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Moret, Francesca (2013) Nanovehicles for medical use: an in vitro evaluation
of cytotoxicity and drug delivery efficiency.
[Tesi di dottorato]

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Abstract (inglese)

The recent progresses offered by nanotechnology in the manipulation of matter lead to the development of several nanoparticles (NPs) and nanodevices for medical applications. In oncology, nanosized objects are particularly attractive as drug delivery systems since it is expected that engineered nanovehicles of appropriate size and functionalised with specific ligands/antibodies will improve the efficacy and selectivity of cancer therapies by exploiting both the passive and active mechanism of tumour targeting. The use of delivery systems is particularly appealing in those therapies in which the administration of the drug in aqueous formulations leads to drug aggregation with decreased activity or scarce bioavailability and tumour selectivity. This is the case of most of the photosensitizers used in photodynamic therapy (PDT), which display hydrophobicity and poor selective accumulation in malignant tissues. In the last decades, PDT is emerging as a promising cancer treatment modality in alternative to conventional therapies, which often demonstrate systemic drug toxicity and multidrug-resistance phenomena. PDT is based on the administration of a photosensitizer (PS) that accumulates in the tumour and after activation with light of appropriate wavelengths, reacts with surrounding molecular oxygen leading to the formation of cytotoxic reactive oxygen species (ROS) with consequent cellular and vasculature damages.
In this PhD thesis, three different nanosystems, namely, liposomes, poly-(D,L-lactide-co-glycolide) nanoparticles (PLGA NPs) and ORganically Modified SILica nanoparticles (ORMOSIL NPs) were considered for the delivery of the second generation PS meta-tetra(hydroxyphenyl)chlorin (m-THPC, Temoporfin) to cancer cells in vitro. In particular, drug delivery efficiency, dark and phototoxicity of the m-THPC nanoparticle-based formulations were evaluated. To improve m-THPC bioavailability and tumour selectivity, in the design of the nanovehicles PEGylation and targeting of NPs were considered as essential strategies in order to prolong NP circulation in the bloodstream and exploit active mechanisms of tumour targeting.
For the delivery of m-THPC using unilamellar liposomes, four different PEGylated liposomal formulations (trade name Fospeg®, provided by Biolitec Research) in which the length (PEG750, PEG2000, PEG5000) and the density (2%, 8%) of PEG were varied, were tested in vitro in normal lung fibroblasts CCD-34Lu and in cancer A549 lung epithelial cells. Compared to drug delivered in the standard solvent (Foscan®, ethanol/PEG 400/water (20:30:50, by vol.)), liposomal m-THPC showed a decreased intracellular uptake in both cell lines, but the presence of the delivery system highly reduced the dark cytotoxicity of the drug. The reduction of the PS dark toxicity increased with the increasing of PEG density on liposome surface, while the length of PEG chains did not affect significantly the toxic effect of m-THPC in the dark. However, photo-toxicity measured in A549 cells was only slightly affected by the reduced uptake of m-THPC delivered by Fospeg®, and the efficiency of PDT-induced cell killing was comparable among the different liposomal formulations. Interestingly, the intracellular localization of m-THPC delivered as Fospeg® or Foscan® was the same (Golgi apparatus and endoplasmic reticulum) suggesting drug release from liposomes, especially in the presence of the serum proteins, being m-THPC only physically entrapped within liposomes. m-THPC release was confirmed by the fact that liposomes covalently labelled with rhodamine were effectively were taken up by cells but, differently from m-THPC, localized in the acidic compartments of the cells. In spite of m-THPC release from liposomes, the Fospeg® formulation was exploited to target actively cancer cells by liposome conjugation with folic acid (FA), being FA-receptors (FRs) over-expressed in several human tumours. Thus, specific uptake and photo-toxicity of FA-targeted liposomes (FA-Fospeg) with respect to liposomes of the same composition but lacking FA (un-targeted Fospeg) was evaluated in KB (FR-positive) and in A549 (FR-negative) cells. The uptake of m-THPC delivered as FA-Fospeg was twice that of un-targeted Fospeg in KB cells; however only a modest fraction (~ 15%) of the targeted vehicle was effectively internalized by FR-mediated endocytosis while nonspecific internalization remained the prevailing mechanism of liposomes uptake in both cell lines. The improved m-THPC uptake obtained with FA-Fospeg in FR over-expressing cells translated into a 1.5 higher photo-induced toxicity.
