increase in tumoral [¹⁷⁷Lu]Lu-DOTATATE uptake is not caused by SSTR2 upregulation, but rather by other mechanisms, e.g., an increased [¹⁷⁷Lu]Lu-DOTATATE circulation time and renal toxicity. However, since both drugs are safely used in humans, the potential of VPA to improve PRRT remains open for investigation. Full article

(This article belongs to the Special Issue Advances in the Development and Application of Targeted Radiopharmaceuticals for Cancer Management)

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8 pages, 1698 KiB

Open AccessArticle

Therapeutic Response of CCKBR-Positive Tumors to Combinatory Treatment with Everolimus and the Radiolabeled Minigastrin Analogue [¹⁷⁷Lu]Lu-PP-F11N

by Michal Grzmil, Stefan Imobersteg, Alain Blanc, Stephan Frank, Roger Schibli and Martin P. Béhé

Pharmaceutics 2021, 13(12), 2156; https://doi.org/10.3390/pharmaceutics13122156 - 15 Dec 2021

Cited by 5 | Viewed by 3548

Abstract

The inhibition of the mammalian target of rapamycin complex 1 (mTORC1) by everolimus (RAD001) was recently shown to enhance the tumor uptake of radiolabeled minigastrin. In this paper, we investigate if this finding can improve the in vivo therapeutic response to [¹⁷⁷ [...] Read more.

The inhibition of the mammalian target of rapamycin complex 1 (mTORC1) by everolimus (RAD001) was recently shown to enhance the tumor uptake of radiolabeled minigastrin. In this paper, we investigate if this finding can improve the in vivo therapeutic response to [¹⁷⁷Lu]Lu-PP-F11N treatment. The N-terminal DOTA-conjugated gastrin analogue PP-F11N (DOTA-(DGlu)₆-Ala-Tyr-Gly-Trp-Nle-Asp-Phe) was used to evaluate treatment efficacy in the human A431/CCKBR xenograft nude mouse model in combination with RAD001. Both RAD001 and [¹⁷⁷Lu]Lu-PP-F11N single treatments as well as their combination inhibited tumor growth and increased survival. In concomitantly treated mice, the average tumor size and median survival time were significantly reduced and extended, respectively, as compared to the monotherapies. The histological analysis of kidney and stomach dissected after treatment with RAD001 and [¹⁷⁷Lu]Lu-PP-F11N did not indicate significant adverse effects. In conclusion, our study data demonstrate the potential of mTORC1 inhibition to substantially improve the therapeutic efficacy of radiolabeled minigastrin analogues in CCKBR-positive cancers. Full article

(This article belongs to the Special Issue Advances in the Development and Application of Targeted Radiopharmaceuticals for Cancer Management)

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14 pages, 2062 KiB

Open AccessArticle

⁶⁸Ga-Radiolabeling and Pharmacological Characterization of a Kit-Based Formulation of the Gastrin-Releasing Peptide Receptor (GRP-R) Antagonist RM2 for Convenient Preparation of [⁶⁸Ga]Ga-RM2

by Adrien Chastel, Delphine Vimont, Stephane Claverol, Marion Zerna, Sacha Bodin, Mathias Berndt, Stéphane Chaignepain, Elif Hindié and Clément Morgat

Pharmaceutics 2021, 13(8), 1160; https://doi.org/10.3390/pharmaceutics13081160 - 28 Jul 2021

Cited by 10 | Viewed by 2856

Abstract

Background: [⁶⁸Ga]Ga-RM2 is a potent Gastrin-Releasing Peptide-receptor (GRP-R) antagonist for imaging prostate cancer and breast cancer, currently under clinical evaluation in several specialized centers around the world. Targeted radionuclide therapy of GRP-R-expressing tumors is also being investigated. We here report the [...] Read more.

