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Open AccessCommunication

Short-Interval, Low-Dose Peptide Receptor Radionuclide Therapy in Combination with PD-1 Checkpoint Immunotherapy Induces Remission in Immunocompromised Patients with Metastatic Merkel Cell Carcinoma

by Alexandra Aicher, Anca Sindrilaru, Diana Crisan, Wolfgang Thaiss, Jochen Steinacker, Meinrad Beer, Thomas Wiegel, Karin Scharffetter-Kochanek, Ambros J. Beer and Vikas Prasad

Pharmaceutics 2022, 14(7), 1466; https://doi.org/10.3390/pharmaceutics14071466 - 14 Jul 2022

Cited by 10 | Viewed by 2639

Abstract

Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer of the elderly, with high metastatic potential and poor prognosis. In particular, the primary resistance to immune checkpoint inhibitors (ICI) in metastatic (m)MCC patients represents a challenge not yet met by any efficient treatment [...] Read more.

Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer of the elderly, with high metastatic potential and poor prognosis. In particular, the primary resistance to immune checkpoint inhibitors (ICI) in metastatic (m)MCC patients represents a challenge not yet met by any efficient treatment modality. Herein, we describe a novel therapeutic concept with short-interval, low-dose ¹⁷⁷Lutetium (Lu)-high affinity (HA)-DOTATATE [¹⁷⁷Lu]Lu-HA-DOTATATE peptide receptor radionuclide therapy (SILD-PRRT) in combination with PD-1 ICI to induce remission in patients with ICI-resistant mMCC. We report on the initial refractory response of two immunocompromised mMCC patients to the PD-L1 inhibitor avelumab. After confirming the expression of somatostatin receptors (SSTR) on tumor cells by [⁶⁸Ga]Ga-HA-DOTATATE-PET/CT (PET/CT), we employed low-dose PRRT (up to six treatments, mean activity 3.5 GBq per cycle) at 3–6 weeks intervals in combination with the PD-1 inhibitor pembrolizumab to restore responsiveness to ICI. This combination enabled the synergistic application of PD-1 checkpoint immunotherapy with low-dose PRRT at more frequent intervals, and was very well tolerated by both patients. PET/CTs demonstrated remarkable responses at all metastatic sites (lymph nodes, distant skin, and bones), which were maintained for 3.6 and 4.8 months, respectively. Both patients eventually succumbed with progressive disease after 7.7 and 8 months, respectively, from the start of treatment with SILD-PRRT and pembrolizumab. We demonstrate that SILD-PRRT in combination with pembrolizumab is safe and well-tolerated, even in elderly, immunocompromised mMCC patients. The restoration of clinical responses in ICI-refractory patients as proposed here could potentially be used not only for patients with mMCC, but many other cancer types currently treated with PD-1/PD-L1 inhibitors. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy)

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15 pages, 2482 KiB

Open AccessArticle

Comparison of Choi, RECIST and Somatostatin Receptor PET/CT Based Criteria for the Evaluation of Response and Response Prediction to PRRT

by Kevin Zwirtz, Juliane Hardt, Güliz Acker, Alexander D. J. Baur, Marianne Pavel, Kai Huang, Winfried Brenner and Vikas Prasad

Pharmaceutics 2022, 14(6), 1278; https://doi.org/10.3390/pharmaceutics14061278 - 16 Jun 2022

Cited by 13 | Viewed by 3064

Abstract

Aim: The most suitable method for assessment of response to peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NET) is still under debate. In this study we aimed to compare size (RECIST 1.1), density (Choi), Standardized Uptake Value (SUV) and a newly defined [...] Read more.

