Journal: Molecular Pharmaceutics

Abbreviation

Mol. Pharmaceutics

Publisher

American Chemical Society

Journal Volumes

ISSN

1543-8384
1543-8392

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2010 - 2019272020 - 202611
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Publications1 - 10 of 38
  • Effects of the Antifolates Pemetrexed and CB3717 on the Tissue Distribution of 99mTc-EC20 in Xenografted and Syngeneic Tumor-Bearing Mice
    Item type: Journal Article
    Müller, Cristina; Reddy, Joseph A.; Leamon, Christopher P.; et al. (2010)
    Molecular Pharmaceutics
  • Combination with Immunocytokines Enhances the Anticancer Activity of Small Molecule Drug Conjugates and Radioligand Therapeutics Targeting Fibroblast Activation Protein
    Item type: Journal Article
    Bocci, Matilde; Lucaroni, Laura; Ravazza, Domenico; et al. (2026)
    Molecular Pharmaceutics
    The targeted delivery of radionuclides and cytotoxic drugs represents a viable alternative to conventional chemotherapy, aiming to improve therapeutic efficacy and reduce systemic toxicity by selective accumulation of the active payload at the tumor site. Our group has developed radioligand therapeutics (RLTs) and small molecule-drug conjugates (SMDCs) targeting fibroblast activation protein (FAP), a tumor-associated antigen abundantly and selectively expressed in the majority of solid human malignancies. Among these, 177Lu-OncoFAP-23 and OncoFAP-GlyPro-MMAE showed selective accumulation in FAP-positive tumors in murine models and demonstrated potent anticancer activity. To further enhance the therapeutic efficacy, combining targeted drugs with immunotherapy may provide synergistic benefits by engaging both direct tumor cell killing and immune system activation. In this work, we explored the combination of FAP-targeting cytotoxic and radioactive therapeutics with three different immunocytokines targeting the Extra Domain B (EDB) of fibronectin: L19-hIL2, L19-mIL12, and L19-mTNF. A therapy experiment in immunocompetent mice bearing low FAP-expressing tumors showed that the combination with L19-hIL2 potentiated the antitumoral activity of 177Lu-OncoFAP-23 and OncoFAP-GlyPro-MMAE. These results provided the motivation for the clinical development of these combinations for treating FAP-positive solid tumors.
  • Design and Preclinical Evaluation of an Albumin-Binding PSMA Ligand for ^64Cu-Based PET Imaging
    Item type: Journal Article
    Umbricht, Christoph A.; Benešová, Martina; Hasler, Roger; et al. (2018)
    Molecular Pharmaceutics
  • Inductively Coupled Plasma Mass Spectrometry-A Valid Method for the Characterization of Metal Conjugates in View of the Development of Radiopharmaceuticals
    Item type: Journal Article
    Wallimann, Rahel H.; Schindler, Patrick; Hensinger, Heloise; et al. (2023)
    Molecular Pharmaceutics
    This study addresses the question whether in-ductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a "proof-of-concept" study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [177Lu]Lu-PSMA-617 (PLU-VICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional gamma-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[177Lu]Lu-PSMA-617 (41 +/- 6% ID/g and 44 +/- 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 +/- 5% ID/g and 44 +/- 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 +/- 2% ID/g vs 10 +/- 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art gamma-counting methodology to detect radioactive ligands.
  • Radiolabeled 111In-FGF-2 Is Suitable for In Vitro/Ex Vivo Evaluations and In Vivo Imaging
    Item type: Journal Article
    Moscaroli, Alessandra; Jones, Gabriel; Lühmann, Tessa; et al. (2017)
