Research

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15 pages, 3428 KiB

Open AccessArticle

A Proof-of-Concept Study on the Therapeutic Potential of Au Nanoparticles Radiolabeled with the Alpha-Emitter Actinium-225

by Evangelia-Alexandra Salvanou, Dimitris Stellas, Charalampos Tsoukalas, Barbara Mavroidi, Maria Paravatou-Petsotas, Nikolaos Kalogeropoulos, Stavros Xanthopoulos, Franck Denat, Gautier Laurent, Rana Bazzi, Stephane Roux and Penelope Bouziotis

Pharmaceutics 2020, 12(2), 188; https://doi.org/10.3390/pharmaceutics12020188 - 21 Feb 2020

Cited by 41 | Viewed by 4193

Abstract

Actinium-225 (²²⁵Ac) is receiving increased attention for its application in targeted radionuclide therapy, due to the short range of its emitted alpha particles in conjunction with their high linear energy transfer, which lead to the eradication of tumor cells while sparing [...] Read more.

Actinium-225 (²²⁵Ac) is receiving increased attention for its application in targeted radionuclide therapy, due to the short range of its emitted alpha particles in conjunction with their high linear energy transfer, which lead to the eradication of tumor cells while sparing neighboring healthy tissue. The objective of our study was the evaluation of a gold nanoparticle radiolabeled with ²²⁵Ac as an injectable radiopharmaceutical form of brachytherapy for local radiation treatment of cancer. Au@TADOTAGA was radiolabeled with ²²⁵Ac at pH 5.6 (30 min at 70 °C), and in vitro stability was evaluated. In vitro cytotoxicity was assessed in U-87 MG cancer cells, and in vivo biodistribution was performed by intravenous and intratumoral administration of [²²⁵Ac]²²⁵Ac-Au@TADOTAGA in U-87 MG tumor-bearing mice. A preliminary study to assess therapeutic efficacy of the intratumorally-injected radio-nanomedicine was performed over a period of 22 days, while the necrotic effect on tumors was evaluated by a histopathology study. We have shown that [²²⁵Ac]²²⁵Ac-Au@TADOTAGA resulted in the retardation of tumor growth after its intratumoral injection in U87MG tumor-bearing mice, even though very low activities were injected per mouse. This gold nanoparticle radiopharmaceutical could be applied as an unconventional brachytherapy in injectable form for local radiation treatment of cancer. Full article

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

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13 pages, 1671 KiB

Open AccessArticle

Combination of Proton Therapy and Radionuclide Therapy in Mice: Preclinical Pilot Study at the Paul Scherrer Institute

by Cristina Müller, Maria De Prado Leal, Marco D. Dominietto, Christoph A. Umbricht, Sairos Safai, Rosalind L. Perrin, Martina Egloff, Peter Bernhardt, Nicholas P. van der Meulen, Damien C. Weber, Roger Schibli and Antony J. Lomax

Pharmaceutics 2019, 11(9), 450; https://doi.org/10.3390/pharmaceutics11090450 - 02 Sep 2019

Cited by 4 | Viewed by 3349

Abstract

Proton therapy (PT) is a treatment with high dose conformality that delivers a highly-focused radiation dose to solid tumors. Targeted radionuclide therapy (TRT), on the other hand, is a systemic radiation therapy, which makes use of intravenously-applied radioconjugates. In this project, it was [...] Read more.