A novel formulation of bare and PEGylated PLGA NPs in which m-THPC was physically entrapped were synthesized (Prof J. Kos, University of Ljubljana) and evaluated in vitro and in vivo for phototherapy and fluorescence-based tumour imaging applications. In vitro studies carried out on A549, MCF10A neo T (breast cancer cells) and U937 (lymphoma derived pro-monocytic cells) cell lines, showed reduced uptake of PEGylated NPs with respect to non PEGylated NPs. As for Fospeg®, the use of the delivery system led to a significant reduction of m-THPC dark toxicity.. As expected for PEGylated NPs, the efficiency of cell internalization of m-THPC entrapped in PEG PLGA was reduced by 50% with respect to that in the standard solvent, but surprisingly cytotoxicity induced in irradiated A549 cells was quite comparable. At 24 h post-injection in vivo biodistribution of bare and PEGylated PLGA NPs compared to Foscan® was assessed in mice, showing very similar drug accumulation in the major organs but reduced skin uptake for both NP formulations. Thus, even if m-THPC release in the presence of serum proteins was measured in vitro, PEGylated PLGA NPs appeared potentially useful as stealth and biodegradable PS delivery systems.
The premature release of the PS from the delivery system was completely avoided with the covalent link of m-THPC to the silane matrix of highly PEGylated ORMOSIL NPs (Prof. F. Mancin, University of Padova). This type of NPs exhibited a very low extent of cell internalization in vitro due to their high degree of PEGylation, making NP targeting an essential prerequisite to enhance intracellular drug delivery. In addition to FA, the RGD peptide and the antibody Cetuximab, which bind respectively the integrin α5ß3 receptor and epidermal growth factor receptor (EGFR), were exploited as targeting agents for ORMOSIL NPs and the specific uptake and photo-toxicity of m-THPC delivered by conjugated NPs were evaluated in vitro. The study revealed how the characteristics of the targeting agents are of crucial importance in determining the performances of targeted PEGylated nanosystems. In fact, the hydrophobic FA was very likely buried in the PEG layer and was unable to drive the selective uptake of ORMOSIL NPs while RGD peptide and Cetuximab antibody displayed some selectivity toward cells over-expressing their receptors (HUVEC cells over-expressing integrin α5ß3 receptors and A431 cells over-expressing EGFR). Unfortunately, the enhanced and selective uptake of m-THPC obtained by the two latter targeted ORMOSIL NPs was not accompanied by efficient and selective photo-induced cytotoxicity; it appeared that the selectivity of NP uptake was achieved in scarce drug cell loading conditions, determining only low PDT efficacy.
The assessment of the biocompatibility of NPs is of fundamental importance for their safe use in nanomedicine. Since ORMOSIL NPs are not well characterised from this point of view, a toxicological characterization of empty ORMOSIL NPs were carried out in vitro in normal (CCD-34Lu) and cancer (A549, NCIH-2347) lung cells. The study included traditional cell viability and cytotoxicity tests (MTS test, LDH release assay, ROS production, cell membrane permeabilization measurements and electron microscopy analyses) in combination with a genome-wide analysis of gene expression profiles of cells exposed to NPs. The results pointed out that different types of cells respond quite differently to NPs and PEGylation of NPs highly affected the cytotoxicity profiles. PEGylation of ORMOSIL NPs completely abolished the toxicity of the nanosystem in CCD-34Lu and NCIH-2347 cells. On the contrary PEG ORMOSIL NPs induced necrotic cell death of A549 by increasing the permeability of the plasma membrane. At sub-lethal concentrations alteration of gene expression and inflammation were measured in A549 cells exposed to. The different response to PEG NPs is very likely explained considering the peculiarity of the cell type and the particular interaction of NPs with cell and internalization mechanisms. In fact, it was shown clearly that NPs internalized in A549 cells localized in and affected the morphology and the functioning of pulmonary surfactant containing lamellar bodies, peculiar of alveolar type II cells of which A459 cells represents an in vitro models.

