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NARDON, CHIARA (2013) Anti-cancer chemotherapeutics in target therapy: from advanced preclinical studies on promising Au(III) peptidomimetics toward the design of new receptor-recognizable metal-based agents. [Tesi di dottorato]

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Abstract (inglese)

At present, though there is no clinically available antineoplastic drug that acts selectively on the tumor tissue, chemotherapy is still the main form of treatment for cancer. To date, platinum-based drugs, whose forerunner is cisplatin, are among the most employed chemotherapeutics in spite of their treatment-related toxicity. Starting from the chemical properties of platinum and the severe toxicological profile of the drug cisplatin, novel Au(III)-dithiocarbamato complexes have been recently designed and biologically studied, showing particularly promising antitumor activity (both in vitro and in vivo), lack of cross-resistance, and reduced toxic and nephrotoxic side-effects compared to cisplatin, accounting for a different mechanism of action. Following these encouraging results, we aimed to exploit the peculiar features of the tumor microenvironment in order to obtain a targeted delivery of our potential drugs into cancer tissues, resulting in further effectiveness increase and side-effects reduction. Accordingly, for a site-specific delivery strategy, we planned to functionalize the dithiocarbamato ligand moiety by means of biomolecules that are internalized into the pathological cells upon binding to a specific cell membrane transporter or a receptor, upregulated compared to healthy cells.
With respect to human transporters, Au(III)-dithiocarbamato complexes functionalized with di- and tripeptides (our second-generation compounds), designed to exploit the peptide transporters PEPT1 and PEPT2, have been recently synthetized and studied, turning out the filing of an international patent, just extended worldwide. On the other hand, in this work the receptor-mediated strategies have been taken into account as well (third-generation compounds).
Concerning the second-generation complexes, preliminary screening tests on different human tumor cell lines indicated AuD6 and AuD8 as suitable candidates for advanced preclinical studies. We report here on their synthesis, chemical characterization and the biological data collected throughout a 6-month stay as a visiting PhD student at the Barbara Ann Karmanos Cancer Institute (Detroit, U.S.A.) in collaboration with Prof. Q. Ping Dou. Several advanced preclinical studies were carried out evaluating the anticancer activity both in vitro and in vivo, the acute toxicity on animal models and providing insights into the mechanism of action in order to enter phase I clinical trials. The triple-negative breast cancer cell line MDA-MB-231 was chosen as a model since these cells are highly metastatic and invasive. Notably, AuD6 and AuD8 overcame the in vitro resistance of cisplatin against this cell line, displayed outstanding anticancer activity on xenografts (subcutaneous administration) and very negligible acute toxicity in mice upon intravenous and per os administrations. In addition to showing a good chemotherapeutic index in terms of toxicity-activity ratio, these two compounds proved strong inhibitors of proteasome – a significant intracellular protein degradation machinery – both in vitro and in vivo. Therefore, a crystallographic study, aimed at investigating the mechanism of inhibition of 20S proteasome by AuD8 (chosen as a model compound), was performed by means of biotechnological methods.
With respect to the pharmacokinetic profile of the considered compounds, serum albumin was taken into account as it is the most abundant plasma protein and it is a well-known carrier of drugs and endogenous substances such as vitamins and lipids. An investigation of the possible interaction between AuD8 and the serum protein was carried out by circular dichroism and fluorescence spectrophotometry, replacing the human serum albumin with the bovine counterpart since they have an almost identical sequence.
Concerning our third-generation of complexes – designed to work as targeted bullets that could go straight to the cancer cells, bypassing normal ones – we focused on the cholecystokinin (CCK) receptors which belong to the G-protein-coupled receptor superfamily and are overexpressed in many neoplasms. The targeted drug delivery has been achieved by complexation of the metal center with the CCK8 peptide. Thus, the CCK8 peptide was first synthesized, purified and characterized by mass spectrometry, elemental analysis, NMR and FT-IR spectroscopies. The corresponding Au(III) dithiocarbamato derivative was then synthesized and partially characterized by 1H-NMR and UV-Vis spectrophotometry.
Afterwards, we addressed our attention also to the “click chemistry” field, designing and developing a versatile gold(III)-based building block to be functionalized with different targeting peptides. The related overexpressed receptors can specifically recognize and bind the corresponding conjugates, thus intaking them into cytoplasm by mediated internalization. An international patent application is going to be filed about this innovative strategy.
More recently, as a natural extension of our previous studies, we have also taken into account Cu(II), being an endogenous metal characterized by very interesting biochemical properties. Concerning the relationship between copper and cancer, it is worth highlighting that copper plays a significant role in angiogenesis and therefore is more abundant in cancer cells than in healthy ones, leading to a selectivity of copper-based anticancer agents toward neoplastic tissues. In the present work, two different classes of Cu(II) dithiocarbamato complexes were designed to gain insights into structure-activity relationships and to get the know-how with respect to the chemical behavior of this transition metal in terms of reaction conditions and stability in different solvents.
Their synthesis, wide chemical characterization and preliminary biological data are herein reported. Overall, these findings will be useful for the future development of the more sophisticated copper-based receptor compounds.

