Peptide nucleic acids (PNAs) are mimics of natural nucleic acids able to target complementary DNA or RNA strands with high sequence specificity and affinity, and are therefore potential excellent candidates in diagnostics, antisense and antigene therapy.1 In place of the ribose phosphodiester backbone of DNA and RNA, PNAs contain a pseudopeptide backbone, composed of N-(2-aminoethyl)glycine units, on which the four nucleobases are inserted. PNAs display high chemical and enzymatic stability towards nucleases, but unmodified PNAs often exhibit low cellular uptake and this feature constitutes a drawback towards its effective use in therapy. One of the strategies to overcome this problem is the conjugation of PNA to metal complexes that can modify their intrinsic physico-chemical and spectroscopic properties.2 In our ongoing studies on PNAs, we have focused our attention on the development of novel bioorganometallic iridium-PNA conjugates that can be employed as dual activity agents for the synergic treatment of cancer, combining antisense therapy based on PNAs and photodynamic therapy (PDT) related to the use of the Ir(III) complex as the photosensitizer[3] , which is able to generate cytotoxic singlet oxygen (1O2) under appropriate excitation light. This complex is also able to penetrate cell membrane, thus it could act as a carrier for the intracellular delivery of PNAs. Furthermore, photoluminescence properties of the Ir(III) complex can be triggered by two-photon excitation, which allows to obtain less cellular damage and deeper in vivo light penetration. In this communication we will report our studies on the synthesis of the Ir(III)-PNA conjugate reported in Figure, in which a PNA tetramer containing all the four nucleobases has been selected as model PNA sequence. The Ir(III)-PNA conjugate has been completely characterized by analytical methods (LC-MS spectroscopy) and by UV-absorption and emission spectroscopy to evaluate its photophysical properties. The yield of 1O2 production has been also measured, confirming that the conjugate maintains the ability to act as a photosensitizer.
Iridium(III)-peptide nucleic acid conjugates as photosensitizer for cancer therapy / R. Dell'Acqua, V. Schifano, M. Dozzi, M. Panigati, D. Maggioni, S. Cauteruccio. ((Intervento presentato al 41. convegno Convegno Nazionale della Divisione di Chimica Organica della Società Chimica Italiana (CDCO) tenutosi a Roma nel 2023.
Iridium(III)-peptide nucleic acid conjugates as photosensitizer for cancer therapy
R. Dell'AcquaPrimo
;V. SchifanoSecondo
;M. Dozzi;M. Panigati;D. MaggioniPenultimo
;S. CauteruccioUltimo
2023
Abstract
Peptide nucleic acids (PNAs) are mimics of natural nucleic acids able to target complementary DNA or RNA strands with high sequence specificity and affinity, and are therefore potential excellent candidates in diagnostics, antisense and antigene therapy.1 In place of the ribose phosphodiester backbone of DNA and RNA, PNAs contain a pseudopeptide backbone, composed of N-(2-aminoethyl)glycine units, on which the four nucleobases are inserted. PNAs display high chemical and enzymatic stability towards nucleases, but unmodified PNAs often exhibit low cellular uptake and this feature constitutes a drawback towards its effective use in therapy. One of the strategies to overcome this problem is the conjugation of PNA to metal complexes that can modify their intrinsic physico-chemical and spectroscopic properties.2 In our ongoing studies on PNAs, we have focused our attention on the development of novel bioorganometallic iridium-PNA conjugates that can be employed as dual activity agents for the synergic treatment of cancer, combining antisense therapy based on PNAs and photodynamic therapy (PDT) related to the use of the Ir(III) complex as the photosensitizer[3] , which is able to generate cytotoxic singlet oxygen (1O2) under appropriate excitation light. This complex is also able to penetrate cell membrane, thus it could act as a carrier for the intracellular delivery of PNAs. Furthermore, photoluminescence properties of the Ir(III) complex can be triggered by two-photon excitation, which allows to obtain less cellular damage and deeper in vivo light penetration. In this communication we will report our studies on the synthesis of the Ir(III)-PNA conjugate reported in Figure, in which a PNA tetramer containing all the four nucleobases has been selected as model PNA sequence. The Ir(III)-PNA conjugate has been completely characterized by analytical methods (LC-MS spectroscopy) and by UV-absorption and emission spectroscopy to evaluate its photophysical properties. The yield of 1O2 production has been also measured, confirming that the conjugate maintains the ability to act as a photosensitizer.Pubblicazioni consigliate
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