Abstract (italiano)

Il recente progresso apportato dalla nanotecnologia nella manipolazione della materia ha portato al conseguente sviluppo di diversi tipi di nanoparticelle e nanodevices per applicazioni biomediche. In campo oncologico, oggetti dalle dimensioni nanometriche si sono dimostrati particolarmente interessanti in qualità di sistemi per la veicolazione di farmaci, poiché si presume che l’ingegnerizzazione dei nanoveicoli e la loro funzionalizzazione con specifici ligandi/anticorpi possa portare ad un miglioramento dell’efficacia e della selettività delle terapie antitumorali sfruttando meccanismi di targeting del tumore sia passivi che attivi. L’utilizzo di sistemi di veicolazione è particolarmente importante nel caso di terapie nelle quali la somministrazione dei farmaci in formulazioni acquose conduce a fenomeni di aggregazione con conseguente diminuzione di attività e di disponibilità nel circolo sanguineo, o nel caso di farmaci con scarsa selettività per il tumore. Appartengono a queste categorie la maggior parte dei fotosensibilizzanti utilizzati in terapia fotodinamica (PDT), poiché farmaci di natura idrofobica e con scarsa selettività di accumulo nei tessuti maligni. Negli ultimi decenni, la PDT si è dimostrata una promettente tecnica di trattamento del cancro in alternativa alle terapie convenzionali che invece generalmente dimostrano alta tossicità sistemica e fenomeni di farmaco-resistenza. La PDT si basa sulla somministrazione di un fotosensibilizzante (PS) che accumulatosi nel tumore, e dopo essere stato attivato con opportune lunghezze d’onda di luce, è in grado di reagire con l’ossigeno molecolare che lo circonda generando specie reattive dell’ossigeno (ROS) altamente citotossiche con conseguente danno cellulare e vascolare. In questa tesi di dottorato, tre diversi nanosistemi quali liposomi, nanoparticelle PLGA (poly-(D,L-lactide-co-glycolide)) e nanoparticelle di silice organicamente modificata (ORMOSIL), sono stati presi in considerazione per la veicolazione del fotosensibilizzante di seconda generazione meta-tetra(hydroxyphenyl)chlorin (m-THPC, Temoporfin) in cellule tumorali in vitro. In particolare, sono state valutate l’efficienza di veicolazione del farmaco, la tossicità buia e fotoindotta delle diverse formulazioni di m-THPC. Per migliorare la biodisponibilità e la selettività per il tumore della m-THPC, nella progettazione dei nanoveicoli sono state considerate quali strategie essenziali la pegilazione e il targeting delle particelle, in modo da prolungare la circolazione dei nanosistemi nel flusso sanguineo e in modo da sfruttare meccanismi attivi di targeting del tumore.
Per la veicolazione della m-THPC utilizzando liposomi unilamellari sono state saggiate in vitro quattro diverse formulazioni liposomiali pegilate (Fospeg®, fornito dalla ditta Biolitec Research) con lunghezza (PEG750, PEG2000, PEG5000) e densità del PEG (2%, 8%) variabili, utilizzando come linee cellulari fibroblasti di polmone normali (CCD-34Lu) e cellule tumorali di epitelio polmonare (A549). Se paragonate al farmaco somministrato in forma libera in soluzione (Foscan®, etanolo/PEG 400/acqua (20:30:50, vol/vol)), le formulazioni liposomiali di m-THPC hanno mostrato una ridotta internalizzazione in entrambe le linee cellulari, ma nello stesso tempo la presenza del sistema di veicolazione ha portato alla significativa riduzione della tossicità buia del farmaco. La riduzione della tossicità buia del farmaco è risultata proporzionale all’aumento della densità di PEG sulla superficie del liposoma mentre la lunghezza delle catene di PEG sembra essere ininfluente nel limitare l’effetto tossico della m-THPC al buio. Comunque, la ridotta internalizzazione della m-THPC veicolata tramite Fospeg® influenza in modo solo parziale la fototossicità misurata in cellule A549, mentre l’efficienza d’induzione di mortalità in seguito a trattamento fotodinamico è risultata paragonabile tra le diverse formulazioni saggiate. Indipendentemente dalla veicolazione tramite Fospeg® o Foscan®, è stata riscontrata la medesima localizzazione intracellulare della m-THPC (apparato del Golgi e reticolo endoplasmatico) suggerendo il possibile rilascio del farmaco dalla formulazione liposomiale in presenza di proteine del siero, essendo la m-THPC solamente fisicamente intrappolata all’interno dei liposomi. Il rilascio della m-THPC è stato confermato dal fatto che liposomi nei quali viene legata covalentemente rodamina vengono effettivamente internalizzati dalle cellule e, differentemente dalla m-THPC, si accumulano nei compartimenti acidi intracellulari.
