Chimeric peptide-based radiopharmaceuticals for glioblastoma imaging and therapy by targeting mHsp70 and enhancing BBB penetration.

Overview

1. Chair of Medicinal and Bioinorganic Chemistry, Department of Chemistry, School of Natural Sciences, Technical University of Munich, Lichtenbergstrasse 4, 85748 Garching bei München, Germany
2. Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, CTN, LRS, Estrada Nacional 10, 2695-066 Bobadela, Portugal
3. Department of Nuclear Medicine, TUM University Hospital, Central Institute for Translational Cancer Research (TranslaTUM), School of Medicine and Health, Technical University of Munich, 81675 Munich, Germany
4. Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, LRS, Estrada Nacional 10, 2695-066 Bobadela, Portugal
5. Fundação GIMM – Gulbenkian Institute for Molecular Medicine, Avenida Professor Egas Moniz, Lisboa, 1649–028, Portugal
6. Instituto de Bioquímica, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, Lisboa, 1649–028, Portugal

Abstract

Glioblastoma (GBM) is the most aggressive form of malignant brain cancer. Here, we synthesized two chimeric peptide-based radiopharmaceuticals (Comb-1 and Comb-2) targeted to the membrane-bound form of heat shock protein 70 (mHsp70), which is overexpressed in GBM tissues, for future theranostic applications. The design concept features a DOTA chelator for coordination to different radiometals tethered directly or via a PEG linker to a chimeric peptide. The latter combines the Hsp70-targeting ability of the TPP sequence with the blood–brain barrier (BBB) penetration of another 7-amino acid sequence (d-PepH3) derived from the dengue virus capsid protein (DEN2C). The two compounds were successfully radiolabelled with gallium-67, suitable for single photon emission computed tomography (SPECT) imaging, or with lutetium-177 for β− therapy. Furthermore, the in vitro properties of the ligand, including lipophilicity (log D7.4), human serum albumin (HSA) binding, and stability in human serum were evaluated. The presence of the TPP sequence affected the half-life of the combinatorial peptides. Cytometry assays performed with a fluorescent analogue of Comb-2 confirmed the binding to mHsp70-expressing U87-MG cells. In an in vitro model, all tracers demonstrated the ability to cross the BBB, indicating that conjugation of the mHsp70-targeting peptide to the PepH3 sequence did not impair its translocating properties. Biodistribution experiments with 67Ga-labeled compounds were performed in naive female CD1 mice and showed brain uptake at 2 min p.i., as well as renal excretion. For the best performing compound [67Ga]Ga-Comb-2 (0.60 ± 0.17% IA g−1 (injected activity per gram)), the biodistribution experiment was also performed with perfusion of the organs after sacrifice, and the results showed retention of radioactivity in the brain (0.14 ± 0.05% IA g−1). Further metabolic studies in murine urine and blood were performed after biodistribution, confirming the stability of the chimeric tracers.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• zenodo:20183561 — at Zenodo; found in “Data availability”

Data availability

Original cytometry data files have been provided on Zenodo, DOI: https://doi.org/10.5281/zenodo.20183561.

The data supporting this article, including abbreviations, additional experimental procedures, characterization data, additional figures and tables, chromatograms, and spectra, are included in the supplementary information (SI). Supplementary information: details on the synthesis and characterization of peptide-based radiotracers, as well as RP-HPLC chromatograms and (HR-) ESI-MS spectra of quality controls and radioactive labeling; and data on stability studies, cytometry analysis, in silico prediction of BBB translocation, biodistribution, and metabolic studies. See DOI: https://doi.org/10.1039/d6sc00011h.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 4 funders, 67 references.

Cite

This paper

Schuderer, F., Silva, R. D. M., Pinto, C. I. G., Koller, L., Stangl, S., Gano, L., Cavaco, M., Castanho, M. A. R., Mendes, F., Kossatz, S., Correia, J. D. G., & Casini, A. (2026). Chimeric peptide-based radiopharmaceuticals for glioblastoma imaging and therapy by targeting mHsp70 and enhancing BBB penetration. Chemical science, 17(29), 14222-14236. https://doi.org/10.1039/d6sc00011h

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