Background: [⁶⁸Ga]Ga-RM2 is a potent Gastrin-Releasing Peptide-receptor (GRP-R) antagonist for imaging prostate cancer and breast cancer, currently under clinical evaluation in several specialized centers around the world. Targeted radionuclide therapy of GRP-R-expressing tumors is also being investigated. We here report the characteristics of a kit-based formulation of RM2 that should ease the development of GRP-R imaging and make it available to more institutions and patients. Methods: Stability of the investigated kits over one year was determined using LC/MS/MS and UV-HPLC. Direct ⁶⁸Ga-radiolabeling was optimized with respect to buffer (pH), temperature, reaction time and shaking time. Conventionally prepared [⁶⁸Ga]Ga-RM2 using an automated synthesizer was used as a comparator. Finally, the [⁶⁸Ga]Ga-RM2 product was assessed with regards to hydrophilicity, affinity, internalization, membrane bound fraction, calcium mobilization assay and efflux, which is a valuable addition to the in vivo literature. Results: The kit-based formulation, kept between 2 °C and 8 °C, was stable for over one year. Using acetate buffer pH 3.0 in 2.5–5.1 mL total volume, heating at 100 °C during 10 min and cooling down for 5 min, the [⁶⁸Ga]Ga-RM2 produced by kit complies with the requirements of the European Pharmacopoeia. Compared with the module production route, the [⁶⁸Ga]Ga-RM2 produced by kit was faster, displayed higher yields, higher volumetric activity and was devoid of ethanol. In in vitro evaluations, the [⁶⁸Ga]Ga-RM2 displayed sub-nanomolar affinity (K_d = 0.25 ± 0.19 nM), receptor specific and time dependent membrane-bound fraction of 42.0 ± 5.1% at 60 min and GRP-R mediated internalization of 24.4 ± 4.3% at 30 min. The [^natGa]Ga-RM2 was ineffective in stimulating intracellular calcium mobilization. Finally, the efflux of the internalized activity was 64.3 ± 6.5% at 5 min. Conclusion: The kit-based formulation of RM2 is suitable to disseminate GRP-R imaging and therapy to distant hospitals without complex radiochemistry equipment. Full article

(This article belongs to the Special Issue Advances in the Development and Application of Targeted Radiopharmaceuticals for Cancer Management)

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18 pages, 3083 KiB

Open AccessArticle

The Use of a Non-Conventional Long-Lived Gallium Radioisotope ⁶⁶Ga Improves Imaging Contrast of EGFR Expression in Malignant Tumours Using DFO-ZEGFR:2377 Affibody Molecule

by Maryam Oroujeni, Tianqi Xu, Katherine Gagnon, Sara S. Rinne, Jan Weis, Javad Garousi, Ken G. Andersson, John Löfblom, Anna Orlova and Vladimir Tolmachev

Pharmaceutics 2021, 13(2), 292; https://doi.org/10.3390/pharmaceutics13020292 - 23 Feb 2021

Cited by 11 | Viewed by 4327

Abstract

Epidermal growth factor receptor (EGFR) is overexpressed in many malignancies. EGFR-targeted therapy extends survival of patients with disseminated cancers. Radionuclide molecular imaging of EGFR expression would make EGFR-directed treatment more personalized and therefore more efficient. A previous study demonstrated that affibody molecule [ [...] Read more.

Epidermal growth factor receptor (EGFR) is overexpressed in many malignancies. EGFR-targeted therapy extends survival of patients with disseminated cancers. Radionuclide molecular imaging of EGFR expression would make EGFR-directed treatment more personalized and therefore more efficient. A previous study demonstrated that affibody molecule [⁶⁸Ga]Ga-DFO-ZEGFR:2377 permits specific positron-emission tomography (PET) imaging of EGFR expression in xenografts at 3 h after injection. We anticipated that imaging at 24 h after injection would provide higher contrast, but this is prevented by the short half-life of ⁶⁸Ga (67.6 min). Here, we therefore tested the hypothesis that the use of the non-conventional long-lived positron emitter ⁶⁶Ga (T_1/2 = 9.49 h, β⁺ = 56.5%) would permit imaging with higher contrast. ⁶⁶Ga was produced by the ⁶⁶Zn(p,n)⁶⁶Ga nuclear reaction and DFO-ZEGFR:2377 was efficiently labelled with ⁶⁶Ga with preserved binding specificity in vitro and in vivo. At 24 h after injection, [⁶⁶Ga]Ga-DFO-ZEGFR:2377 provided 3.9-fold higher tumor-to-blood ratio and 2.3-fold higher tumor-to-liver ratio than [⁶⁸Ga]Ga-DFO-ZEGFR:2377 at 3 h after injection. At the same time point, [⁶⁶Ga]Ga-DFO-ZEGFR:2377 provided 1.8-fold higher tumor-to-blood ratio, 3-fold higher tumor-to-liver ratio, 1.9-fold higher tumor-to-muscle ratio and 2.3-fold higher tumor-to-bone ratio than [⁸⁹Zr]Zr-DFO-ZEGFR:2377. Biodistribution data were confirmed by whole body PET combined with magnetic resonance imaging (PET/MRI). The use of the positron emitter ⁶⁶Ga for labelling of DFO-ZEGFR:2377 permits PET imaging of EGFR expression at 24 h after injection and improves imaging contrast. Full article

