Metabolically Stabilized Peptidomimetics for Improved Tumour Targeting

Regulatory peptides are a class of biomolecules with ideal characteristics for the development of tumour-targeting radiopharmaceuticals. They exhibit a high, specific accumulation in tumours but not in healthy tissue and a favourable pharmacokinetic profile. A drawback of using such peptides for the selective delivery of attached radionuclides to tumours is their low stability due to rapid degradation by enzymes (proteases) before they can reach their target (tumours). It is known from the literature that enhancing the metabolic stability of a peptide carrier can substantially increase its uptake in tumours and metastases. Despite considerable research efforts directed towards the stabilization of the peptides without influencing their favourable biological characteristics, no general approach has yet been identified. We have recently introduced a novel “click chemistry” methodology to achieve this goal. We use metabolically stable 1,2,3-triazole heterocycles as biosiosteres of labile amide bonds of the peptides. We were able to show that the obtained, radiolabelled peptidomimetics exhibit an increased stability and, as a result, a significantly improved tumour uptake in mice.

Selected publications:

[1] “1,2,3-Triazoles as Amide Bond Mimics: Triazole Scan Yields Protease-Resistant Peptidomimetics for Tumor Targeting” I. E. Valverde, A. Bauman,  C. A. Kluba, S. Vomstein, M. Walter, T. L. Mindt Angewandte Chemie International Edition 2013, 52, 8957-8960.
[2] “1,2,3-Triazole Stabilized Neurotensin-Based Radiopeptidomimetics for Improved Tumor Targeting” A. Mascarin, I. E. Valverde, S. Vomstein, T. L. Mindt Bioconjugate Chemistry 2015; 26, 2143–2152.
[3] “Design of Radiolabeled Minigastrin Analogs by Multiple Amide-to-Triazole Substitutions for Enhanced Tumor Targeting” N. M. Grob, S. Schmid, R. Schibli, M. Béhé, T. L. Mindt Journal of Medicinal Chemistry 2020, 63, 4496-4505.
[4] “1,4-Disubstituted 1,2,3-Triazoles as Amide Bond Surrogate for the Stabilisation of Linear Peptides with Biological Activity” L. M. Recnik, W. Kandioller, T. L. Mindt Molecules 2020, 25, 3576-3602.
[5]  “1,5-Disubstituted 1,2,3-Triazoles as Amide Bond Isosteres Yield Novel Tumor-Targeting Minigastrin Analogs” N. M. Grob, R. Schibli, M. Behe, I. E. Valverde, T. L. Mindt Medicinal Chemistry Letters 2021, 12, 585-592.

Funding
Austrian Science Fund Grant N° P 31477-B28
Previous grants (2011-2019): Swiss National Science Foundation Grants No 205321_132280, 2021_157076

Principle Investigator
Prof. Dr. Thomas L. Mindt

Co-Investigators
Dr. Wolfgang Kandioller (University of Vienna), Dr. Berthold Nock (Demokritos, Athens)

Funding: kEUR 430

Duration: 2018-2023

Radiostar – Novel Chelators for Radio-Lanthanides and -Actinides

Radioactive labelled drugs (radiopharmaceuticals) are used in nuclear medicine for the diagnosis and therapy of cancer. In recent year, new therapeutic radiometals have emerged and showed great potential for targeted tumour therapy. For example, the alpha particle emitting radiometal actinium-225 (Ac-225) is particularly of current interest for endoradiotherapy. Medical applications of radioactive metals require chelators to attach them to tumour-targeting biomolecules (e.g., proteins). Such chelators must form complexes with the radiometal of sufficient stability so that the radioactive label does not dissociate from the bioconjugate in vivo. Suitable chelators are known for a number of radioactive transition metals. However, the size and complexation chemistry is different for the lanthanides and actinides (e.g., Ac-225). As a result, only few examples of chelators for these radiometals have been investigated and no ideal candidate has yet been reported. There is a clear need for new chelators that will facilitate and expedite clinical applications of the emerging and promising radioactive lanthanides and actinides.

Based on previously developed chemistry, novel chelators for lanthanides and actinides will be synthesized and attached to biomolecules. The bioconjugates will be labelled with radiometals and fully evaluated in vitro (e.g. on cells) for their stability and tumour targeting properties (e.g., affinity towards the target). Promising candidates will be selected and used for studies in mice bearing tumour xenografts (biodistribution experiments and small animal PET/CT imaging).