Proton therapy (PT) is a treatment with high dose conformality that delivers a highly-focused radiation dose to solid tumors. Targeted radionuclide therapy (TRT), on the other hand, is a systemic radiation therapy, which makes use of intravenously-applied radioconjugates. In this project, it was aimed to perform an initial dose-searching study for the combination of these treatment modalities in a preclinical setting. Therapy studies were performed with xenograft mouse models of folate receptor (FR)-positive KB and prostate-specific membrane antigen (PSMA)-positive PC-3 PIP tumors, respectively. PT and TRT using ¹⁷⁷Lu-folate and ¹⁷⁷Lu-PSMA-617, respectively, were applied either as single treatments or in combination. Monitoring of the mice over nine weeks revealed a similar tumor growth delay after PT and TRT, respectively, when equal tumor doses were delivered either by protons or by β¯-particles, respectively. Combining the methodologies to provide half-dose by either therapy approach resulted in equal (PC-3 PIP tumor model) or even slightly better therapy outcomes (KB tumor model). In separate experiments, preclinical positron emission tomography (PET) was performed to investigate tissue activation after proton irradiation of the tumor. The high-precision radiation delivery of PT was confirmed by the resulting PET images that accurately visualized the irradiated tumor tissue. In this study, the combination of PT and TRT resulted in an additive effect or a trend of synergistic effects, depending on the type of tumor xenograft. This study laid the foundation for future research regarding therapy options in the situation of metastasized solid tumors, where surgery or PT alone are not a solution but may profit from combination with systemic radiation therapy. Full article

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

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13 pages, 9360 KiB

Open AccessArticle

Therapeutic Potential of ⁴⁷Sc in Comparison to ¹⁷⁷Lu and ⁹⁰Y: Preclinical Investigations

by Klaudia Siwowska, Patrycja Guzik, Katharina A. Domnanich, Josep M. Monné Rodríguez, Peter Bernhardt, Bernard Ponsard, Roger Hasler, Francesca Borgna, Roger Schibli, Ulli Köster, Nicholas P. van der Meulen and Cristina Müller

Pharmaceutics 2019, 11(8), 424; https://doi.org/10.3390/pharmaceutics11080424 - 20 Aug 2019

Cited by 25 | Viewed by 3962

Abstract

Targeted radionuclide therapy with ¹⁷⁷Lu- and ⁹⁰Y-labeled radioconjugates is a clinically-established treatment modality for metastasized cancer. ⁴⁷Sc is a therapeutic radionuclide that decays with a half-life of 3.35 days and emits medium-energy β⁻-particles. In this study, ⁴⁷Sc [...] Read more.

Targeted radionuclide therapy with ¹⁷⁷Lu- and ⁹⁰Y-labeled radioconjugates is a clinically-established treatment modality for metastasized cancer. ⁴⁷Sc is a therapeutic radionuclide that decays with a half-life of 3.35 days and emits medium-energy β⁻-particles. In this study, ⁴⁷Sc was investigated, in combination with a DOTA-folate conjugate, and compared to the therapeutic properties of ¹⁷⁷Lu-folate and ⁹⁰Y-folate, respectively. In vitro, ⁴⁷Sc-folate demonstrated effective reduction of folate receptor-positive ovarian tumor cell viability similar to ¹⁷⁷Lu-folate, but ⁹⁰Y-folate was more potent at equal activities due to the higher energy of emitted β⁻-particles. Comparable tumor growth inhibition was observed in mice that obtained the same estimated absorbed tumor dose (~21 Gy) when treated with ⁴⁷Sc-folate (12.5 MBq), ¹⁷⁷Lu-folate (10 MBq), and ⁹⁰Y-folate (5 MBq), respectively. The treatment resulted in increased median survival of 39, 43, and 41 days, respectively, as compared to 26 days in untreated controls. There were no statistically significant differences among the therapeutic effects observed in treated groups. Histological assessment revealed no severe side effects two weeks after application of the radiofolates, even at double the activity used for therapy. Based on the decay properties and our results, ⁴⁷Sc is likely to be comparable to ¹⁷⁷Lu when employed for targeted radionuclide therapy. It may, therefore, have potential for clinical translation and be of particular interest in tandem with ⁴⁴Sc or ⁴³Sc as a diagnostic match, enabling the realization of radiotheragnostics in future. Full article

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

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20 pages, 4390 KiB

Open AccessArticle

Evaluation of Tumor-Targeting Properties of an Antagonistic Bombesin Analogue RM26 Conjugated with a Non-Residualizing Radioiodine Label Comparison with a Radiometal-Labelled Counterpart

by Maryam Oroujeni, Ayman Abouzayed, Fanny Lundmark, Bogdan Mitran, Anna Orlova, Vladimir Tolmachev and Ulrika Rosenström