(This article belongs to the Special Issue Advances in the Development and Application of Targeted Radiopharmaceuticals for Cancer Management)

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14 pages, 3171 KiB

Open AccessArticle

Preclinical Evaluation of ^99mTc-Labeled GRPR Antagonists maSSS/SES-PEG₂-RM26 for Imaging of Prostate Cancer

by Ayman Abouzayed, Sara S. Rinne, Hamideh Sabahnoo, Jens Sörensen, Vladimir Chernov, Vladimir Tolmachev and Anna Orlova

Pharmaceutics 2021, 13(2), 182; https://doi.org/10.3390/pharmaceutics13020182 - 30 Jan 2021

Cited by 10 | Viewed by 3655

Abstract

Background: Gastrin-releasing peptide receptor (GRPR) is an important target for imaging of prostate cancer. The wide availability of single-photon emission computed tomography/computed tomography (SPECT/CT) and the generator-produced ^99mTc can be utilized to facilitate the use of GRPR-targeting radiotracers for diagnostics of prostate [...] Read more.

Background: Gastrin-releasing peptide receptor (GRPR) is an important target for imaging of prostate cancer. The wide availability of single-photon emission computed tomography/computed tomography (SPECT/CT) and the generator-produced ^99mTc can be utilized to facilitate the use of GRPR-targeting radiotracers for diagnostics of prostate cancers. Methods: Synthetically produced mercaptoacetyl-Ser-Ser-Ser (maSSS)-PEG₂-RM26 and mercaptoacetyl-Ser-Glu-Ser (maSES)-PEG₂-RM26 (RM26 = d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH₂) were radiolabeled with ^99mTc and characterized in vitro using PC-3 cells and in vivo, using NMRI or PC-3 tumor bearing mice. SPECT/CT imaging and dosimetry calculations were performed for [^99mTc]Tc-maSSS-PEG₂-RM26. Results: Peptides were radiolabeled with high yields (>98%), demonstrating GRPR specific binding and slow internalization in PC-3 cells. [^99mTc]Tc-maSSS-PEG₂-RM26 outperformed [^99mTc]Tc-maSES-PEG_2-RM26 in terms of GRPR affinity, with a lower dissociation constant (61 pM vs 849 pM) and demonstrating higher tumor uptake. [^99mTc]Tc-maSSS-PEG₂-RM26 had tumor-to-blood, tumor-to-muscle, and tumor-to-bone ratios of 97 ± 56, 188 ± 32, and 177 ± 79, respectively. SPECT/CT images of [^99mTc]Tc-maSSS-PEG₂-RM26 clearly visualized the GRPR-overexpressing tumors. The dosimetry estimated for [^99mTc]Tc-maSSS-PEG₂-RM26 showed the highest absorbed dose in the small intestine (1.65 × 10⁻³ mGy/MBq), and the effective dose is 3.49 × 10⁻³ mSv/MBq. Conclusion: The GRPR antagonist maSSS-PEG₂-RM26 is a promising GRPR-targeting agent that can be radiolabeled through a single-step with the generator-produced ^99mTc and used for imaging of GRPR-expressing prostate cancer. Full article

(This article belongs to the Special Issue Advances in the Development and Application of Targeted Radiopharmaceuticals for Cancer Management)

