Spinal Cord Injury (SCI) remains one of the most devastating condition among neurological diseases, due to its pathologic consequences. It is estimated that this lesion affects about 330.000 European people, and it is one of the leading causes of disability in Italy. Usually, these injuries are the result of traumatic events (for example, a motor vehicle accident or a sport injury or by violence such as gunshot wound), but many also are the outcome of non-traumatic causes as consequence of medical treatments or diseases, such as polio and split spine or the presence of tumoral mass. Currently, there is no effective strategy for the treatment of SCI: medical care immediately after the lesion, including immobilizing and bracing to stabilize the spine, can best help to minimize the damage of neural cells. SCI involves also different kind of damage to distinct types of cells; the environment if spinal cord changes drastically during the first few weeks after injury, because immune cells flow in, toxic substances are released and a scar is formed, which generates permanent interruption of information transmission to and from the central nervous system. About this, tissue engineering is a widely accepted as being the future in regenerative medicine and health care. It studies the smart combination of cells and materials to replace damaged or missing parts of living tissues: it points toward the synthesis of a biological active and compatible structure able to carry functional drugs and cells that, for example in SCI, can suppress the damaging inflammation (preventing spread of injury), protect the cells at the injury site from further damage by releasing therapeutic substances and replacing dead nerve cells with new one, capable of promoting reconnection between interrupted nerve fibers. Emerging strategies in regenerative medicine confirm a very strong interest in hydrogel as great candidates for both cell and drug delivery, allowing the building of biocompatible three-dimensional polymer network with cells and drug directly included inside gel and then released in a controlled way. Focusing on the drug delivery aspect of those systems, hydrogels are not the best option as drug delivery systems because they can load just hydrophilic compounds, due to their nature, and release is often too fast to achieve the correct therapeutic profile. On the other side, polymeric nanoparticles have demonstrated to be very effective carrier for drug delivery, but mainly because of their dimensions, tend to diffuse all over the organism, losing part of their efficacy. For this reason, last decades study, suggest that the combination of those two biomedical devices, hydrogels and nanoparticles, to achieve the best therapeutic effect in situ, assuring the correct delivery of drugs of any nature (hydrophilic or hydrophobic) in time, avoiding under and overdosing and subsequent side effect. In this thesis, it is studied the possibility to synthetize biodegradable and biocompatible polymeric nanoparticles, based on PEG-b-PLA copolymer, via different production methods. Those nanoparticles have also demonstrated to be suitable for functionalization with well-defined surface charge, through physical absorption of ionic surfactants on particle surface. This feature allows to create nanocluster, on one side; in the other side to relate with charged hydrogel network, such as AC1, AC6 and AC6+CMC through electrostatic interaction, creating a drug delivery system with the modulable release capability of multiple drugs loaded
La lesione del midollo spinale rimane, ad oggi, una delle più problematiche patologie neurologiche a causa dei conseguenti effetti a lungo termine. È stimato, che circa 330.000 cittadini europei siano affetti da tale patologia, che, anche in Italia, rimane una delle maggiori cause di disabilità. Tipicamente queste lesioni derivano da eventi traumatici, come incidenti d’auto o in ambito sportivo, come anche come conseguenza di eventi violenti, come ferite da arma da fuoco. In aggiunta a queste cause, poi, occorre considerare anche fonti non traumatiche, come la presenza di patologie quali la poliomielite, spina bifida o ancora tumori. Fino ad ora non esiste un trattamento risolutivo per le lesioni del midollo spinale: anche i trattamenti medici che vengono somministrati immediatamente dopo la lesione, inclusa l’immobilizzazione e il rinforzo per la stabilizzazione della colonna, possono solo aiutare a minimizzare il danno alle cellule nervose. Tale patologia, infatti, modifica drasticamente l’ambiente del midollo spinale, in quanto, durante le prime settimane post-infortunio, le cellule del sistema immunitario vengono richiamate nel sito del danno, vengono rilasciate sostanze tossiche e si forma una cicatrice che genera una discontinuità permanente nella trasmissione di informazioni da e per il sistema nervoso centrale. In questo contesto, l’ingegneria tissutale tende ad essere ampiamente configurata come tecnologia promettente per la medicina rigenerativa e per la cura della salute. L’ “ingegneria dei tessuti” fonda i suoi principi sullo studio e l’applicazione di una intelligente combinazione di cellule e materiali in grado di poter sostituire parti mancanti o riparare quelle danneggiate di tessuti viventi. In generale, si tratta di “costruire” una struttura biologicamente attiva e compatibile, capace di trasportare farmaci e/o cellule appropriati che, ad esempio nel caso della lesione spinale, possano portare alla soppressione dell’infiammazione (prevenendo così la diffusione della lesione), alla protezione delle cellule nel sito di lesione da ulteriori danni attraverso il rilascio di sostanze terapeutiche e alla sostituzione di cellule nervose morte con nuove, capaci di stimolare la riconnessione tra le fibre nervose interrotte. Le nuove strategie nella medicina rigenerativa confermano un grande interesse nei confronti degli