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Figueras E, Martins A, Borbély A, et al. Octreotide Conjugates for Tumor Targeting and Imaging. Pharmaceutics. 2019;11(5)doi: 10.3390/pharmaceutics11050220.
Figueras, E., Martins, A., Borbély, A., Le Joncour, V., Cordella, P., Perego, R., Modena, D., Pagani, P., Esposito, S., Auciello, G., Frese, M., Gallinari, P., Laakkonen, P., Steinkühler, C., & Sewald, N. (2019). Octreotide Conjugates for Tumor Targeting and Imaging. Pharmaceutics, 11(5), . https://doi.org/10.3390/pharmaceutics11050220
Figueras, Eduard, et al. "Octreotide Conjugates for Tumor Targeting and Imaging." Pharmaceutics vol. 11,5 (2019). doi: https://doi.org/10.3390/pharmaceutics11050220
Figueras E, Martins A, Borbély A, Le Joncour V, Cordella P, Perego R, Modena D, Pagani P, Esposito S, Auciello G, Frese M, Gallinari P, Laakkonen P, Steinkühler C, Sewald N. Octreotide Conjugates for Tumor Targeting and Imaging. Pharmaceutics. 2019 May 07;11(5). doi: 10.3390/pharmaceutics11050220. PMID: 31067748; PMCID: PMC6571972.
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Pharmaceutics. 2019 May 07;11(5). doi: 10.3390/pharmaceutics11050220.

Octreotide Conjugates for Tumor Targeting and Imaging.

Pharmaceutics

Eduard Figueras, Ana Martins, Adina Borbély, Vadim Le Joncour, Paola Cordella, Raffaella Perego, Daniela Modena, Paolo Pagani, Simone Esposito, Giulio Auciello, Marcel Frese, Paola Gallinari, Pirjo Laakkonen, Christian Steinkühler, Norbert Sewald

Affiliations

  1. Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstraße 25, DE-33615 Bielefeld, Germany. [email protected].
  2. Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstraße 25, DE-33615 Bielefeld, Germany. [email protected].
  3. Exiris srl, Via di Castel Romano 100, IT-00128 Rome, Italy. [email protected].
  4. Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstraße 25, DE-33615 Bielefeld, Germany. [email protected].
  5. Translational Cancer Medicine, Research Programs Unit, Haartmaninkatu 8, FI-00014 University Helsinki, Finland. [email protected].
  6. Italfarmaco SpA, Via dei Lavoratori 54, IT-20092 Cinisello Balsamo, Italy. [email protected].
  7. Italfarmaco SpA, Via dei Lavoratori 54, IT-20092 Cinisello Balsamo, Italy. [email protected].
  8. Italfarmaco SpA, Via dei Lavoratori 54, IT-20092 Cinisello Balsamo, Italy. [email protected].
  9. Italfarmaco SpA, Via dei Lavoratori 54, IT-20092 Cinisello Balsamo, Italy. [email protected].
  10. IRBM SpA, Via Pontina km. 30,600, IT-00071 Pomezia, Italy. [email protected].
  11. IRBM SpA, Via Pontina km. 30,600, IT-00071 Pomezia, Italy. [email protected].
  12. Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstraße 25, DE-33615 Bielefeld, Germany. [email protected].
  13. Exiris srl, Via di Castel Romano 100, IT-00128 Rome, Italy. [email protected].
  14. Translational Cancer Medicine, Research Programs Unit, Haartmaninkatu 8, FI-00014 University Helsinki, Finland. [email protected].
  15. Exiris srl, Via di Castel Romano 100, IT-00128 Rome, Italy. [email protected].
  16. Italfarmaco SpA, Via dei Lavoratori 54, IT-20092 Cinisello Balsamo, Italy. [email protected].
  17. Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstraße 25, DE-33615 Bielefeld, Germany. [email protected].

PMID: 31067748 PMCID: PMC6571972 DOI: 10.3390/pharmaceutics11050220

Abstract

Tumor targeting has emerged as an advantageous approach to improving the efficacy and safety of cytotoxic agents or radiolabeled ligands that do not preferentially accumulate in the tumor tissue. The somatostatin receptors (SSTRs) belong to the G-protein-coupled receptor superfamily and they are overexpressed in many neuroendocrine tumors (NETs). SSTRs can be efficiently targeted with octreotide, a cyclic octapeptide that is derived from native somatostatin. The conjugation of cargoes to octreotide represents an attractive approach for effective tumor targeting. In this study, we conjugated octreotide to cryptophycin, which is a highly cytotoxic depsipeptide, through the protease cleavable Val-Cit dipeptide linker using two different self-immolative moieties. The biological activity was investigated in vitro and the self-immolative part largely influenced the stability of the conjugates. Replacement of cryptophycin by the infrared cyanine dye Cy5.5 was exploited to elucidate the tumor targeting properties of the conjugates in vitro and in vivo. The compound efficiently and selectively internalized in cells overexpressing SSTR2 and accumulated in xenografts for a prolonged time. Our results on the in vivo properties indicate that octreotide may serve as an efficient delivery vehicle for tumor targeting.

Keywords: cryptophycin; cytotoxic payloads; imaging; octreotide; small molecule drug conjugates; tumor targeting

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