Aim: The most suitable method for assessment of response to peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NET) is still under debate. In this study we aimed to compare size (RECIST 1.1), density (Choi), Standardized Uptake Value (SUV) and a newly defined ZP combined parameter derived from Somatostatin Receptor (SSR) PET/CT for prediction of both response to PRRT and overall survival (OS). Material and Methods: Thirty-four NET patients with progressive disease (F:M 23:11; mean age 61.2 y; SD ± 12) treated with PRRT using either Lu-177 DOTATOC or Lu-177 DOTATATE and imaged with Ga-68 SSR PET/CT approximately 10–12 weeks prior to and after each treatment cycle were retrospectively analyzed. Median duration of follow-up after the first cycle was 63.9 months (range 6.2–86.2). A total of 77 lesions (2–8 per patient) were analyzed. Response assessment was performed according to RECIST 1.1, Choi and modified EORTC (MORE) criteria. In addition, a new parameter named ZP, the product of Hounsfield unit (HU) and SUVmean (Standard Uptake Value) of a tumor lesion, was tested. Further, SUV values (max and mean) of the tumor were normalized to SUV of normal liver parenchyma. Tumor response was defined as CR, PR, or SD. Gold standard for comparison of baseline parameters for prediction of response of individual target lesions to PRRT was change in size of lesions according to RECIST 1.1. For prediction of overall survival, the response after the first and second PRRT were tested. Results: Based on RECIST 1.1, Choi, MORE, and ZP, 85.3%, 64.7%, 61.8%, and 70.6% achieved a response whereas 14.7%, 35.3%, 38.2%, and 29.4% demonstrated PD (progressive disease), respectively. Baseline ZP and ZPnormalized were found to be the only parameters predictive of lesion progression after three PRRT cycles (AUC ZP 0.753; 95% CI 0.6–0.9, p 0.037; AUC ZPnormalized 0.766; 95% CI 0.6–0.9; p 0.029). Based on a cut-off-value of 1201, ZP achieved a sensitivity of 86% and a specificity of 67%, while ZPnormalized reached a sensitivity of 86% and a specificity of 76% at a cut-off-value of 198. Median OS in the total cohort was not reached. In univariate analysis amongst all parameters, only patients having progressive disease according to MORE after the second cycle of PRRT were found to have significantly shorter overall survival (median OS in objective responders not reached, in PD 29.2 months; p 0.015). Patients progressive after two cycles of PRRT according to ZP had shorter OS compared to those responding (median OS for responders not reached, for PD 47.2 months, p 0.066). Conclusions: In this explorative study, we showed that Choi, RECIST 1.1, and SUVmax-based response evaluation varied significantly from each other. Only patients showing progressive disease after two PRRT cycles according to MORE criteria had a worse prognosis while baseline ZP and ZPnormalized performed best in predicting lesion progression after three cycles of PRRT. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy)

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15 pages, 2617 KiB

Open AccessArticle

Evaluation of Aminopolycarboxylate Chelators for Whole-Body Clearance of Free ²²⁵Ac: A Feasibility Study to Reduce Unexpected Radiation Exposure during Targeted Alpha Therapy

by Mitsuyoshi Yoshimoto, Yukie Yoshii, Hiroki Matsumoto, Mitsuhiro Shinada, Masashi Takahashi, Chika Igarashi, Fukiko Hihara, Tomoko Tachibana, Ayano Doi, Tatsuya Higashi, Hirofumi Fujii and Kohshin Washiyama

Pharmaceutics 2021, 13(10), 1706; https://doi.org/10.3390/pharmaceutics13101706 - 16 Oct 2021

Cited by 8 | Viewed by 2994

Abstract

Actinium-225 (²²⁵Ac) is a promising radionuclide used in targeted alpha therapy (TAT). Although ²²⁵Ac labeling of bifunctional chelating ligands is effective, previous in vivo studies reported that free ²²⁵Ac can be released from the drugs and that such free [...] Read more.

Actinium-225 (²²⁵Ac) is a promising radionuclide used in targeted alpha therapy (TAT). Although ²²⁵Ac labeling of bifunctional chelating ligands is effective, previous in vivo studies reported that free ²²⁵Ac can be released from the drugs and that such free ²²⁵Ac is predominantly accumulated in the liver and could cause unexpected toxicity. To accelerate the clinical development of ²²⁵Ac TAT with a variety of drugs, preparing methods to deal with any unexpected toxicity would be valuable. The aim of this study was to evaluate the feasibility of various chelators for reducing and excreting free ²²⁵Ac and compare their chemical structures. Nine candidate chelators (D-penicillamine, dimercaprol, Ca-DTPA, Ca-EDTA, CyDTA, GEDTA TTHA, Ca-TTHA, and DO3A) were evaluated in vitro and in vivo. The biodistribution and dosimetry of free ²²⁵Ac were examined in mice before an in vivo chelating study. The liver exhibited pronounced ²²⁵Ac uptake, with an estimated human absorbed dose of 4.76 Sv_RBE5/MBq. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, significantly reduced ²²⁵Ac retention in the liver (22% and 30%, respectively). Significant ²²⁵Ac reductions were observed in the heart and remainder of the body with both Ca-DTPA and Ca-TTHA, and in the lung, kidney, and spleen with Ca-TTHA. In vitro interaction analysis supported the in vivo reduction ability of Ca-DTPA and Ca-TTHA. In conclusion, aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, were effective for whole-body clearance of free ²²⁵Ac. This feasibility study provides useful information for reducing undesirable radiation exposure from free ²²⁵Ac. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy)

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16 pages, 3008 KiB

Open AccessArticle

Development of a Compartmental Pharmacokinetic Model for Molecular Radiotherapy with ¹³¹I-CLR1404

by Sara Neira, Araceli Gago-Arias, Isabel Gónzalez-Crespo, Jacobo Guiu-Souto and Juan Pardo-Montero

Pharmaceutics 2021, 13(9), 1497; https://doi.org/10.3390/pharmaceutics13091497 - 17 Sep 2021

Viewed by 3137

Abstract

Pharmacokinetic modeling of the radiopharmaceuticals used in molecular radiotherapy is an important step towards accurate radiation dosimetry of such therapies. In this paper, we present a pharmacokinetic model for CLR1404, a phospholipid ether analog that, labeled with ¹²⁴I/¹³¹I, has emerged [...] Read more.

