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Gallon, Elena (2014) Sistema innovativo vescicolare pH sensibile per il direzionamento di sirna al tumore. Novel pH responsive polymeric vesicles
for siRNA delivery to the tumor.
[Tesi di dottorato]

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Abstract (inglese)

Supramolecular drug carriers based on physical assembly of “smart” polymers have emerged in last decades to obtain novel carriers for the tumor therapy. These systems are designed to target cancer tissue, preserve the therapeutic activity of loaded drug and reduce their systemic side-effects. Amphiphilic copolymers can be assembled in vesicles that can be loaded with hydrophilic and/or hydrophobic drugs.
The research project was aimed at synthesizing a triblock pH-responsive polymer to be assembled in vesicles for the delivery of specific siRNA to cancer cells to silence specific functions involved in the tumor progression. According to its nanometric size, the colloidal drug delivery system is intended to undergo passive accumulation in the cancer tissue by EPR effect and access selectively the cytosol by cancer cell biorecognition. Once the vesicles are localized in the endosomes, their pH responsiveness will guarantee for the disassembling of the carrier and the release of the siRNA payload.
The vesicles forming polymer was synthesized in order to respond to the acid environment in the endosomal and lysosomal compartments with prompt disassembly of the nanocarrier and consequent siRNA release. The triblock copolymers include two hydrophilic blocks at the terminal ends, namely 1.9 kDa or 3.5kDa PEG and poly-glycerolmethacrylate (GMA), and a central pH sensitive block, imidazole hexyl methacrylate (ImHeMA) that control the assembly and disassembly of the vesiscles. The polymer obtained with the 3.5kDa PEG is intended to be conjugated with the targeting agent folic acid to confer biorecongnition properties to the polimersomes. The vesicles were prepared by mixing the polymers obtained with 1.9 kDa and 3.5 kDa at adequate ratios. The copolymers with ratio 90:10 w/w polymers 1.9 kDa and 3.5 kDa self-assemble in vesicles at pH 7.4 with a mean size of 100 nm as detected by light scattering analysis and are very stable at room temperature. At 37°C the stability of vesicles was modulated by increasing the ratio of the copolymer 3.5 kDa PEG. Vesicles obtained with ratio 90:10 w/w polymers 1.9 kDa and 3.5 kDa were imaged by TEM microscopy showing a spherical shape and high size homogeneity. The polymeric vesicles were found to loads very efficiently double stranded DNA (dsDNA) sequences with a 14% molar loading yield as shown by UV-Vis spectrometry and release them in 8 hours when incubated at pH 5, while vesicles showed very limited DNA release at pH 7.4. The physical assembly of the dsDNA with the pH responsive triblock copolymer was controlled by the environmental pH: gel retardation electrophoresis showed that the polymer and dsDNA completely associate at a N/P ratio of 2/1 at pH 5, while no association was observed up to a N/P ratio of 20/1 at pH 7.4 where the ImHeMA block is neutral.
Cell viability assay performed on B16F10 mouse melanoma cells showed a remarkable biocompatibility of the polymeric vesicles at concentration of 1, 2, 3 mg/mL. The high hemolytic activity of the polymer at acidic pH (pH 5) support for the capacity of the material to induce endosomal membrane disruption. The results displayed a 70% hemolytic activity at pH 5, while in physiological condition (pH 7.4) no red blood cell lysis was detected. Polymer formulations, with and without the folate-tipped terminal ends, were incubated with KB human cervical carcinoma cell line and MCF7 human breast adenocarcinoma cell line, that overexpress and do not express the folate receptor respectively, to investigate active targeting properties of the folate tipped vesicles. The uptake of vesicles loaded with cyanine 3 labeled dsDNA, that was evaluated by fluorescence spectroscopy on cell lisate and by cytometry, was 3 times higher in KB cells compared to MCF-7 cells. Vesicles loaded with double strand siRNA for the silencing of luciferase were investigated on luciferase transfected B16F10 cells that express the folate receptor. The decrease of bioluminescence in cell sample treated with siRNA loaded folate targeted vesicles was 30% with respect to control empty vesicles.
The above results were confirmed by confocal microscopy carried out with the same cancer cell lines. Confocal microscopy showed a significantly higher accumulation of the fluorescently labeled dsDNA in KB cells and a major localization of the macromolecule at the nuclear compartment

Abstract (italiano)