Funding
Austrian Research Promotion Agency, Bridge-1 Project

Principle Investigator
Prof. Dr. Thomas L. Mindt

Co-Investigators
Dr. Christoph Denk (Technical University of Vienna) Clemens Pichler (DSD-Pharma, AT)

Funding: kEUR 450

Duration: 2020-2023

Marker für die Aktivität von Albumin-bindenden Verbindungen

Es gibt mehr und mehr Anhaltspunkte, dass sich Krebszellen in ihren Strategien Nährstoffe aufzunehmen von gesundem Gewebe unterscheiden. Speziell ihre erhöhte Aufnahme von Plasmaproteinen, wie zum Beispiel Albumin, stellt einen vielversprechenden Ansatzpunkt für die Therapie dar. Dies konnte bereits durch den klinischen Erfolg von Medikamenten wie Abraxane (ein Albumin-Paclitaxel Nanopartikel) oder Aldoxorubicin (ein Albumin-bindendes Doxorubicin) unterstrichen wird. Auf Grund dessen ist es von großem Interesse weitere Medikamente zu entwickeln, welche über Albumin spezifisch in die Krebszelle transportiert werden. Zu diesem Zweck haben wir kürzlich die erste Albumin-bindende Prodrug von Oxaliplatin entwickelt. Diese neue Verbindung, welche vielversprechende Aktivität gegen Dickdarmkrebs zeigt, wäre eine gute Möglichkeit das häufig in Kolorektalkrebs verabreichte FOLFOX Schema (Folinsäure, 5-Fluorouracil und Oxaliplatin) zu verbessern. Doch obwohl das Potential der Albumin-vermittelten Therapie für die Behandlung von Krebserkrankungen schon klinisch geprüft wurde, ist das Wissen über die Unter-schiede im Albumin Metabolismus zwischen Krebszellen und gesunden Zellen überraschend gering.

Die Ziele des hier präsentierten Antrags sind einerseits das bessere Verstehen der Albumin Homöostase in Dickdarmkarzinomen und andererseits das Verwenden dieses Wissen für die präklinische Entwicklung einer neuen Albumin-bindenden Oxaliplatin-Prodrug.

Ein Schwerpunkt bildet die Rolle potenzieller Biomarker (z.B. K-RAS) in der Albuminaufnahme von malignen Zellen. Dies soll im Rahmen dieses Projektes durch verschiedenen zell-und molekularbiologischer Methoden analysiert werden. Zusätzlich wird eine neue PET Bildgebungsplattform, unter der Verwendung von ⁸⁹Zr-markierten Albuminkonjugaten, etabliert. Diese soll die Untersuchung der Albuminaufnahme in Tumorknoten in vivo in einer nicht invasiven und quantitativen Art und Weise ermöglichen und so als Hilfsmittel für die Stratifizierung zukünftiger Patientenkohorten herangezogen werden können.

Funding
Austrian Science Fund No P 32886-B

Principle Investigator
Prof. Dr. Petra Heffeter (Medical University of Vienna)

Co-Investigators
Prof. Dr. Thomas Mindt (LBIAD), Prof. Dr. Christian Kowol (University of Vienna)

Funding: kEUR 400

Duration: 2020-2024

Bi-Metallic Complexes for Synergistic and Theranostic Applications

The use of metals in medicine is very versatile, ranging from different diagnostic to therapeutic applications. This project aims at the combination of two metal-based therapies in order to increase the therapeutic efficacy in comparison to the individual treatments alone. Namely, we will combine photodynamic therapy (PDT) with nuclear radioendotherapy (RET). For PDT, metal-containing compounds are excited by light and subsequently, because in aqueous biological media, reactive oxygen species are produced that destroy the surrounding diseased tissue (tumors, infections (viruses) etc.). RET utilizes radioactive metals whose ionizing radiation is toxic and also destroys the surrounding diseased tissue. Goal of this project is to chemically combine two suitable metals (ruthenium and rhenium) in one construct that allows for simultaneous PDT and RET. The bi-metallic compounds will be conjugated to a targeted biomolecule (e.g., antibody) that serves as carrier for the selective transport of the therapeutic cargo to the diseased site while sparing healthy tissue. The bi-metallic compounds and conjugates thereof will be tested biologically (e.g., on cells) in order to investigate the interplay of the two therapies.

Funding
Austrian Science Fund (AT), Agence Nationale de la Recherche (FR) No I 5721

Principle Investigators
Prof. Dr. Thomas Mindt (University of Vienna; AT), Prof. Dr. Gilles Gasser (Chimie ParisTech; FR)

Funding: kEUR 450

Duration: 2021-2025