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Gaio, Elisa (2018) Synergic interaction of chemotherapy and PDT by co-delivery of DTX and photosensitizers in nanoparticles. [Ph.D. thesis]

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Abstract (italian or english)

The combinations of two or more drugs/treatment modalities are increasingly considered very useful tools to increase efficacy and reduce side effects of anticancer therapies. To this aim, photodynamic therapy (PDT) is being widely investigated in combination with established therapeutic modalities including chemotherapy. In this connection, the progresses in the field of nanomedicine led to the production of nanocarriers offering opportunities to ameliorate the control of drug concentration ratios that is a prerequisite for obtaining synergic effects in combination therapy.
In this PhD thesis, PLGA-PEI hyaluronic acid (HA)-targeted nanoparticles (NPs) and keratin NPs were used for the co-delivery to cancer cells in vitro of the chemotherapeutic docetaxel (DTX) in combination with the PDT photosensitizers meso-tetraphenyl chlorin disulphonate (TPCS2a) or chlorin e6 (Ce6). To improve tumor selectivity, in the design of PLGA-PEI NPs, HA was selected for the active targeting of CD44 receptor overexpressed by cancer cells. PLGA-PEI NPs co-loaded with DTX and TPCS2a at fixed drug ratios were tested in DTX –sensitive (HeLa, MDA-MB-231 and MCF-7) and –resistant (HeLa-R) cells grown in 2D and 3D cultures. As 3D cultures, spheroids and mammospheres were used as avascular tumor models and cultures enriched of cancer stem cells (CSCs), respectively. In HeLa and MDA-MB-231 monolayers the highest synergism, evaluated by the Combination index (CI), between chemotherapy and PDT was found at DTX/TPCS2a ratio of 1:35 and co-loaded in the same NP (DTX/TPCS2a-NPs). Interestingly, strong synergism of chemotherapy and PDT was found also in the DTX -resistant cells where the dose of chemotherapeutic could be reduced by ~100 times with DTX/TPCS2a-NPs with respect to monotherapy. In spheroids, the DTX/TPCS2a-NPs at 1:35 ratio gave a strong antagonism (CI >1), while, in these 3D tumor cell models, DTX/TPCS2a ratios 1:3 and 1:5 gave synergism. In spheroids generated from DTX –resistant cells the 1:3 concentration ratio was significantly better in terms of synergism as shown by lower CI values. Combination treatments with DTX and TPCS2a co-loaded in the same NP suppressed also sphere formation, due to the presence of CSCs. Different results were obtained with mammospheres generated from MDA-MB-231 and MCF-7 breast cancer cells, very likely because of the different percentages of CSCs in the two culture models. Based on these results, we demonstrated the advantage of using HA-targeted layer-by-layer NPs as carriers of DTX and TPCS2a to finely control the drug ratio inside the NPs and to precisely deliver the payloads in cancer cells.
Combination of chemotherapy and PDT was also performed co-encapsulating DTX and Ce6 in keratin-based NPs (DTX/Ce6-KNP) prepared by the aggregation method and with a ratio 1.8:1. The cytotoxic effects of combined chemotherapy and PDT, in comparison with monotherapies, and CI analysis were investigated in HeLa and HeLa-R cells in monolayers as well as 3D tumor spheroids. Combination therapy using DTX/Ce6-KNP caused only slight synergism in DTX –sensitive cell monolayers while clear synergism was found in drug resistant cells. Notably, the combination of free drugs caused antagonism. The efficacy of DTX/Ce6-KNP was also assessed in spheroids of DTX -sensitive and -resistant cells where strongest synergism and highest reduction of spheroid volume were observed. In conclusion, these results highlight that: i) the co-delivery of PSs for PDT and chemotherapeutics in NPs allows the control of drug concentration ratios for obtaining synergic interactions; ii) optimized drug ratios determined in 2D cell tumor models do not reproduce synergic interactions in the 3D models and poses the question of the most reliable in vitro models for screening combination therapy; iii) combination of chemotherapy and PDT appears particularly useful for treating drug-resistant tumors.