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Review

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18 pages, 1184 KiB

Open AccessReview

¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) Functionalized Gold Nanoparticles (GNPs) for Plasmonic Photothermal Ablation of Cancer: A Review

by Mariano Pontico, Miriam Conte, Francesca Petronella, Viviana Frantellizzi, Maria Silvia De Feo, Dario Di Luzio, Roberto Pani, Giuseppe De Vincentis and Luciano De Sio

Pharmaceutics 2023, 15(2), 319; https://doi.org/10.3390/pharmaceutics15020319 - 18 Jan 2023

Cited by 6 | Viewed by 2172

Abstract

The meeting and merging between innovative nanotechnological systems, such as nanoparticles, and the persistent need to outperform diagnostic-therapeutic approaches to fighting cancer are revolutionizing the medical research scenario, leading us into the world of nanomedicine. Photothermal therapy (PTT) is a non-invasive thermo-ablative treatment [...] Read more.

The meeting and merging between innovative nanotechnological systems, such as nanoparticles, and the persistent need to outperform diagnostic-therapeutic approaches to fighting cancer are revolutionizing the medical research scenario, leading us into the world of nanomedicine. Photothermal therapy (PTT) is a non-invasive thermo-ablative treatment in which cellular hyperthermia is generated through the interaction of near-infrared light with light-to-heat converter entities, such as gold nanoparticles (GNPs). GNPs have great potential to improve recovery time, cure complexity, and time spent on the treatment of specific types of cancer. The development of gold nanostructures for photothermal efficacy and target selectivity ensures effective and deep tissue-penetrating PTT with fewer worries about adverse effects from nonspecific distributions. Regardless of the thriving research recorded in the last decade regarding the multiple biomedical applications of nanoparticles and, in particular, their conjugation with drugs, few works have been completed regarding the possibility of combining GNPs with the cancer-targeted pharmaceutical fluorodeoxyglucose (FDG). This review aims to provide an actual scenario on the application of functionalized GNP-mediated PTT for cancer ablation purposes, regarding the opportunity given by the ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) functionalization. Full article

(This article belongs to the Special Issue Advances in the Development and Application of Targeted Radiopharmaceuticals for Cancer Management)

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17 pages, 662 KiB

Open AccessReview

Advances in ¹⁷⁷Lu-PSMA and ²²⁵Ac-PSMA Radionuclide Therapy for Metastatic Castration-Resistant Prostate Cancer

by Sui Wai Ling, Erik de Blois, Eline Hooijman, Astrid van der Veldt and Tessa Brabander

Pharmaceutics 2022, 14(10), 2166; https://doi.org/10.3390/pharmaceutics14102166 - 11 Oct 2022

Cited by 32 | Viewed by 3964

Abstract

For patients with metastatic castration-resistant prostate cancer (mCRPC), the survival benefit of classic treatment options with chemotherapy and drugs targeting androgen signaling is limited. Therefore, beta and alpha radionuclide therapy (RNT) have emerged as novel treatment options for patients with mCRPC. Radioligands target [...] Read more.

For patients with metastatic castration-resistant prostate cancer (mCRPC), the survival benefit of classic treatment options with chemotherapy and drugs targeting androgen signaling is limited. Therefore, beta and alpha radionuclide therapy (RNT) have emerged as novel treatment options for patients with mCRPC. Radioligands target the prostate-specific membrane antigen (PSMA) epitopes, which are upregulated up to a thousand times more in prostate cancer cells compared to the cells in normal tissues. For this reason, PSMA is an excellent target for both imaging and therapy. Over the past years, many studies have investigated the treatment effects of lutetium-177 labeled PSMA (¹⁷⁷Lu-PSMA) and actinium-225 labeled PSMA (²²⁵Ac-PSMA) RNT in patients with mCRPC. While promising results have been achieved, this field is still in development. In this review, we have summarized and discussed the clinical data of ¹⁷⁷Lu-PSMA and ²²⁵Ac-PSMA RNT in patients with mCRPC. Full article

(This article belongs to the Special Issue Advances in the Development and Application of Targeted Radiopharmaceuticals for Cancer Management)

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