Pharmaceutics 2019, 11(8), 380; https://doi.org/10.3390/pharmaceutics11080380 - 02 Aug 2019

Cited by 5 | Viewed by 4041

Abstract

Radiolabelled antagonistic bombesin analogues are successfully used for targeting of gastrin-releasing peptide receptors (GRPR) that are overexpressed in prostate cancer. Internalization of antagonistic bombesin analogues is slow. We hypothesized that the use of a non-residualizing radioiodine label might not affect the tumour uptake [...] Read more.

Radiolabelled antagonistic bombesin analogues are successfully used for targeting of gastrin-releasing peptide receptors (GRPR) that are overexpressed in prostate cancer. Internalization of antagonistic bombesin analogues is slow. We hypothesized that the use of a non-residualizing radioiodine label might not affect the tumour uptake but would reduce the retention in normal organs, where radiopharmaceutical would be internalized. To test this hypothesis, tyrosine was conjugated via diethylene glycol linker to N-terminus of an antagonistic bombesin analogue RM26 to form Tyr-PEG₂-RM26. [¹¹¹In]In-DOTA-PEG₂-RM26 was used as a control with a residualizing label. Tyr-PEG₂-RM26 was labelled with ¹²⁵I with 95% radiochemical purity and retained binding specificity to GRPR. The IC₅₀ values for Tyr-PEG₂-RM26 and DOTA-PEG₂-RM26 were 1.7 ± 0.3 nM and 3.3 ± 0.5 nM, respectively. The cellular processing of [¹²⁵I]I-Tyr-PEG₂-RM26 by PC-3 cells showed unusually fast internalization. Biodistribution showed that uptake in pancreas and tumour was GRPR-specific for both radioconjugates. Blood clearance of [¹²⁵I]I-Tyr-PEG₂-RM26 was appreciably slower and activity accumulation in all organs was significantly higher than for [¹¹¹In]In-DOTA-PEG₂-RM26. Tumor uptake of [¹¹¹In]In-DOTA-PEG₂-RM26 was significantly higher than for [¹²⁵I]I-Tyr-PEG₂-RM26, resulting in higher tumour-to-organ ratio for [¹¹¹In]In-DOTA-PEG₂-RM26 at studied time points. Incorporation of amino acids with hydrophilic side-chains next to tyrosine might overcome the problems associated with the use of tyrosine as a prosthetic group for radioiodination. Full article

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

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18 pages, 4962 KiB

Open AccessArticle

Synthesis and Preclinical Evaluation of Radio-Iodinated GRPR/PSMA Bispecific Heterodimers for the Theranostics Application in Prostate Cancer

by Ayman Abouzayed, Cheng-Bin Yim, Bogdan Mitran, Sara S. Rinne, Vladimir Tolmachev, Mats Larhed, Ulrika Rosenström and Anna Orlova

Pharmaceutics 2019, 11(7), 358; https://doi.org/10.3390/pharmaceutics11070358 - 23 Jul 2019

Cited by 17 | Viewed by 4835

Abstract

Gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) are overexpressed in most prostate cancers. GRPR expression is higher in early stages while PSMA expression increases with progression. The possibility of targeting both markers with a single theranostics radiotracer could improve patient management. [...] Read more.

Gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) are overexpressed in most prostate cancers. GRPR expression is higher in early stages while PSMA expression increases with progression. The possibility of targeting both markers with a single theranostics radiotracer could improve patient management. Three GRPR/PSMA-targeting bispecific heterodimers (urea derivative PSMA-617 and bombesin-based antagonist RM26 linked via X-triazolyl-Tyr-PEG2, X = PEG2 (BO530), (CH₂)₈ (BO535), none (BO536)) were synthesized by solid-phase peptide synthesis. Peptides were radio-iodinated and evaluated in vitro for binding specificity, cellular retention, and affinity. In vivo specificity for all heterodimers was studied in PC-3 (GRPR-positive) and LNCaP (PSMA-positive) xenografts. [¹²⁵I]I-BO530 was evaluated in PC-3pip (GRPR/PSMA-positive) xenografts. Micro single-photon emission computed tomography/computed tomography (microSPECT/CT) scans were acquired. The heterodimers were radiolabeled with high radiochemical yields, bound specifically to both targets, and demonstrated high degree of activity retention in PC-3pip cells. Only [¹²⁵I]I-BO530 demonstrated in vivo specificity to both targets. A biodistribution study of [¹²⁵I]I-BO530 in PC-3pip xenografted mice showed high tumor activity uptake (30%–35%ID/g at 3 h post injection (pi)). Activity uptake in tumors was stable and exceeded all other organs 24 h pi. Activity uptake decreased only two-fold 72 h pi. The GRPR/PSMA-targeting heterodimer [¹²⁵I]I-BO530 is a promising agent for theranostics application in prostate cancer. Full article

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

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11 pages, 1788 KiB

Open AccessArticle

Comparative Radioimmunotherapy of Experimental Melanoma with Novel Humanized Antibody to Melanin Labeled with 213Bismuth and 177Lutetium

by Kevin J. H. Allen, Rubin Jiao, Mackenzie E. Malo, Connor Frank, Darrell R. Fisher, David Rickles and Ekaterina Dadachova

Pharmaceutics 2019, 11(7), 348; https://doi.org/10.3390/pharmaceutics11070348 - 18 Jul 2019

Cited by 16 | Viewed by 3687

Abstract

Melanoma is a cancer with increasing incidence and there is a need for alternatives to immunotherapy within effective approaches to treatment of metastatic melanoma. We performed comparative radioimmunotherapy (RIT) of experimental B16-F10 melanoma with novel humanized IgG to melanin h8C3 labeled with a [...] Read more.

Melanoma is a cancer with increasing incidence and there is a need for alternatives to immunotherapy within effective approaches to treatment of metastatic melanoma. We performed comparative radioimmunotherapy (RIT) of experimental B16-F10 melanoma with novel humanized IgG to melanin h8C3 labeled with a beta emitter, ¹⁷⁷Lu, and an alpha-emitter, ²¹³Bi, as well as biodistribution, microSPECT/CT imaging, and mouse and human dosimetry calculations. microSPECT/CT imaging showed that a humanized antibody that targets “free” melanin in the tumor microenvironment had high tumor uptake in B16F10 murine melanoma in C57Bl/6 mice, with little to no uptake in naturally melanized tissues. Extrapolation of the mouse dosimetry data to an adult human demonstrated that doses delivered to major organs and the whole body by ¹⁷⁷Lu-h8C3 would be approximately two times higher than those delivered by ²¹³Bi-h8C3, while the doses to the tumor would be almost similar. RIT results indicated that ²¹³Bi-h8C3 was more effective in slowing down the tumor growth than ¹⁷⁷Lu-h8C3, while both radiolabeled antibodies did not produce significant hematologic or systemic side effects. We concluded that h8C3 antibody labeled with ²¹³Bi is a promising reagent for translation into a clinical trial in patients with metastatic melanoma. Full article

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

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14 pages, 3390 KiB

Open AccessArticle

Elucidating the Influence of Tumor Presence on the Polymersome Circulation Time in Mice

by Robin M. de Kruijff, René Raavé, Annemarie Kip, Janneke Molkenboer-Kuenen, Stefan J. Roobol, Jeroen Essers, Sandra Heskamp and Antonia G. Denkova

Pharmaceutics 2019, 11(5), 241; https://doi.org/10.3390/pharmaceutics11050241 - 20 May 2019

Cited by 18 | Viewed by 3349

Abstract

The use of nanoparticles as tumor-targeting agents is steadily increasing, and the influence of nanoparticle characteristics such as size and stealthiness have been established for a large number of nanocarrier systems. However, not much is known about the impact of tumor presence on [...] Read more.