idrogel come efficienti veicoli di trasporto sia di cellule che di principi attivi: strutture polimeriche tridimensionali dotate di elevata biocompatibilità e possibilità di rilascio controllato dei farmaci e delle cellule caricate. Focalizzando l’attenzione sull’aspetto del drug delivery, gli idrogel non si rivelano in realtà la migliore opzione per il rilascio di farmaci, sia perché possono essere caricati solo di farmaci idrofilici, essendo strutture a base acquosa, sia perché spesso il rilascio di farmaci per via diffusiva è spesso troppo veloce per ottenere l’attesa efficacia terapeutica. D’altra parte, le nanoparticelle si sono dimostrate essere degli efficienti veicoli farmacologici, ma per via delle loro dimensioni, tendono a spostarsi dal luogo della lesione e diffondersi in tutto l’organismo, perdendo così parte della loro efficacia. Per questo motivo, soprattutto negli ultimi decenni, la ricerca ha suggerito la combinazione di questi due sistemi, nanoparticelle e idrogel, per superare le rispettive limitazioni e ottenere un sistema in grado di ottenere il miglior effetto terapeutico possibile in situ, assicurando il corretto rilascio di farmaci di qualsiasi genere (idrofilici e idrofobici) nel tempo, evitando sotto o sovradosaggi e i conseguenti effetti collaterali. In questa tesi si è studiata la possibilità di sintetizzare nanoparticelle polimeriche, biodegradabili e biocompatibili, basate su polimero PEG-b-PLA, secondo diverse metodologie di produzione. Tali particelle si sono dimostrate anche adatte per essere funzionalizzate con una carica netta superficiale, conferita da surfattanti ionici fisicamente adsorbiti sulla superficie della particella. Questa caratteristica ha permesso la creazione, da un lato, di nanocluster, dall’altro l’interazione elettrostatica con idrogel carichi, come AC1, AC6 e AC&+CMC. Il risultato è stata la realizzazione di un sistema composito per il drug delivery che permettesse sia la carica di farmaci idrofilici e/o idrofobici che la possibilità di modulare le velocità di rilascio di tali composti grazie alle interazioni elettrostatiche tra nanoparticelle e idrogel.
Hydrogel-nanoparticles as versatile system for controlled drug delivery
NEGRI, ANNA
2016/2017
Abstract
Spinal Cord Injury (SCI) remains one of the most devastating condition among neurological diseases, due to its pathologic consequences. It is estimated that this lesion affects about 330.000 European people, and it is one of the leading causes of disability in Italy. Usually, these injuries are the result of traumatic events (for example, a motor vehicle accident or a sport injury or by violence such as gunshot wound), but many also are the outcome of non-traumatic causes as consequence of medical treatments or diseases, such as polio and split spine or the presence of tumoral mass. Currently, there is no effective strategy for the treatment of SCI: medical care immediately after the lesion, including immobilizing and bracing to stabilize the spine, can best help to minimize the damage of neural cells. SCI involves also different kind of damage to distinct types of cells; the environment if spinal cord changes drastically during the first few weeks after injury, because immune cells flow in, toxic substances are released and a scar is formed, which generates permanent interruption of information transmission to and from the central nervous system. About this, tissue engineering is a widely accepted as being the future in regenerative medicine and health care. It studies the smart combination of cells and materials to replace damaged or missing parts of living tissues: it points toward the synthesis of a biological active and compatible structure able to carry functional drugs and cells that, for example in SCI, can suppress the damaging inflammation (preventing spread of injury), protect the cells at the injury site from further damage by releasing therapeutic substances and replacing dead nerve cells with new one, capable of promoting reconnection between interrupted nerve fibers. Emerging strategies in regenerative medicine confirm a very strong interest in hydrogel as great candidates for both cell and drug delivery, allowing the building of biocompatible three-dimensional polymer network with cells and drug directly included inside gel and then released in a controlled way. Focusing on the drug delivery aspect of those systems, hydrogels are not the best option as drug delivery systems because they can load just hydrophilic compounds, due to their nature, and release is often too fast to achieve the correct therapeutic profile. On the other side, polymeric nanoparticles have demonstrated to be very effective carrier for drug delivery, but mainly because of their dimensions, tend to diffuse all over the organism, losing part of their efficacy. For this reason, last decades study, suggest that the combination of those two biomedical devices, hydrogels and nanoparticles, to achieve the best therapeutic effect in situ, assuring the correct delivery of drugs of any nature (hydrophilic or hydrophobic) in time, avoiding under and overdosing and subsequent side effect. In this thesis, it is studied the possibility to synthetize biodegradable and biocompatible polymeric nanoparticles, based on PEG-b-PLA copolymer, via different production methods. Those nanoparticles have also demonstrated to be suitable for functionalization with well-defined surface charge, through physical absorption of ionic surfactants on particle surface. This feature allows to create nanocluster, on one side; in the other side to relate with charged hydrogel network, such as AC1, AC6 and AC6+CMC through electrostatic interaction, creating a drug delivery system with the modulable release capability of multiple drugs loadedFile | Dimensione | Formato | |
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https://hdl.handle.net/10589/134966