Abstract (a different language)

Le combinazioni di due o più farmaci sono sempre più frequentemente considerate come strategie utili al fine di aumentare l’efficacia e ridurre gli effetti collaterali delle terapie antitumorali. A questo scopo, la terapia fotodinamica (PDT) è stata ampiamente studiata in combinazione con la chemioterapia. In questo contesto, i progressi nel campo della nanomedicina hanno portato alla produzione di nanoveicoli che offrono l’opportunità di migliorare il controllo del rapporto di concentrazione tra i farmaci che costituisce un prerequisito per ottenere un effetto sinergico nella terapia combinata.
In questa tesi di dottorato, nanoparticelle (NPs) di PLGA-PEI ricoperte di acido ialuronico (HA) e nanoparticelle di cheratina sono state utilizzate per il co-delivery a cellule tumorali in vitro del chemioterapico docetaxel (DTX) in combinazione con i fotosensibilizzanti (PSs) meso-tetrafenil clorina disulfonata (TPCS2a) o clorina e6 (Ce6). Per aumentare la selettività nei confronti del tumore, HA è stato usato nella sintesi di NPs per la sua capacità di legare il recettore CD44 sovraespresso dalle cellule tumorali. PLGA-PEI NPs co-caricate con DTX e TPCS2a in precisi rapporti di concentrazione sono state testate in cellule DTX –sensibili (HeLa, MDA-MB-231 e MCF-7) e –resistenti (HeLa-R) cresciute come monostrato cellulare e come colture 3D (sferoidi e mammosfere arricchite in cellule tumorali staminali CSCs). Nel monostrato di cellule HeLa e MDA-MB-231 il più alto sinergismo, valutato mediante il calcolo dell’indice di combinazione (CI), è stato osservato con il rapporto di concentrazione DTX/TPCS2a 1:35 co-somministrati nella stessa NP (DTX/TPCS2a-NPs). Un forte sinergismo si osserva anche in cellule DTX-resistenti nelle quali la dose del chemioterapico può essere ridotta di ~100 volte usando DTX/TPCS2a-NPs rispetto alla monoterapia. Negli sferoidi, DTX/TPCS2a-NPs 1:35 causa un forte antagonismo (CI > 1), DTX/TPCS2a-NPs 1:3 e 1:5 hanno un effetto sinergico. Il trattamento combinato con DTX e TPCS2a co-caricati nella stessa NP ha inoltre la capacità di sopprimere la formazione di sfere dovuta alla presenza di CSCs. Esperimenti eseguiti su mammosfere generate da cellule MDA-MB-231 e MCF-7 hanno mostrato risultati diversi probabilmente a causa della diversa percentuale di CSCs presente nei due modelli cellulari. Sulla base di questi risultati, abbiamo dimostrato il vantaggio dell’utilizzo di PLGA-PEI-HA NPs come veicolo per il DTX e la TPCS2a al fine di controllare in modo accurato il rapporto di concentrazione dei farmaci caricati nella NP e di veicolare il trattamento selettivamente alle cellule tumorali.
La combinazione di chemioterapia e PDT è stata inoltre studiata co-caricando DTX e Ce6 in particelle di cheratina (DTX/Ce6-KNP) sintetizzate mediante il metodo di aggregazione con un rapport 1.8:1. L’effetto citotossico della combinazione rispetto ai singoli trattamenti e l’analisi del CI sono stati valutati in cellule HeLa e HeLa-R. La terapia combinata usando DTX/Ce6-KNP causa solo un lieve sinergismo in cellule DTX-sensibili, mentre in cellule chemio-resistenti si può osservare un chiaro effetto sinergico della terapia combinata. La combinazione dei farmaci liberi causa invece antagonismo. L’efficacia di DTX/Ce6-KNP è stata inoltre valutata in sferoidi di HeLa e HeLa-R nei quali sono stati osservati il maggior sinergismo e la maggiore riduzione del volume degli sferoidi trattati. In conclusione, questi risultati evidenziano che: i) il co-delivery di PSs e chemioterapici in NPs permette il controllo del rapporto di concentrazione al fine di ottenere un’interazione sinergica; ii) rapporti di concentrazione ottimali identificati in modelli tumorali 2D non mostrano un effetto sinergico in modelli 3D e pongono la questione del più affidabile modello in vitro per studiare la combinazione di terapie; iii) la combinazione di chemioterapia e PDT appare particolarmente utile per il trattamento di tumori farmaco-resistenti.

EPrint type:Ph.D. thesis
Tutor:Reddi, Elena
Supervisor:Moret, Francesca
Ph.D. course:Ciclo 31 > Corsi 31 > BIOSCIENZE
Data di deposito della tesi:30 November 2018
Anno di Pubblicazione:30 November 2018
Key Words:terapia combinata, chemioterapia, PDT, nanoparticelle
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/15 Biologia farmaceutica
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:11517
Depositato il:06 Nov 2019 10:28
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