Abstract (italiano)

Attualmente, sebbene a livello clinico non vi siano farmaci in grado di agire selettivamente sui tessuti tumorali, la chemioterapia rimane la strategia d’elezione nel trattamento del cancro. Ad oggi, i farmaci a base di platino (cisplatino, carboplatino ecc.) sono tra i più utilizzati in ambito terapeutico nonostante la loro elevata tossicità accessoria. Prendendo come starting point le proprietà chimiche del platino e il pesante profilo tossicologico del cisplatino, sono stati recentemente progettati e testati biologicamente nuovi complessi ditiocarbammici di Au(III). Quest’ultimi hanno mostrato un’attività antitumorale particolarmente promettente (sia in vitro che in vivo), mancanza di resistenza crociata con il cisplatino e ridotta tossicità sia sistemica che renale, mettendo in luce un differente meccanismo di azione rispetto al chemioterapico di riferimento. Sulla base di questi risultati incoraggianti, ci siamo proposti di sfruttare le caratteristiche peculiari del microambiente tumorale al fine di ottenere un rilascio mirato dei nostri potenziali farmaci nei tessuti cancerosi con conseguente amplificazione dell’efficacia chemioterapica e ulteriore riduzione degli effetti collaterali. Per ottenere quindi un rilascio sito-specifico, abbiamo progettato di funzionalizzare il legante ditiocarbammico con biomolecole capaci di essere riconosciute e assimilate dalle cellule cancerose in seguito al legame con uno specifico trasportatore o recettore di membrana, sovraespresso rispetto alla cellula sana.
Per quanto concerne i trasportatori presenti nel corpo umano, sono stati recentemente sintetizzati e studiati dei complessi ditiocarbammici di Au(III) funzionalizzati con di- e tripeptidi (d’ora in avanti denominati composti di 2° generazione), progettati per sfruttare i trasportatori peptidici PEPT1 e PEPT2. Il valore dei primi risultati biologici ottenuti ha portato al deposito di un brevetto PCT, esteso recentemente in numerosi Paesi del mondo. Come naturale prosieguo delle ricerche precedenti, in questo lavoro sono state prese in considerazione anche altre strategie mediate dai recettori sovraespressi nei tumori al fine di ottenere i nostri composti di 3° generazione.
Con riferimento ai composti di 2° generazione, test preliminari di screening, condotti su svariate linee cellulari tumorali umane, hanno indicato AuD6 e AuD8 quali candidati adatti per ulteriori studi preclinici approfonditi. La loro sintesi e caratterizzazione chimica sono qui riportate insieme ai risultati biologici raccolti personalmente nei laboratori del “Barbara Ann Karmanos Cancer Institute” (Detroit, U.S.A) durante un periodo di ricerca di sei mesi sotto la supervisione del Prof. Q.Ping Dou. Sono stati condotti numerosi studi avanzati per valutare l’attività antitumorale sia in vitro sia in vivo e per delucidare un possibile meccanismo di azione nell’ipotesi di accesso alla fase di sperimentazione clinica I; è stata infine testata la tossicità acuta su modelli animali con risultati estremamente interessanti. E’ stata scelta come modello, date le sue elevate capacità invasive e metastatiche, la linea cellulare MDA-MB-231 (tumore della mammella triplo-negativo). E’ da sottolineare che questa linea cellulare è resistente al cisplatino mentre sia AuD6 che AuD8 hanno mostrato una buona attività antiproliferativa nelle prove in vitro, notevole attività antitumorale su modelli xenografici (somministrazione sottocutanea) e tossicità acuta trascurabile nei topi sia per via endovenosa che orale. Oltre a possedere un buon indice chemioterapico in termini di rapporto tossicità/efficacia, questi due composti sono risultati, sia in vitro che in vivo, dei potenti inibitori del proteasoma, importante complesso multicatalitico intracellulare deputato all’idrolisi di substrati proteici. Si è di conseguenza condotta un’indagine cristallografica mirata a delucidare il meccanismo di inibizione del proteasoma 20S da parte di AuD8 (composto modello) mediante tecniche biotecnologiche.
