Speaker
Descrizione
Cancer theragnostics is an emerging field of nuclear medicine that allows the integration of imaging and radiotherapy. It is based on the use of a pair of radiopharmaceuticals with the same molecular structure, one containing a positron-emitting isotope (such as fluorine-18 (18F) or gallium-68 (68Ga)) for PET imaging, aiding disease staging, therapy selection and monitoring. The other containing an alpha- or beta-emitting nuclide, such as lutetium-177 (177Lu), for targeted radiotherapy [1]. In recent years, several selective radiotracers have been developed and approved for clinical use based on differences in the overexpression of proteins on the cell surfaces of normal and malignant cells [2]. However, standard monospecific radiotracers are often ineffective due to the heterogeneity of the tumour and the complex interactions between the neoplastic cells and the surrounding microenvironment [3]. These radiotracers also suffer from limited tumor retention, reducing their therapeutic utility [4]. To address these limitations, multimeric agents able to hit multiple targets simultaneously have been developed, enhancing tumor specificity, uptake, sensitivity, and retention compared to traditional agents [5] – [7].
This project aims to develop novel classes of multimeric theragnostic agents selectively targeting the tumor microenvironment, utilizing integrin ligands (RGD peptides), fibroblast activation protein inhibitors (FAPI), and carbonic anhydrase ligands (CA IX/XII). These compounds will be labelled with 18F for in vivo PET imaging to assess tumor uptake and biodistribution and at the University Medical Center Groningen (UMCG) will be labelled with 177Lu for in vitro studies to assess cellular uptake, affinity, specificity and antitumour activity. For both in vivo imaging studies and in vitro therapeutic effect assessment, the performance of multimeric compounds will be compared to their monomeric counterparts.
Currently, radiolabelling protocols with 18F have been optimised for monomeric radiotracers. In detail, decay-corrected radiochemical yields of 30.9 ± 2.5 % and 28.3 ± 3 0 %, with a molar activity of 3.0 ± 0.2 GBq/umol and 1.9 ± 0.7 GBq/umol, were obtained for [18F]AlF-NOTA-FAPI-04 and [18F]AlF-NOTA-RGDfK, respectively. Both radiotracers showed a radiochemical purity (RCP) ≥97 % and stability in PBS and FBS for two hours. For [18F]AlF-NOTA-CA IX/XII, although optimal radiolabelling conditions were identified, the purification failed to meet the standards for animal use (RCP >95%), requiring further purification of the precursor by the NERUOFARBA department of the University of Florence. In addition, the first in vivo PET imaging studies were carried out on a B16F10 syngeneic mouse model of melanoma with the monomeric [18F]AlF-NOTA-FAPI-04 and [18F]AlF-NOTA-RGDfK radiotracers with the aim of highlighting their tumour uptake and biodistribution for a subsequent comparative study with the corresponding multimeric radiotracer."
[1] Zoi V, Giannakopoulou M, Alexiou GA, Bouziotis P, Thalasselis S, Tzakos AG, Fotopoulos A, Papadopoulos AN, Kyritsis AP, Sioka C. Nuclear Medicine and Cancer Theragnostics: Basic Concepts. Diagnostics (Basel). 2023 Sep 26;13(19):3064. doi: 10.3390/diagnostics13193064. PMID: 37835806; PMCID: PMC10572920.
[2] Y.-Y. Huang, "An Overview of PET Radiopharmaceuticals in Clinical Use: Regulatory, Quality and Pharmacopeia Monographs of the United States and Europe," in Nuclear Medicine Physics, IntechOpen, 2019. doi: 10.5772/intechopen.79227.
[3] D. F. Quail and J. A. Joyce, "Microenvironmental regulation of tumor progression and metastasis," Nat. Med., vol. 19, no. 11, pp. 1423– 1437, Nov. 2013, doi: 10.1038/nm.3394
[4] C. D. van der Heide and S. U. Dalm, “Radionuclide imaging and therapy directed towards the tumor microenvironment: a multi-cancer approach for personalized medicine,” Eur. J. Nucl. Med. Mol. Imaging, vol. 49, no. 13, pp. 4616–4641, Nov. 2022, doi: 10.1007/s00259-022-05870-1.
[5] J. Zang et al., “Synthesis, preclinical evaluation and radiation dosimetry of a dual targeting PET tracer [ 68 Ga]Ga-FAPI-RGD,” Theranostics, vol. 12, no. 16, pp. 7180–7190, 2022, doi: 10.7150/thno.79144.
[6] Y. Gai et al., “Evaluation of an Integrin α v β 3 and Aminopeptidase N Dual-Receptor Targeting Tracer for Breast Cancer Imaging,” Mol. Pharm., vol. 17, no. 1, pp. 349–358, Jan. 2020, doi: 10.1021/acs.molpharmaceut.9b01134.
[7] Y. Zheng et al., “Evaluation of Lung Cancer and Neuroendocrine Neoplasm in a Single Scan by Targeting Both Somatostatin Receptor and Integrin αvβ3,” Clin. Nucl. Med., vol. 44, no. 9, pp. 687–694, Sep. 2019, doi: 10.1097/RLU.0000000000002680.