The use of nanoparticles as tumor-targeting agents is steadily increasing, and the influence of nanoparticle characteristics such as size and stealthiness have been established for a large number of nanocarrier systems. However, not much is known about the impact of tumor presence on nanocarrier circulation times. This paper reports on the influence of tumor presence on the in vivo circulation time and biodistribution of polybutadiene-polyethylene oxide (PBd-PEO) polymersomes. For this purpose, polymersomes were loaded with the gamma-emitter ¹¹¹In and administered intravenously, followed by timed ex vivo biodistribution. A large reduction in circulation time was observed for tumor-bearing mice, with a circulation half-life of merely 5 min (R² = 0.98) vs 117 min (R² = 0.95) in healthy mice. To determine whether the rapid polymersome clearance observed in tumor-bearing mice was mediated by macrophages, chlodronate liposomes were administered to both healthy and tumor-bearing mice prior to the intravenous injection of radiolabeled polymersomes to deplete their macrophages. Pretreatment with chlodronate liposomes depleted macrophages in the spleen and liver and restored the circulation time of the polymersomes with no significant difference in circulation time between healthy mice and tumor-bearing mice pretreated with clodronate liposomes (15.2 ± 1.2% ID/g and 13.6 ± 2.7% ID/g, respectively, at 4 h p.i. with p = 0.3). This indicates that activation of macrophages due to tumor presence indeed affected polymersome clearance rate. Thus, next to particle design, the presence of a tumor can also greatly impact circulation times and should be taken into account when designing studies to evaluate the distribution of polymersomes. Full article

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

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Review

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21 pages, 1274 KiB

Open AccessReview

The Future of PSMA-Targeted Radionuclide Therapy: An Overview of Recent Preclinical Research

by Eline A.M. Ruigrok, Wytske M. van Weerden, Julie Nonnekens and Marion de Jong

Pharmaceutics 2019, 11(11), 560; https://doi.org/10.3390/pharmaceutics11110560 - 29 Oct 2019

Cited by 52 | Viewed by 8424

Abstract

Prostate specific membrane antigen (PSMA) has become a major focus point in the research and development of prostate cancer (PCa) imaging and therapeutic strategies using radiolabeled tracers. PSMA has shown to be an excellent target for PCa theranostics because of its high expression [...] Read more.

Prostate specific membrane antigen (PSMA) has become a major focus point in the research and development of prostate cancer (PCa) imaging and therapeutic strategies using radiolabeled tracers. PSMA has shown to be an excellent target for PCa theranostics because of its high expression on the membrane of PCa cells and the increase in expression during disease progression. Therefore, numerous PSMA-targeting tracers have been developed and (pre)clinically studied with promising results. However, many of these PSMA-targeting tracers show uptake in healthy organs such as the salivary glands, causing radiotoxicity. Furthermore, not all patients respond to PSMA-targeted radionuclide therapy (TRT). This created the necessity of additional preclinical research studies in which existing tracers are reevaluated and new tracers are developed in order to improve PSMA-TRT by protecting the (PSMA-expressing) healthy organs and improving tumor uptake. In this review we will give an overview of the recent preclinical research projects regarding PCa-TRT using PSMA-specific radiotracers, which will give an indication of where the PSMA-TRT research movement is going and what we can expect in future clinical trials. Full article

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

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28 pages, 2343 KiB

Open AccessReview

The Significance of NK1 Receptor Ligands and Their Application in Targeted Radionuclide Tumour Therapy

by Agnieszka Majkowska-Pilip, Paweł Krzysztof Halik and Ewa Gniazdowska

Pharmaceutics 2019, 11(9), 443; https://doi.org/10.3390/pharmaceutics11090443 - 01 Sep 2019

Cited by 34 | Viewed by 5952

Abstract

To date, our understanding of the Substance P (SP) and neurokinin 1 receptor (NK1R) system shows intricate relations between human physiology and disease occurrence or progression. Within the oncological field, overexpression of NK1R and this SP/NK1R system have been implicated in cancer cell [...] Read more.

