Mini-review: Targeted radiopharmaceuticals incorporating reversible, low molecular weight albumin binders

Brandt, Marie; Cardinale, Jens; Giammei, Carolina; Guarrochena, Xabier; Happl, Barbara; Jouini, Nédra; Mindt, Thomas L.

doi:10.1016/j.nucmedbio.2019.01.006

Cited by 30 publications

(22 citation statements)

References 43 publications

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“…The albumin is a major protein in blood plasma and actively used in formation of albumin-based drug delivery systems because of selective accumulation into the solid tumor via so-called the enhanced permeation and retention (EPR) effect [128]. At the moment, there is already existed the first albumin based antineoplastic agent approved by the FDA, which is called Abraxane.…”

Section: Introductionmentioning

confidence: 99%

“…These HSA binders possess a high affinity towards HSA and can be coated with targeting ligands and radionuclides, forming HSA-binding conjugates. The concept of using reversible HSA-binders to modulate the blood circulation time and hence the pharmacokinetic profile of radiolabeled molecules was adapted and applied by other groups [128]. Besides HSA in an individual form, the radionuclide (usually 99m Tc) labeled HSA aggregates are widely used in clinics.…”

Section: Introductionmentioning

confidence: 99%

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Current outlook on radionuclide delivery systems: from design consideration to translation into clinics

et al. 2019

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Radiopharmaceuticals have proven to be effective agents, since they can be successfully applied for both diagnostics and therapy. Effective application of relevant radionuclides in pre-clinical and clinical studies depends on the choice of a sufficient delivery platform. Herein, we provide a comprehensive review on the most relevant aspects in radionuclide delivery using the most employed carrier systems, including, (i) monoclonal antibodies and their fragments, (ii) organic and (iii) inorganic nanoparticles, and (iv) microspheres. This review offers an extensive analysis of radionuclide delivery systems, the approaches of their modification and radiolabeling strategies with the further prospects of their implementation in multimodal imaging and disease curing. Finally, the comparative outlook on the carriers and radionuclide choice, as well as on the targeting efficiency of the developed systems is discussed.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Current outlook on radionuclide delivery systems: from design consideration to translation into clinics

et al. 2019

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“…Previous studies have shown that enhanced stability with reduced receptor affinity leads to minor or no improvement in the biodistribution of the peptidomimetics [ 16 , 17 ]. Therefore, unless the conjugates are functionalized with pharmacokinetic modifiers (preventing them from rapid renal elimination [ 31 ]), a favorable receptor interaction outweighs an increase in stability. Already, at 1 h p.i., the 177 Lu-labeled PP-F11N, and NMG 2 and 3 were cleared from the blood (<0.5% i.A./g), and only low levels of radioactivity were found in CCK2R-negative tissues or organs, resulting in an excellent tumor-to-background ratio.…”

Section: Discussionmentioning

confidence: 99%

Improved Tumor-Targeting with Peptidomimetic Analogs of Minigastrin 177Lu-PP-F11N

Grob

Schibli

Béhé

et al. 2021

Cancers

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The cholecystokinin-2 receptor (CCK2R) is an attractive target in nuclear medicine due to its overexpression by different tumors. Several radiolabeled peptidic ligands targeting the CCK2R have been investigated in the past; however, their low stability against proteases can limit their uptake in tumors and metastases. Substitution of single or multiple amide bonds with metabolically stable 1,4-disubstituted 1,2,3-triazoles as amide bond bioisosteres proved a promising strategy for improving the tumor-targeting properties of a truncated analog of minigastrin. In this study, we applied the previously studied structural modifications to improve the pharmacokinetic and pharmacodynamic properties of PP-F11N, a minigastrin analog currently in clinical trials. Novel minigastrins (NMGs) as analogs of PP-F11N with one or two amide bonds substituted by 1,2,3-triazoles were synthesized, radiolabeled with 177Lu3+, and subjected to full evaluation in vitro (cell internalization, receptor affinity, stability in blood plasma) and in vivo (stability, biodistribution, SPECT/CT imaging). NMGs with triazoles inserted between the amino acids DGlu10-Ala11 and/or Tyr12-Gly13 showed a significantly increased cellular uptake and affinity toward the CCK2R in vitro. Resistance against the metabolic degradation of the NMGs was comparable to those of the clinical candidate PP-F11N. Imaging by SPECT/CT and biodistribution studies demonstrated a higher uptake in CCK2R-positive tumors but also in the CCK2R-positive stomach. The peptidomimetic compounds showed a slow tumor washout and high tumor-to-kidney ratios. The structural modifications led to the identification of analogs with promising properties for progression to clinical applications in the diagnosis and therapy of CCK2R-positive neoplasms.

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“…More detailed studies reviewing the main findings related to pharmacokinetic modifications of PSMA inhibitors have been published elsewhere [109,110]. Due to the lack of clinical data, it is currently unclear which role the albumin-binding inhibitors will have in the field of PSMA-TRT.…”

Section: Pharmacokinetic Modifications: Albumin Binders Charged Spacers and Cleavable Linkersmentioning

confidence: 99%

PSMA-Targeting Radiopharmaceuticals for Prostate Cancer Therapy: Recent Developments and Future Perspectives

Fakiri

Geis

Ayada

et al. 2021

Cancers

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Prostate cancer (PC) is the second most common cancer among men, with 1.3 million yearly cases worldwide. Among those cancer-afflicted men, 30% will develop metastases and some will progress into metastatic castration-resistant prostate cancer (mCRPC), which is associated with a poor prognosis and median survival time that ranges from nine to 13 months. Nevertheless, the discovery of prostate specific membrane antigen (PSMA), a marker overexpressed in the majority of prostatic cancerous tissue, revolutionised PC care. Ever since, PSMA-targeted radionuclide therapy has gained remarkable international visibility in translational oncology. Furthermore, on first clinical application, it has shown significant influence on therapeutic management and patient care in metastatic and hormone-refractory prostate cancer, a disease that previously had remained immedicable. In this article, we provide a general overview of the main milestones in the development of ligands for PSMA-targeted radionuclide therapy, ranging from the firstly developed monoclonal antibodies to the current state-of-the-art low molecular weight entities conjugated with various radionuclides, as well as potential future efforts related to PSMA-targeted radionuclide therapy.

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Mini-review: Targeted radiopharmaceuticals incorporating reversible, low molecular weight albumin binders

Cited by 30 publications

References 43 publications

Current outlook on radionuclide delivery systems: from design consideration to translation into clinics

Current outlook on radionuclide delivery systems: from design consideration to translation into clinics

Improved Tumor-Targeting with Peptidomimetic Analogs of Minigastrin 177Lu-PP-F11N

PSMA-Targeting Radiopharmaceuticals for Prostate Cancer Therapy: Recent Developments and Future Perspectives

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