Per quanto riguarda il profilo farmacocinetico dei composti in esame, si è preliminarmente considerata l’albumina sierica dato che è la principale proteina plasmatica ed è un noto trasportatore di farmaci e sostanze endogene quali vitamine e lipidi. Si è pertanto condotto uno studio al fine di verificare l’instaurarsi o meno di un’interazione tra AuD8 e la proteina del siero mediante dicroismo circolare e spettrofotometria di fluorescenza. In questi esperimenti si è utilizzato l’albumina bovina dato che condivide un’elevata omologia di sequenza con la controparte umana.
Per quanto concerne i composti di 3° generazione – progettati anch’essi per agire in modo mirato sulle cellule cancerose e quindi capaci di eludere quelle sane – ci siamo concentrati sui recettori delle colecistochinine (CCK), iperespressi in parecchi tumori e appartenenti alla famiglia di recettori accoppiati alle proteine G. Il rilascio mirato del farmaco è possibile mediante complessazione del centro metallico con il peptide CCK8. Tale peptide è stato sintetizzato, purificato e caratterizzato tramite spettrometria di massa, analisi elementare, NMR ed FT-IR. Il corrispondente derivato ditiocarbammico di Au(III) è stato successivamente sintetizzato e caratterizzato parzialmente mediante spettroscopia 1H-NMR e spettrofotometria UV-Vis.
Successivamente abbiamo sfruttato la cosiddetta “click chemistry” nelle fasi di progettazione e sviluppo di un’unità versatile a base di Au(III) da funzionalizzare con diversi peptidi recettoriali. In seguito al legame con il corrispondente peptide, tali recettori sono solitamente in grado di trasferire nel citoplasma il coniugato metallo-peptide. Una domanda di brevetto internazionale è in fase di deposito per proteggere la proprietà intellettuale del nostro approccio.
Come naturale prosecuzione delle nostre ricerche, più recentemente si è utilizzato il metallo endogeno Cu(II) viste le sue interessanti proprietà biochimiche. La scelta del Cu(II) non è stata casuale ma dettata dal ruolo fondamentale che esso gioca nell’angiogenesi portandolo ad essere presente in concentrazione più elevata nelle cellule cancerose rispetto alle cellule sane. Tale peculiarità è stata sfruttata nella progettazione di agenti antitumorali a base di Cu(II) selettivi verso i tessuti neoplastici. Sono state preparate due diverse classi di complessi ditiocarbammici di Cu(II) al fine di ricavare possibili relazioni struttura-attività e conoscere approfonditamente il comportamento chimico di questo metallo di transizione in termini di condizioni di reazione da adottare e stabilità in diversi solventi. In questa tesi sono riportate le loro sintesi, caratterizzazioni chimiche e i dati biologici preliminari. Nel loro complesso, le informazioni qui raccolte saranno utilizzate per lo sviluppo futuro di composti a base rameica da inserire nel campo delle terapie mirate in oncologia.

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Tipo di EPrint:Tesi di dottorato
Relatore:FREGONA, DOLORES
Dottorato (corsi e scuole):Ciclo 25 > Scuole 25 > SCIENZE MOLECOLARI > SCIENZE CHIMICHE
Data di deposito della tesi:31 Gennaio 2013
Anno di Pubblicazione:31 Gennaio 2013
Parole chiave (italiano / inglese):gold, copper, cancer, proteasome
Settori scientifico-disciplinari MIUR:Area 03 - Scienze chimiche > CHIM/03 Chimica generale e inorganica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Chimiche
Codice ID:5316
Depositato il:16 Ott 2013 11:37
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