Negli ultimi decenni sono stati sviluppati, in maniera sempre più consistente, drug carriers supramolecolari per la terapia tumorale capaci di aggregare in nanostrutture grazie all'utilizzo di polimeri "intelligenti". Questi sistemi sono stati progettati in modo tale da essere direzionati selettivamente al tessuto tumorale, mantenere l'efficacia terapeutica del farmaco caricato e ridurre gli effetti collaterali a livello sistemico. Polimeri con proprietà anfifiliche sono in grado di formare vescicole, chiamate anche polimerosomi, che possono essere caricate con farmaci idrofilici/idrofobici.
Il progetto di ricerca qui riportato ha avuto come fine ultimo la sintesi di un copolimero pH-sensibile a tre blocchi in grado di aggregare in vescicole utilizzate per il delivery di specifici silencing RNA (siRNA) alle cellule cancerose con lo scopo di rendere silenti specifici meccanismi coinvolti nel processo di progressione tumorale. Grazie alle sue nano-dimensioni, il sistema di drug-delivery colloidale è previsto andare incontro ad accumulazione passiva nel tessuto tumorale per Enhanced Permeability and Retention Effect (EPR) ed avere accesso selettivamente al comparto cellulare citosolico grazie al bioriconoscimento da parte della cellula tumorale. Una volta all'interno degli endosomi, la capacità delle vescicole polimeriche di rispondere in maniera differente ai diversi pH renderà possibile la disaggregazione del carrier e il rilascio del siRNA caricato.
I polimeri utilizzati sono stati sintetizzati in modo tale da rispondere con una rapida disaggregazione del nano-sistema una volta in contatto con l'ambiente acido caratteristico dei compartimenti endosomiali e lisosomiali, ottenendo quindi il rilascio del siRNA.
I polimeri a tre blocchi utilizzati presentano due monomeri idrofilici alle estremità, chiamati poly-ethilenglycole (PEG) 1.9 kDa - 3.5 kDa e poly-glycerolmethacrylate (GMA), e inoltre un blocco centrale pH sensibile, poly-imidazole hexyl methacrylate (ImHEMA) che guida la formazione e la disaggregazione delle vescicole. Il polimero ottenuto con PEG 3.5 kDa verrà coniugato all'agente direzionante acido folico per conferire proprietà di bioriconoscimento cellulare ai polimerosomi.
I polimerosomi sono stati preparati miscelando i polimeri ottenuti con 1.9 e 3.5 kDa in rapporti adeguati. I copolimeri in rapporto 90:10 w/w formano vescicole stabili a pH 7.4 e temperatura ambiente con un diametro medio di 100 nm. La stabilità dei polimerosomi a 37°C è stata modulata aumentando il rapporto del copolimero PEG 3.5 kDa. Vescicole ottenute con rapporto di polimeri 90/10 w/w 1.9 kDa e 3.5 kDa sono state caratterizzate morfologicamente al microscopio elettronico a trasmissione TEM mettendo in evidenza forma sferica e alta omogeneità dimensionale. Le vescicole polimeriche caricano efficacemente sequenze di DNA doppia elica (dsDNA) con una resa molare del 14% come dimostrato da analisi spettrofotometriche. Il dsDNA viene rilasciato in 8 ore quando i polimerosomi vengono incubati a pH 5; a pH 7.4 invece il rilascio è risultato essere quasi nullo. La capacità del polimero di complessare il dsDNA è controllata dal pH esterno: studi di ritardo elettroforetico hanno evidenziato che il polimero e il dsDNA sono completamente associati per rapporti N (gruppi amminici del polimero) /P (gruppi fosfato del DNA) di 2/1 a pH 5. Nessuna formazione di complessi è stata osservata per N/P ratio fino a 20/1 a pH 7.4, condizioni cui l’unità imidazolica risulta pressochè neutra.
Studi di citotossicità eseguiti su cellule B16F10 da melanoma di topo hanno mostrato una buona biocompatibilità delle vescicole polimeriche a concentrazioni di 1, 2, 3 mg/mL. La alta attività emolitica del polimero a pH acido (pH 5) conferma la capacità del materiale nell’indurre la lisi della membrana endosomiale. In dettaglio, i risultati hanno mostrato un’attività emolitica pari al 70% a pH 5, mentre in condizioni fisiologiche (pH 7.4) non è stata rilevata alcuna lisi dei globuli rossi.
Le formulazioni polimeriche, con e senza agente di targeting, sono state incubate con cellule KB da cancro alla cervice uterina e cellule MCF7 da adenocarcinoma mammario, le quali rispettivamente sovreaesprimono e non sovraesprimono il recettore folato, in modo tale da studiare l’efficacia di direzionamento di polimerosomi aventi il folato sulla loro superficie. L’internalizzazione di vescicole caricate con dsDNA marcato per mezzo del fluoroforo cyanine-3, valutato mediante analisi fluorimetrica su lisato cellulare e per mezzo di citofluorimetria, ha dimostrato essere di circa 3 volte maggiore per cellule KB comparate a MCF7. Quindi, polimerosomi caricati con ds-siRNA per il silenziamento dell’enzima luciferasi sono state testate su cellule B16F10 trasfettate con il promotore per l’enzima e sovraesprimenti il recettore per il folato. L’esperimento ha mostrato una diminuzione della bioluminescenza imputata all'attività luciferasica del 30% rispetto alle vescicole vuote.
I risultati riportati sono stati confermati grazie a studi di microscopia confocale eseguiti sulle stesse linee cellulari sopra descritte. Le immagini hanno evidenziato un accumulo di dsDNA marcato in modo significativamente più elevato in cellule KB e con una maggiore localizzazione della macromolecola nel compartimento nucleare

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Tipo di EPrint:Tesi di dottorato
Relatore:Salmaso, Stefano
Dottorato (corsi e scuole):Ciclo 26 > Scuole 26 > SCIENZE MOLECOLARI > SCIENZE FARMACEUTICHE
Data di deposito della tesi:29 Gennaio 2014
Anno di Pubblicazione:29 Gennaio 2014
Parole chiave (italiano / inglese):Vescicole/vesicles, polimerosomi/polymersomes, pH sensibile/pH sensitive, direzionamento/delivery, dsDNA/dsDNA, ds-siRNA/ds-siRNA, tumore/tumor
Settori scientifico-disciplinari MIUR:Area 03 - Scienze chimiche > CHIM/09 Farmaceutico tecnologico applicativo
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze del Farmaco
Codice ID:6545
Depositato il:14 Nov 2014 08:41
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