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Development of ruthenium theranostic prodrugs for cancer therapy
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Resumo(s)
Cancer is a major public health problem and a leading cause of mortality worldwide. Despite the clinical success of various chemotherapeutic medications, these are usually not selective and thus frequently cause considerable harmful effects on tissues that are not malignant. Furthermore, late diagnosis leads to survival rates remaining low. In this work we aimed to address these limitations through the development of smart theranostic agents. Theranostics, combining therapy and diagnostic, are used for cancer therapy as their diagnostic agent enables the identification of tumors while the therapeutic agent is used for treatment.
The structure of the theranostic agent planned in this work is based on a ruthenium complex that has previously shown to be very effective in vitro against several tumors, conjugated to a diagnostic agent with selective affinity for Bcl-2, which are overexpressed proteins in the cancer cells. This diagnostic agent is comprised of a targeting unit, which is responsible for the affinity, and a probe that allows for monitorization of the biodistribution and drug delivery. This extremely precise system is expected to remain inactive throughout distribution. However, the linker is expected to break when it reaches the target, enabling both the release of the ruthenium complex drug in its active form, and the activation of the probe.
In this work, evaluation of two methods for the preparation of the targeting unit was performed; synthesis of the probe was achieved with high yields (60-90%) by two different routes; various methods of isolation were studied; derivatization of the probe was studied through two synthetic strategies. Regarding the therapeutic agent, five Ru(II) complexes were synthesized, of which one is a new complex; two new Ru(II)-Probe conjugates were synthesized; the new complex and the conjugates were characterized by NMR, UV-Vis and FTIR; the stability of the new complex and both conjugates was evaluated over 24 h by UV-Vis in DMSO and 95:5 DMEM/DMSO solutions.
Descrição
Tese de mestrado, Química (Química), 2023, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Teranósticos Conjugados Ru(II)-Sonda Terapia contra o cancro Fluorescência Teses de mestrado - 2023