Pharmacokinetic modeling of the radiopharmaceuticals used in molecular radiotherapy is an important step towards accurate radiation dosimetry of such therapies. In this paper, we present a pharmacokinetic model for CLR1404, a phospholipid ether analog that, labeled with ¹²⁴I/¹³¹I, has emerged as a promising theranostic agent. We follow a systematic approach for the model construction based on a decoupling process applied to previously published experimental data, and using the goodness-of-fit, Sobol’s sensitivity analysis, and the Akaike Information Criterion to construct the optimal form of the model, investigate potential simplifications, and study factor prioritization. This methodology was applied to previously published experimental human time-activity curves for 9 organs. The resulting model consists of 17 compartments involved in the CLR1404 metabolism. Activity dynamics in most tissues are well described by a blood contribution plus a two-compartment system, describing fast and slow uptakes. The model can fit both clinical and pre-clinical kinetic data of ¹²⁴I/¹³¹I. In addition, we have investigated how simple fits (exponential and biexponential) differ from the complete model. Such fits, despite providing a less accurate description of time-activity curves, may be a viable alternative when limited data is available in a practical case. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy)

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21 pages, 5915 KiB

Open AccessArticle

Targeted Radionuclide Therapy Using Auger Electron Emitters: The Quest for the Right Vector and the Right Radionuclide

by Malick Bio Idrissou, Alexandre Pichard, Bryan Tee, Tibor Kibedi, Sophie Poty and Jean-Pierre Pouget

Pharmaceutics 2021, 13(7), 980; https://doi.org/10.3390/pharmaceutics13070980 - 29 Jun 2021

Cited by 19 | Viewed by 4163

Abstract

Auger electron emitters (AEEs) are attractive tools in targeted radionuclide therapy to specifically irradiate tumour cells while sparing healthy tissues. However, because of their short range, AEEs need to be brought close to sensitive targets, particularly nuclear DNA, and to a lower extent, [...] Read more.

Auger electron emitters (AEEs) are attractive tools in targeted radionuclide therapy to specifically irradiate tumour cells while sparing healthy tissues. However, because of their short range, AEEs need to be brought close to sensitive targets, particularly nuclear DNA, and to a lower extent, cell membrane. Therefore, radioimmunoconjugates (RIC) have been developed for specific tumour cell targeting and transportation to the nucleus. Herein, we assessed, in A-431_CEA-luc and SK-OV-3_1B9 cancer cells that express low and high levels of HER2 receptors, two ¹¹¹In-RIC consisting of the anti-HER2 antibody trastuzumab conjugated to NLS or TAT peptides for nuclear delivery. We found that NLS and TAT peptides improved the nuclear uptake of ¹¹¹In-trastuzumab conjugates, but this effect was limited and non-specific. Moreover, it did not result in a drastic decrease of clonogenic survival. Indium-111 also contributed to non-specific cytotoxicity in vitro due to conversion electrons (30% of the cell killing). Comparison with [¹²⁵I]I-UdR showed that the energy released in the cell nucleus by increasing the RIC’s nuclear uptake or by choosing an AEE that releases more energy per decay should be 5 to 10 times higher to observe a significant therapeutic effect. Therefore, new Auger-based radiopharmaceuticals need to be developed. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy)

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16 pages, 3697 KiB

Open AccessArticle

Radioimmunotheranostic Pair Based on the Anti-HER2 Monoclonal Antibody: Influence of Chelating Agents and Radionuclides on Biological Properties

by Ana Cláudia Camargo Miranda, Sofia Nascimento dos Santos, Leonardo Lima Fuscaldi, Luiza Mascarenhas Balieiro, Maria Helena Bellini, Maria Inês Calil Cury Guimarães and Elaine Bortoleti de Araújo

Pharmaceutics 2021, 13(7), 971; https://doi.org/10.3390/pharmaceutics13070971 - 27 Jun 2021

Cited by 6 | Viewed by 3269

Abstract

The oncogene HER2 is an important molecular target in oncology because it is associated with aggressive disease and the worst prognosis. The development of non-invasive imaging techniques and target therapies using monoclonal antibodies is a rapidly developing field. Thus, this work proposes the [...] Read more.

The oncogene HER2 is an important molecular target in oncology because it is associated with aggressive disease and the worst prognosis. The development of non-invasive imaging techniques and target therapies using monoclonal antibodies is a rapidly developing field. Thus, this work proposes the study of the radioimmunotheranostic pair, [¹¹¹In]In-DTPA-trastuzumab and [¹⁷⁷Lu]Lu-DOTA-trastuzumab, evaluating the influence of the chelating agents and radionuclides on the biological properties of the radioimmunoconjugates (RICs). The trastuzumab was immunoconjugated with the chelators DTPA and DOTA and radiolabeled with [¹¹¹In]InCl₃ and [¹⁷⁷Lu]LuCl₃, respectively. The stability of the RICs was evaluated in serum, and the immunoreactive and internalization fractions were determined in SK-BR-3 breast cancer cells. The in vivo pharmacokinetics and dosimetry quantification and the ex vivo biodistribution were performed in normal and SK-BR-3 tumor-bearing mice. The data showed that there was no influence of the chelating agents and radionuclides on the immunoreactive and internalization fractions of RICs. In contrast, they influenced the stability of RICs in serum, as well as the pharmacokinetics, dosimetry and biodistribution profiles. Therefore, the results showed that the nature of the chelating agent and radionuclide could influence the biological properties of the radioimmunotheranostic pair. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy)

