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oai:recercat.cat:10256/281222026-01-17T00:56:36Zcom_2072_452955com_2072_2054col_2072_453073

A nucleus-directed bombesin derivative for targeted delivery of metallodrugs to cancer cells Barrabés Vera, Sílvia Ng-Choi, Iteng Martínez Lorente, Mª Ángeles Manzano, Blanca R. Jalón, Félix A. Espino, Gustavo Feliu Soley, Lidia Planas i Grabuleda, Marta Llorens Duran, Rafael de Massaguer i Vall-llovera, Anna Agencia Estatal de Investigación Bombesina -- Síntesi Bombesin -- Synthesis Medicaments antineoplàstics Antineoplastic agents Cèl·lules canceroses Cancer cells We have synthesized a set of bombesin derivatives with the aim of exploring their tumor targeting properties to deliver metal-based chemotherapeutics into cancer cells. Peptide QRLGNQWAVGHLL-NH2 (BN3) was selected based on its high internalization in gastrin-releasing peptide receptor (GRPR)-overexpressing PC-3 cells. Three metallopeptides were prepared by incorporating the terpyridine Pt(II) complex [PtCl(cptpy)]Cl (1) (cptpy = 4′-(4-carboxyphenyl)-2,2′:6,2″-terpyridine) at the N-terminus of BN3 or at the NƐ- or Nα-amino group of an additional Lys residue (1-BN3, Lys-1-BN3 and 1-Lys-BN3, respectively). 1-Lys-BN3 displayed the best cytotoxic activity (IC50: 19.2 ± 1.7 μM) and similar ability to intercalate into DNA than complex 1. Moreover, the polypyridine Ru(II) complex [Ru(bpy)2)(cmbpy)](PF6)2 (2) (bpy = 2,2′-bipyridine; cmbpy = 4-methyl-2,2′-bipyridine-4′-carboxylic acid), with proven activity as photosensitizer, was coupled to BN3 leading to metallopeptide 2-Lys-BN3. Upon photoactivation, 2-Lys-BN3 displayed 2.5-fold higher cytotoxicity against PC-3 cells (IC50: 7.6 ± 1.0 μM) than complex 2. To enhance the accumulation of the drugs into the cell nucleus, the nuclear localization signal (NLS) PKKKRKV was incorporated at the N-terminus of BN3. NLS-BN3 displayed higher cellular internalization along with nuclear biodistribution. Accordingly, metallopeptides 1-NLS-BN3 and 2-NLS-BN3 showed increased cytotoxicity (IC50: 12.0 ± 1.1 μM and 2.3 ± 1.1 μM). Interestingly, the phototoxic index of 2-NLS-BN3 was 8-fold higher than that of complex 2. Next, the selectivity towards cancer cells was explored using 1BR3.G fibroblasts. Higher selectivity indexes were obtained for 1-NLS-BN3 and 2-NLS-BN3 than for the unconjugated complexes. These results prove NLS-BN3 effective for targeted delivery of metallodrugs to GRPR-overexpressing cells and for enhancing the cytotoxic efficacy of metal-based photosensitizers This work was supported by the University of Girona (grants MPCUdG2016/038 and MPCUdG2016/076); the Spanish Ministerio de Ciencia, Innovación y Universidades (grants RTI2018-100709-B-C21 and RTI2018-100709-B-C22) and Junta de Castilla La Mancha-FEDER funds (SBPLY/19/180501/000260) 2020-11 info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion peer-reviewed http://hdl.handle.net/10256/28122 32919249 http://hdl.handle.net/10256/28122 eng info:eu-repo/semantics/altIdentifier/doi/10.1016/j.jinorgbio.2020.111214 info:eu-repo/semantics/altIdentifier/issn/0162-0134 info:eu-repo/semantics/altIdentifier/eissn/1873-3344 RTI2018-100709-B-C22 info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-100709-B-C22/ES/NUEVOS METALOFARMACOS DISEÑADOS PARA INCREMENTAR LA SELECTIVIDAD. USO DE FOTOTERAPIA Y VEHICULIZACION CON LIGANDOS DIRIGIDOS A TUMORES/ Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess application/pdf Elsevier © Journal of Inorganic Biochemistry, 2020, vol. 212, art. núm. 111214 Articles publicats (D-Q)