Nonostante il rilascio del fotosensibilizzante dai liposomi, la formulazione Fospeg® è comunque stata utilizzata per veicolare selettivamente la m-THPC in cellule cancerose tramite la coniugazione dei liposomi con acido folico, essendo i recettori del folato sovraespressi in diversi tumori umani. Quindi sono state valutate l’internalizzazione specifica e la fototossicità di liposomi coniugati con folato (liposomi folato) rispetto a liposomi della stessa composizione ma privi di acido folico (liposomi non coniugati) in cellule KB e A549, rispettivamente positive e negative per l’espressione di recettori del folato. In cellule KB, l’internalizzazione della m-THPC si è rivelata doppia in caso di veicolazione con liposomi folato, malgrado solo una modesta parte (~15%) dei nanosistemi coniugati con folato siano effettivamente internalizzati tramite meccanismi di endocitosi mediata da recettore, essendo invece un’internalizzazione di tipo aspecifico il meccanismo prevalente per l’internalizzazione dei liposomi in entrambe le linee cellulari saggiate. In ogni caso, all’aumentato accumulo di m-THPC ottenuto tramite la veicolazione con Fospeg coniugato con folato in cellule che sovra esprimono il recettore, ne è conseguita una tossicità dopo irradiamento aumentata di circa 1.5 volte.
Riguardo invece la veicolazione di m-THPC tramite particelle PLGA, formulazioni nude o pegilate sono state sintetizzate (Prof. J. Kos, Università di Lubiana) e saggiate sia in vitro che in vivo per la loro potenziale applicazione in fototerapia o in diagnosi dei tumori, sfruttando la fluorescenza del fotosensibilizzante fisicamente intrappolato all’interno delle particelle. Studi in vitro condotti su cellule A549, MCF10A neo T (derivate da tumore del seno) e U937 (cellule pro-monocitiche derivate da linfoma), hanno mostrato una ridotta internalizzazione della formulazione di m-THPC pegilata rispetto a quella nuda. Anche con particelle PLGA e come già visto per il Fospeg®, l’utilizzo di un sistema di veicolazione porta alla significativa riduzione della citotossicità buia della m-THPC. L’efficienza d’internalizzazione del fotosensibilizzante veicolato tramite particelle PLGA pegilate viene ridotta circa del 50% rispetto alla sua veicolazione nella formulazione standard ma sorprendentemente l’effetto citotossico indotto in cellule A549 irradiate è quasi paragonabile. La biodistribuzione della m-THPC (veicolata tramite nanoparticelle PLGA nude o pegilate o nella formulazione standard) è stata valutata 24 ore dopo la sua iniezione in topi, mostrando una simile distribuzione nei vari organi ma una significativa riduzione dell’accumulo a livello epidermico per entrambe le formulazioni nanoparticellari. Quindi, nonostante anche per le particelle PLGA pegilate sia stato misurato il rilascio di m-THPC in presenza di proteine sieriche, esse appaiono un buon sistema di veicolazione di fotosensibilizzanti soprattutto per le loro caratteristiche ‘stealth’ e per la loro biodegradabilità.