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17 pages, 6786 KiB

Open AccessArticle

Comparative Preclinical Evaluation of HER2-Targeting ABD-Fused Affibody^® Molecules ¹⁷⁷Lu-ABY-271 and ¹⁷⁷Lu-ABY-027: Impact of DOTA Position on ABD Domain

by Yongsheng Liu, Anzhelika Vorobyeva, Tianqi Xu, Anna Orlova, Annika Loftenius, Theresa Bengtsson, Per Jonasson, Vladimir Tolmachev and Fredrik Y. Frejd

Pharmaceutics 2021, 13(6), 839; https://doi.org/10.3390/pharmaceutics13060839 - 7 Jun 2021

Cited by 12 | Viewed by 4202

Abstract

Radiolabeled Affibody-based targeting agent ¹⁷⁷Lu-ABY-027, a fusion of an anti-HER2 Affibody molecule with albumin binding domain (ABD) site-specifically labeled at the C-terminus, has demonstrated a promising biodistribution profile in mice; binding of the construct to albumin prevents glomerular filtration and significantly reduces [...] Read more.

Radiolabeled Affibody-based targeting agent ¹⁷⁷Lu-ABY-027, a fusion of an anti-HER2 Affibody molecule with albumin binding domain (ABD) site-specifically labeled at the C-terminus, has demonstrated a promising biodistribution profile in mice; binding of the construct to albumin prevents glomerular filtration and significantly reduces renal uptake. In this study, we tested the hypothesis that site-specific positioning of the chelator at helix 1 of ABD, at a maximum distance from the albumin binding site, would further increase the strength of binding to albumin and decrease the renal uptake. The new construct, ABY-271 with DOTA conjugated at the back of ABD, has been labelled with ¹⁷⁷Lu. Targeting properties of ¹⁷⁷Lu-ABY-271 and ¹⁷⁷Lu-ABY-027 were compared directly. ¹⁷⁷Lu-ABY-271 specifically accumulated in SKOV-3 xenografts in mice. The tumor uptake of ¹⁷⁷Lu-ABY-271 exceeded uptake in any other organ 24 h and later after injection. However, the renal uptake of ¹⁷⁷Lu-ABY-271 was two-fold higher than the uptake of ¹⁷⁷Lu-ABY-027. Thus, the placement of chelator on helix 1 of ABD does not provide desirable reduction of renal uptake. To conclude, minimal modification of the design of Affibody molecules has a strong effect on biodistribution, which cannot be predicted a priori. This necessitates extensive structure-properties relationship studies to find an optimal design of Affibody-based targeting agents for therapy. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy)

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14 pages, 2578 KiB

Open AccessArticle

Efficacy and Safety of [²²⁵Ac]Ac-PSMA-617 Augmented [¹⁷⁷Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Highly Advanced mCRPC with Poor Prognosis

by Florian Rosar, Jonas Krause, Mark Bartholomä, Stephan Maus, Tobias Stemler, Ina Hierlmeier, Johannes Linxweiler, Samer Ezziddin and Fadi Khreish

Pharmaceutics 2021, 13(5), 722; https://doi.org/10.3390/pharmaceutics13050722 - 14 May 2021

Cited by 38 | Viewed by 3710

Abstract

The use of ²²⁵Ac in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), either as monotherapy or in combination with ¹⁷⁷Lu, is a promising therapy approach in patients with metastatic castration-resistant prostate carcinoma (mCRPC). In this study, we report the efficacy and [...] Read more.

The use of ²²⁵Ac in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), either as monotherapy or in combination with ¹⁷⁷Lu, is a promising therapy approach in patients with metastatic castration-resistant prostate carcinoma (mCRPC). In this study, we report the efficacy and safety of [²²⁵Ac]Ac-PSMA-617 augmented [¹⁷⁷Lu]Lu-PSMA-617 RLT in ¹⁷⁷Lu-naive mCRPC patients (n = 15) with poor prognosis (presence of visceral metastases, high total tumor burden with diffuse bone metastases or a short PSA doubling time of <2 months). Biochemical (by PSA serum value) and molecular imaging response (by [⁶⁸Ga]Ga-PSMA-11 PET/CT) was assessed after two cycles of [¹⁷⁷Lu]Lu-PSMA-617 RLT, with at least one [²²⁵Ac]Ac-PSMA-617 augmentation. In addition, PSA-based progression-free survival (PSA-PFS), overall survival (OS) and toxicity (according to CTCAE) were analyzed. We observed a biochemical- and molecular imaging-based partial remission in 53.3% (8/15) and 66.7% (10/15) of patients, respectively. The median PSA-PFS and OS was 9.1 and 14.8 months, respectively. No serious acute adverse events were recorded. Two out of fifteen patients experienced grade 3 anemia. No other grade 3/4 toxicities were observed. RLT-related xerostomia (grade 1/2) was recorded in 2/15 patients. Our data showed a high clinical efficacy with a favorable side effects profile of [²²⁵Ac]Ac-PSMA-617 augmented [¹⁷⁷Lu]Lu-PSMA-617 RLT in this highly challenging patient cohort. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy)