    Molecular Pharmaceutics
  • 64Cu- and 68Ga-Based PET Imaging of Folate Receptor-Positive Tumors: Development and Evaluation of an Albumin-Binding NODAGA-Folate
    Item type: Journal Article
    Farkas, Renáta; Siwowska, Klaudia; Ametamey, Simon M.; et al. (2016)
    Molecular Pharmaceutics
  • Noninternalizing Targeted Cytotoxics for Cancer Therapy
    Item type: Journal Article
    Casi, Giulio; Neri, Dario (2015)
    Molecular Pharmaceutics
  • Albumin-Binding PSMA Ligands: Optimization of the Tissue Distribution Profile
    Item type: Journal Article
    Benešová, Martina; Umbricht, Christoph A.; Schibli, Roger; et al. (2018)
    Molecular Pharmaceutics
  • Biocompatible Polymer Nanoformulation To Improve the Release and Safety of a Drug Mimic Molecule Detectable via ICP-MS
    Item type: Journal Article
    Ferrari, Raffaele; Talamini, Laura; Violatto, Martina Bruna; et al. (2017)
    Molecular Pharmaceutics
  • Design and Preclinical Evaluation of Novel uPAR-Targeting Radiopeptides Modified with an Albumin-Binding Entity
    Item type: Journal Article
    Beyer, Darja; Vaccarin, Christian; Schmid, Jerome V.; et al. (2025)
    Molecular Pharmaceutics
    Several studies have focused on the development and application of radiolabeled DOTA-AE105 for targeting the urokinase-type plasminogen activator receptor (uPAR), which is expressed on various cancer types. The aim of this project was to design and evaluate novel uPAR-targeting radiopeptides with improved pharmacokinetic properties in view of their therapeutic application. Five peptides (uPAR-01, uPAR-02, uPAR-03, uPAR-04, and uPAR-05) were synthesized based on the AE105 peptide backbone, a DOTA chelator, and the 4-(p-iodophenyl)butanoate moiety as an albumin binder. The peptides were obtained in 20-29 synthetic steps using solid-phase peptide synthesis with a 6-34% overall yield. In saline, the $^{177}$Lu-labeled peptides (100 MBq/nmol) were stable (>93% intact radiopeptides) in the presence of L-ascorbic acid over 24 h. The new radiopeptides were also stable (>98% intact radiopeptides) in mouse and human blood plasma, while only ~13% of [$^{177}$Lu]Lu-DOTA-AE105 was intact after a 4 h incubation period. The uPAR-binding affinities (K$_D$ values) determined with uPAR-transfected human embryonic kidney cells (HEK-uPAR) ranged from 10 to 57 nM and were, thus, similar to that of [$^{177}$Lu]Lu-DOTA-AE105 (K$_D$: 20 $\pm$ 1 nM). Compared to [$^{177}$Lu]Lu-DOTA-AE105, the radiopeptides showed the anticipated increased binding affinity to plasma proteins both in mouse (31- to 104-fold) and human blood plasma (43- to 136-fold). The tissue distribution of the novel radiopeptides in nude mice bearing HEK-uPAR xenografts showed substantial activity retention in the blood (12-16% IA/g and 4.5-13% IA/g at 4 and 24 h p.i., respectively), while [$^{177}$Lu]Lu-DOTA-AE105 was rapidly cleared (<0.1% IA/g at 4 h p.i.). As a result, the accumulation of the new radiopeptides in HEK-uPAR xenografts (3.6-11% and 3.1-10% IA/g at 4 and 24 h p.i., respectively) was increased in comparison to that of [$^{177}$Lu]Lu-DOTA-AE105 (<1% IA/g at 4 h p.i.). Importantly, the metabolic stability of the new radiopeptides in mice was enhanced as compared to that of [$^{177}$Lu]Lu-DOTA-AE105. [Lu-177]Lu-uPAR-02 showed the most promising tissue distribution profile with over 10-fold higher activity retention in the HEK-uPAR xenograft than observed after injection of [$^{177}$Lu]Lu-DOTA-AE105. As a result, the xenograft-to-kidney ratio of [$^{177}$Lu]Lu-uPAR-02 was >3-fold higher than that of [$^{177}$Lu]Lu-DOTA-AE105.
Publications1 - 10 of 38