Il rilascio prematuro del fotosensibilizzante è stato invece completamente limitato con il legame covalente della m-THPC alla matrice silanica di particelle ORMOSIL altamente pegilate (Prof. F. Mancin, Università di Padova). Tuttavia questo tipo di particelle ha mostrato un’internalizzazione intracellulare estremamente bassa derivata dall’elevato grado di pegilazione, ponendo come requisito essenziale il targeting delle particelle. In qualità di agenti di targeting per le particelle ORMOSIL pegilate sono stati valutati, oltre al folato, anche il peptide ciclico RGD e l’anticorpo Cetuximab, essendo questi ultimi in grado di legarsi rispettivamente ad integrine α5ß3 e al recettore del fattore di crescite dell’epidermide (EGFR). L’internalizzazione selettiva e la fototossicità della m-THPC veicolata tramite le tre diverse nanoparticelle funzionalizzate sono state valutate in vitro in opportuni sistemi cellulari. Tale studio ha mostrato come le caratteristiche dell’agente di targeting influenzino in modo sostanziale la selettività di tali nanosistemi pegilati. Infatti, mentre il folato altamente idrofobico si ripiega verosimilmente verso la corona di PEG rendendosi inefficace nel guidare selettivamente le particelle ORMOSIL, il peptide RGD e l’anticorpo Cetuximab hanno mostrato una certa selettività nei confronti di cellule sovraesprimenti i rispettivi recettori (cellule HUVEC sovraesprimenti recettori per le integrine α5ß3 e cellule A431 sovraesperimenti EGFR). Tuttavia, l’aumentato accumulo selettivo della m-THPC ottenuto tramite la coniugazione delle nanoparticelle con RGD e Cetuximab non ha portato ad una conseguente aumentata efficienza e selettività nell’induzione di citotossicità in seguito ad irradiamento. Tale risultato è verosimilmente imputabile al fatto che la selettività di accumulo delle nanoparticelle viene raggiunta in condizioni nelle quali la disponibilità del farmaco nelle cellule è troppo bassa, con conseguente scarsa efficacia dopo trattamento fotodinamico.
La valutazione della biocompatibilità delle nanoparticelle risulta di fondamentale importanza per un’applicazione sicura della nanotecnologia in campo medico. Quindi, poiché le nanoparticelle ORMOSIL non sono ancora state ben caratterizzate da tale punto di vista, un loro profilo tossicologico è stato tracciato in vitro in cellule polmonari normali (CCD-34Lu) e tumorali (A549, NCIH-2347). Nello studio sono stati combinati esperimenti tradizionali di valutazione della vitalità cellulare e della citotossicità (test MTS, saggio del rilascio di LDH, valutazione della produzione di ROS, misure di permeabilizzazione di membrana, analisi di microscopia elettronica) con un’analisi dei profili di espressione genica estesa all’intero genoma di cellule esposte alle nanoparticelle. I risultati hanno mostrato come diversi tipi di cellule rispondono in modo abbastanza differente all’esposizione alle nanoparticelle e come la pegilazione influisce fortemente sui profili di citotossicità. Infatti, la pegilazione delle particelle ORMOSIL è in grado di abolire completamente la tossicità dei nanosistemi in cellule CCD-34Lu e NCIH-2347 mentre le stesse particelle pegilate inducono morte per necrosi in cellule A549, aumentandone la permeabilità di membrana. Inoltre nelle medesime cellule, concentrazioni sub-letali di nanoparticelle inducono infiammazione e alterazione dell’espressione genica. La differente risposta all’esposizione alle nanoparticelle pegilate delle cellule A549 è spiegabile considerando la peculiarità di questo tipo cellulare, e in particolare l’interazione delle particelle stesse con le cellule e il loro meccanismo d’internalizzazione. Infatti, è stato mostrato in modo chiaro che le nanoparticelle vengono internalizzate in corpi lamellari contenenti il surfattante polmonare, peculiari di cellule alveolari di tipo II, delle quali le cellule A549 rappresentano un modello in vitro. Tale accumulo delle nanoparticelle nei corpi lamellari porta alla modifica della morfologia degli stessi e una pesante alterazione della loro funzionalità.

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Tipo di EPrint:Tesi di dottorato
Relatore:Celotti, Lucia
Correlatore:Reddi, Elena
Dottorato (corsi e scuole):Ciclo 24 > Scuole 24 > BIOSCIENZE E BIOTECNOLOGIE > BIOTECNOLOGIE
Data di deposito della tesi:24 Aprile 2013
Anno di Pubblicazione:24 Aprile 2013
Parole chiave (italiano / inglese):liposomes, ORMOSIL nanoparticles, PLGA nanoparticles, drug delivery, photodynamic therapy, nanotoxicology. liposomi, nanoparticelle ORMOSIL, nanoparticelle PLGA, delivery di farmaci, terapia fotodinamica, nanotossicologia
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/15 Biologia farmaceutica
Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:6107
Depositato il:16 Ott 2013 10:31
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