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15 pages, 1821 KiB

Open AccessArticle

Development of [²²⁵Ac]Ac-PSMA-I&T for Targeted Alpha Therapy According to GMP Guidelines for Treatment of mCRPC

by Eline L. Hooijman, Yozlem Chalashkan, Sui Wai Ling, Figen F. Kahyargil, Marcel Segbers, Frank Bruchertseifer, Alfred Morgenstern, Yann Seimbille, Stijn L. W. Koolen, Tessa Brabander and Erik de Blois

Pharmaceutics 2021, 13(5), 715; https://doi.org/10.3390/pharmaceutics13050715 - 13 May 2021

Cited by 40 | Viewed by 9990

Abstract

Recently, promising results of the antitumor effects were observed in patients with metastatic castration-resistant prostate cancer treated with ¹⁷⁷Lu-labeled PSMA-ligands. Radionuclide therapy efficacy may even be improved by using the alpha emitter Ac-225. Higher efficacy is claimed due to high linear energy [...] Read more.

Recently, promising results of the antitumor effects were observed in patients with metastatic castration-resistant prostate cancer treated with ¹⁷⁷Lu-labeled PSMA-ligands. Radionuclide therapy efficacy may even be improved by using the alpha emitter Ac-225. Higher efficacy is claimed due to high linear energy transfer specifically towards PSMA positive cells, causing more double-strand breaks. This study aims to manufacture [²²⁵Ac]Ac-PSMA-I&T according to good manufacturing practice guidelines for the translation of [²²⁵Ac]Ac-PSMA-I&T into a clinical phase 1 dose escalation study. Quencher addition during labeling was investigated. Quality control of [²²⁵Ac]Ac-PSMA-I&T was based on measurement of Fr-221 (218 keV), in equilibrium with Ac-225 in approximately six half-lives of Fr-221 (T½ = 4.8 min). Radio-(i)TLC methods were utilized for identification of the different radiochemical forms, gamma counter for concentration determination, and HPGe-detector for the detection of the radiochemical yield. Radiochemical purity was determined by HPLC. The final patient dose was prepared and diluted with an optimized concentration of quenchers as during labeling, with an activity of 8–12 MBq (±5%), pH > 5.5, 100 ± 20 μg/dose, PSMA-I&T, radiochemical yield >95%, radiochemical purity >90% (up to 3 h), endotoxin levels of <5 EU/mL, osmolarity of 2100 mOsmol, and is produced according to current guidelines. The start of the phase I dose escalation study is planned in the near future. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy)

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11 pages, 1695 KiB

Open AccessArticle

Competition (‘Steal’ Phenomenon) between [⁶⁸Ga]Ga-PSMA-11 Uptake in Prostate Tumor Tissue Versus Healthy Tissue

by Esmée C. A. van der Sar, Bart de Keizer, Marnix G. E. H. Lam and Arthur J. A. T. Braat

Pharmaceutics 2021, 13(5), 699; https://doi.org/10.3390/pharmaceutics13050699 - 11 May 2021

Cited by 3 | Viewed by 1828

Abstract

We aimed to clarify whether a steal ‘phenomenon’ exists by investigating if uptake of ‘prostate specific membrane antigen’ (PSMA) in prostate tumor tissue correlates with the uptake in healthy tissue. Patients with prostate cancer referred for a [⁶⁸Ga]Ga-PSMA-11 PET/CT were identified [...] Read more.

We aimed to clarify whether a steal ‘phenomenon’ exists by investigating if uptake of ‘prostate specific membrane antigen’ (PSMA) in prostate tumor tissue correlates with the uptake in healthy tissue. Patients with prostate cancer referred for a [⁶⁸Ga]Ga-PSMA-11 PET/CT were identified retrospectively. Semi-automated quantitative image analysis was performed; fractional healthy tissue [⁶⁸Ga]Ga-PSMA-11 uptake volume (HT-PSMA (SUV*cm³)) in the lacrimal, submandibular, and parotid glands, and kidneys, and the fractional total lesion [⁶⁸Ga]Ga-PSMA-11 uptake volume (TL-PSMA (SUV*cm³)) of prostate cancer were used. Ninety-two patients, age 78 ± 8 years, were analyzed. Median TL-PSMA was 703.37 SUV*cm³ (IQR 119.56–2778.20), median HT-PSMA of the lacrimal, submandibular, and parotid glands, and kidneys was: 13.69 (IQR 7.29–19.06), 194.75 (IQR 133.67–276.53), 552.54 (IQR 379.98–737.16), and 8092.75 SUV*cm³ (IQR 5793.02–11,385.86), respectively. A significant (p-value ≤ 0.001) but weak–moderate correlation was found between the TL-PSMA and HT-PSMA of the parotid- and submandibular glands, and kidneys (correlation coefficient of −0.447, −0.345, and −0.394, respectively). No correlation was found between TL-PSMA and HT-PSMA of the lacrimal glands. The existence of a ‘steal’ phenomenon cannot be confirmed in this study. Healthy tissue uptake of [⁶⁸Ga]Ga-PSMA-11 is only partially influenced by TL-PSMA. Thus, modification of therapeutic PSMA activity should not be adjusted based on TL-PSMA alone. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy)