To date, our understanding of the Substance P (SP) and neurokinin 1 receptor (NK1R) system shows intricate relations between human physiology and disease occurrence or progression. Within the oncological field, overexpression of NK1R and this SP/NK1R system have been implicated in cancer cell progression and poor overall prognosis. This review focuses on providing an update on the current state of knowledge around the wide spectrum of NK1R ligands and applications of radioligands as radiopharmaceuticals. In this review, data concerning both the chemical and biological aspects of peptide and nonpeptide ligands as agonists or antagonists in classical and nuclear medicine, are presented and discussed. However, the research presented here is primarily focused on NK1R nonpeptide antagonistic ligands and the potential application of SP/NK1R system in targeted radionuclide tumour therapy. Full article

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

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25 pages, 2619 KiB

Open AccessReview

Therapeutic Applications of Pretargeting

by Marjolein Verhoeven, Yann Seimbille and Simone U. Dalm

Pharmaceutics 2019, 11(9), 434; https://doi.org/10.3390/pharmaceutics11090434 - 01 Sep 2019

Cited by 39 | Viewed by 4972

Abstract

Targeted therapies, such as radioimmunotherapy (RIT), present a promising treatment option for the eradication of tumor lesions. RIT has shown promising results especially for hematologic malignancies, but the therapeutic efficacy is limited by unfavorable tumor-to-background ratios resulting in high radiotoxicity. Pretargeting strategies can [...] Read more.

Targeted therapies, such as radioimmunotherapy (RIT), present a promising treatment option for the eradication of tumor lesions. RIT has shown promising results especially for hematologic malignancies, but the therapeutic efficacy is limited by unfavorable tumor-to-background ratios resulting in high radiotoxicity. Pretargeting strategies can play an important role in addressing the high toxicity profile of RIT. Key to pretargeting is the concept of decoupling the targeting vehicle from the cytotoxic agent and administrating them separately. Studies have shown that this approach has the ability to enhance the therapeutic index as it can reduce side effects caused by off-target irradiation and thereby increase curative effects due to higher tolerated doses. Pretargeted RIT (PRIT) has been explored for imaging and treatment of different cancer types over the years. This review will give an overview of the various targeted therapies in which pretargeting has been applied, discussing PRIT with alpha- and beta-emitters and as part of combination therapy, plus its use in drug delivery systems. Full article

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

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23 pages, 1372 KiB

Open AccessReview

Beyond the Barrier: Targeted Radionuclide Therapy in Brain Tumors and Metastases

by Janik Puttemans, Tony Lahoutte, Matthias D’Huyvetter and Nick Devoogdt

Pharmaceutics 2019, 11(8), 376; https://doi.org/10.3390/pharmaceutics11080376 - 01 Aug 2019

Cited by 17 | Viewed by 3930

Abstract

Brain tumors are notoriously difficult to treat. The blood-brain barrier provides a sanctuary site where residual and metastatic cancer cells can evade most therapeutic modalities. The delicate nature of the brain further complicates the decision of eliminating as much tumorous tissue as possible [...] Read more.

Brain tumors are notoriously difficult to treat. The blood-brain barrier provides a sanctuary site where residual and metastatic cancer cells can evade most therapeutic modalities. The delicate nature of the brain further complicates the decision of eliminating as much tumorous tissue as possible while protecting healthy tissue. Despite recent advances in immunotherapy, radiotherapy and systemic treatments, prognosis of newly diagnosed patients remains dismal, and recurrence is still a universal problem. Several strategies are now under preclinical and clinical investigation to optimize delivery and maximize the cytotoxic potential of pharmaceuticals with regards to brain tumors. This review provides an overview of targeted radionuclide therapy approaches for the treatment of primary brain tumors and brain metastases, with an emphasis on biological targeting moieties that specifically target key biomarkers involved in cancer development. Full article

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

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