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13 pages, 3095 KiB

Open AccessCommunication

Simultaneous Visualization of ¹⁶¹Tb- and ¹⁷⁷Lu-Labeled Somatostatin Analogues Using Dual-Isotope SPECT Imaging

by Francesca Borgna, Patrick Barritt, Pascal V. Grundler, Zeynep Talip, Susan Cohrs, Jan Rijn Zeevaart, Ulli Köster, Roger Schibli, Nicholas P. van der Meulen and Cristina Müller

Pharmaceutics 2021, 13(4), 536; https://doi.org/10.3390/pharmaceutics13040536 - 12 Apr 2021

Cited by 28 | Viewed by 5733

Abstract

The decay of terbium-161 results in the emission of β¯-particles as well as conversion and Auger electrons, which makes terbium-161 interesting for therapeutic purposes. The aim of this study was to use dual-isotope SPECT imaging in order to demonstrate visually that terbium-161 and [...] Read more.

The decay of terbium-161 results in the emission of β¯-particles as well as conversion and Auger electrons, which makes terbium-161 interesting for therapeutic purposes. The aim of this study was to use dual-isotope SPECT imaging in order to demonstrate visually that terbium-161 and lutetium-177 are interchangeable without compromising the pharmacokinetic profile of the radiopharmaceutical. The ¹⁶¹Tb- and ¹⁷⁷Lu-labeled somatostatin (SST) analogues DOTATOC (agonist) and DOTA-LM3 (antagonist) were tested in vitro to demonstrate equal properties regarding distribution coefficients and cell uptake into SST receptor-positive AR42J tumor cells. The radiopeptides were further investigated in AR42J tumor-bearing nude mice using the method of dual-isotope (terbium-161/lutetium-177) SPECT/CT imaging to enable the visualization of their distribution profiles in the same animal. Equal pharmacokinetic profiles were demonstrated for either of the two peptides, irrespective of whether it was labeled with terbium-161 or lutetium-177. Moreover, the visualization of the sub-organ distribution confirmed similar behavior of ¹⁶¹Tb- and ¹⁷⁷Lu-labeled SST analogues. The data were verified in quantitative biodistribution studies using either type of peptide labeled with terbium-161 or lutetium-177. While the radionuclide did not have an impact on the organ distribution, this study confirmed previous data of a considerably higher tumor uptake of radiolabeled DOTA-LM3 as compared to the radiolabeled DOTATOC. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy)

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14 pages, 1330 KiB

Open AccessArticle

One Step Closer to Clinical Translation: Enhanced Tumor Targeting of [^99mTc]Tc-DB4 and [¹¹¹In]In-SG4 in Mice Treated with Entresto

by Panagiotis Kanellopoulos, Aikaterini Kaloudi, Maritina Rouchota, George Loudos, Marion de Jong, Eric P. Krenning, Berthold A. Nock and Theodosia Maina

Pharmaceutics 2020, 12(12), 1145; https://doi.org/10.3390/pharmaceutics12121145 - 26 Nov 2020

Cited by 11 | Viewed by 2605

Abstract

Background: Peptide radioligands may serve as radionuclide carriers to tumor sites overexpressing their cognate receptor for diagnostic or therapeutic purposes. Treatment of mice with the neprilysin (NEP)-inhibitor phosphoramidon was previously shown to improve the metabolic stability and tumor uptake of biodegradable radiopeptides. Aiming [...] Read more.

Background: Peptide radioligands may serve as radionuclide carriers to tumor sites overexpressing their cognate receptor for diagnostic or therapeutic purposes. Treatment of mice with the neprilysin (NEP)-inhibitor phosphoramidon was previously shown to improve the metabolic stability and tumor uptake of biodegradable radiopeptides. Aiming to clinical translation of this methodology, we herein investigated the impact of the approved pill Entresto, releasing the potent NEP-inhibitor LBQ657 in vivo, on the stability and tumor uptake of two radiopeptides. Methods: The metabolic stability of [^99mTc]Tc-DB4 (DB4, N₄-Pro-Gln-Arg-Tyr-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Nle-NH₂) and [¹¹¹In]In-SG4 (SG4, DOTA-DGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH₂) was tested in LBQ657/Entresto-treated mice vs. untreated controls. The uptake in gastrin-releasing peptide receptor (GRPR)-, or cholecystokinin subtype 2 receptor (CCK₂R)-positive tumors respectively, was compared between LBQ657/Entresto-treated mice and untreated controls. Results: LBQ657/Entresto treatment induced marked stabilization of [^99mTc] Tc-DB4 and [¹¹¹In]In-SG4 in peripheral mice blood, resulting in equally enhanced tumor uptake at 4 h post-injection. Accordingly, the [^99mTc]Tc-DB4 uptake of 7.13 ± 1.76%IA/g in PC-3 tumors increased to 16.17 ± 0.71/17.50 ± 3.70%IA/g (LBQ657/Entresto) and the [¹¹¹In]In-SG4 uptake of 3.07 ± 0.87%IA/g in A431-CCK₂R(+) tumors to 8.11 ± 1.45/9.61 ± 1.70%IA/g. Findings were visualized by SPECT/CT. Conclusions: This study has shown the efficacy of Entresto to notably improve the profile of [^99mTc]Tc-DB4 and [¹¹¹In]In-SG4 in mice, paving the way for clinical translation of this approach. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy)

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12 pages, 2747 KiB

Open AccessArticle

Evaluation of Actinium-225 Labeled Minigastrin Analogue [²²⁵Ac]Ac-DOTA-PP-F11N for Targeted Alpha Particle Therapy

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

Pharmaceutics 2020, 12(11), 1088; https://doi.org/10.3390/pharmaceutics12111088 - 12 Nov 2020

Cited by 23 | Viewed by 4116

Abstract

The overexpression of cholecystokinin B receptor (CCKBR) in human cancers led to the development of radiolabeled minigastrin analogues for targeted radionuclide therapy, which aims to deliver cytotoxic radiation specifically to cancer cells. Alpha emitters (e.g., actinium-225) possess high potency in cancer cell-killing and [...] Read more.

The overexpression of cholecystokinin B receptor (CCKBR) in human cancers led to the development of radiolabeled minigastrin analogues for targeted radionuclide therapy, which aims to deliver cytotoxic radiation specifically to cancer cells. Alpha emitters (e.g., actinium-225) possess high potency in cancer cell-killing and hold promise for the treatment of malignant tumors. In these preclinical studies, we developed and evaluated CCKBR-targeted alpha particle therapy. The cellular uptake and cytotoxic effect of actinium-225 labeled and HPLC-purified minigastrin analogue [²²⁵Ac]Ac-PP-F11N were characterized in the human squamous cancer A431 cells transfected with CCKBR. Nude mice bearing A431/CCKBR tumors were used for biodistribution and therapy studies followed by histological analysis and SPECT/CT imaging. In vitro, [²²⁵Ac]Ac-PP-F11N showed CCKBR-specific and efficient internalization rate and potent cytotoxicity. The biodistribution studies of [²²⁵Ac]Ac-PP-F11N revealed CCKBR-specific uptake in tumors, whereas the therapeutic studies demonstrated dose-dependent inhibition of tumor growth and extended mean survival time, without apparent toxicity. The histological analysis of kidney and stomach indicated no severe adverse effects after [²²⁵Ac]Ac-PP-F11N administration. The post-therapy SPECT-CT images with [¹¹¹In]In-PP-F11N confirmed no CCKBR-positive tumor left in the mice with complete remission. In conclusion, our study demonstrates therapeutic efficacy of [²²⁵Ac]Ac-PP-F11N without acute radiotoxicity in CCKBR-positive cancer model. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy)

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Review

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31 pages, 1085 KiB

Open AccessReview

⁹⁰Y/¹⁷⁷Lu-DOTATOC: From Preclinical Studies to Application in Humans

by Licia Uccelli, Alessandra Boschi, Corrado Cittanti, Petra Martini, Stefano Panareo, Eugenia Tonini, Alberto Nieri, Luca Urso, Matteo Caracciolo, Luca Lodi, Aldo Carnevale, Melchiore Giganti and Mirco Bartolomei

Pharmaceutics 2021, 13(9), 1463; https://doi.org/10.3390/pharmaceutics13091463 - 13 Sep 2021

Cited by 26 | Viewed by 5192

Abstract

The PRRT (Peptide Receptor Radionuclide Therapy) is a promising modality treatment for patients with inoperable or metastatic neuroendocrine tumors (NETs). Progression-free survival (PFS) and overall survival (OS) of these patients are favorably comparable with standard therapies. The protagonist in this type of therapy [...] Read more.

The PRRT (Peptide Receptor Radionuclide Therapy) is a promising modality treatment for patients with inoperable or metastatic neuroendocrine tumors (NETs). Progression-free survival (PFS) and overall survival (OS) of these patients are favorably comparable with standard therapies. The protagonist in this type of therapy is a somatostatin-modified peptide fragment ([Tyr3] octreotide), equipped with a specific chelating system (DOTA) capable of creating a stable bond with β-emitting radionuclides, such as yttrium-90 and lutetium-177. In this review, covering twenty five years of literature, we describe the characteristics and performances of the two most used therapeutic radiopharmaceuticals for the NETs radio-treatment: [⁹⁰Y]Y-DOTATOC and [¹⁷⁷Lu]Lu-DOTATOC taking this opportunity to retrace the most significant results that have determined their success, promoting them from preclinical studies to application in humans. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy)

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50 pages, 2264 KiB

Open AccessReview

Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The “Hopeful Eight”

by Romain Eychenne, Michel Chérel, Férid Haddad, François Guérard and Jean-François Gestin

Pharmaceutics 2021, 13(6), 906; https://doi.org/10.3390/pharmaceutics13060906 - 18 Jun 2021

Cited by 125 | Viewed by 11293

Abstract

Among all existing radionuclides, only a few are of interest for therapeutic applications and more specifically for targeted alpha therapy (TAT). From this selection, actinium-225, astatine-211, bismuth-212, bismuth-213, lead-212, radium-223, terbium-149 and thorium-227 are considered as the most suitable. Despite common general features, [...] Read more.

Among all existing radionuclides, only a few are of interest for therapeutic applications and more specifically for targeted alpha therapy (TAT). From this selection, actinium-225, astatine-211, bismuth-212, bismuth-213, lead-212, radium-223, terbium-149 and thorium-227 are considered as the most suitable. Despite common general features, they all have their own physical characteristics that make them singular and so promising for TAT. These radionuclides were largely studied over the last two decades, leading to a better knowledge of their production process and chemical behavior, allowing for an increasing number of biological evaluations. The aim of this review is to summarize the main properties of these eight chosen radionuclides. An overview from their availability to the resulting clinical studies, by way of chemical design and preclinical studies is discussed. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy)

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18 pages, 642 KiB

Open AccessReview

Combination Therapy, a Promising Approach to Enhance the Efficacy of Radionuclide and Targeted Radionuclide Therapy of Prostate and Breast Cancer

by Tyrillshall S. T. Damiana and Simone U. Dalm

Pharmaceutics 2021, 13(5), 674; https://doi.org/10.3390/pharmaceutics13050674 - 7 May 2021

Cited by 11 | Viewed by 3816

Abstract

In recent years, radionuclide therapy (RT) and targeted radionuclide therapy (TRT) have gained great interest in cancer treatment. This is due to promising results obtained in both preclinical and clinical studies. However, a complete response is achieved in only a small percentage of [...] Read more.

In recent years, radionuclide therapy (RT) and targeted radionuclide therapy (TRT) have gained great interest in cancer treatment. This is due to promising results obtained in both preclinical and clinical studies. However, a complete response is achieved in only a small percentage of patients that receive RT or TRT. As a consequence, there have been several strategies to improve RT and TRT outcomes including the combination of these treatments with other well-established anti-cancer therapies, for example, chemotherapy. Combinations of RT and TRT with other therapies with distinct mechanisms of action represent a promising strategy. As for prostate cancer and breast cancer, the two most prevalent cancer types worldwide, several combination-based therapies have been evaluated. In this review, we will provide an overview of the RT and TRT agents currently used or being investigated in combination with hormone therapy, chemotherapy, immunotherapy, and external beam radiation therapy for the treatment of prostate cancer and breast cancer. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy)

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25 pages, 3690 KiB

Open AccessReview

Bismuth-213 for Targeted Radionuclide Therapy: From Atom to Bedside

by Stephen Ahenkorah, Irwin Cassells, Christophe M. Deroose, Thomas Cardinaels, Andrew R. Burgoyne, Guy Bormans, Maarten Ooms and Frederik Cleeren

Pharmaceutics 2021, 13(5), 599; https://doi.org/10.3390/pharmaceutics13050599 - 21 Apr 2021

Cited by 75 | Viewed by 8237

Abstract

In contrast to external high energy photon or proton therapy, targeted radionuclide therapy (TRNT) is a systemic cancer treatment allowing targeted irradiation of a primary tumor and all its metastases, resulting in less collateral damage to normal tissues. The α-emitting radionuclide bismuth-213 ( [...] Read more.

In contrast to external high energy photon or proton therapy, targeted radionuclide therapy (TRNT) is a systemic cancer treatment allowing targeted irradiation of a primary tumor and all its metastases, resulting in less collateral damage to normal tissues. The α-emitting radionuclide bismuth-213 (²¹³Bi) has interesting properties and can be considered as a magic bullet for TRNT. The benefits and drawbacks of targeted alpha therapy with ²¹³Bi are discussed in this review, covering the entire chain from radionuclide production to bedside. First, the radionuclide properties and production of ²²⁵Ac and its daughter ²¹³Bi are discussed, followed by the fundamental chemical properties of bismuth. Next, an overview of available acyclic and macrocyclic bifunctional chelators for bismuth and general considerations for designing a ²¹³Bi-radiopharmaceutical are provided. Finally, we provide an overview of preclinical and clinical studies involving ²¹³Bi-radiopharmaceuticals, as well as the future perspectives of this promising cancer treatment option. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy)

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