Polymeric nanoparticles (NPs) represent a promising strategy for the delivery of different kinds of drugs in many therapeutic applications, due to their ability to modify the circulation time in the body and the temporal release of the active compounds. The goal of these systems is to modify the temporal and spatial biodistribution of a known drug in order to increase its efficacy against the diseased tissue and decrease its side effects against the healthy tissues. Polymeric carriers have many advantages over other kinds of materials used for drug delivery applications. They are safe, biocompatible and can be biodegradable. Moreover, due to the discovery of new controlled polymerization techniques almost every part of their structure can be handled. For this reason, their biological properties, such as binding efficiency, circulation time, rate of degradation and release, can be tuned in order to optimize their therapeutic performances. The most investigated application in drug delivery is cancer chemotherapy. One the main strategies adopted to improve the biodistribution of a nanocarrier in this case is the exploitation of the so-called enhanced permeability and retention effect (EPR). However, the recent clinical trials of drug formulations based on this concept have shown reduced toxicity but not improved therapeutic efficacy. To overcome this major limitation, an active targeting strategy based on a ligand-receptor interaction has to be exploited. The active targeting of a nanocarrier is not influenced just by the nature of the ligand-receptor pair. The overall structure of the carrier plays a rule in the in vivo performance of the targeting system. In particular, the surface accessibility of the ligand, the length and nature of the spacer, the avidity behavior for multivalent ligands, the circulation time of the carrier and the presence of hydrophilic neutral polymers able to decrease the reticuloendothelial system uptake are factors that have to be taken into account. Moreover, other disease associated to other cells and inflammation processes are characterized by specific receptors that could be exploited by ligand-functionalized polymeric carriers. The aim of this thesis is to explore new strategies for the production polymeric nanocarriers for different drug delivery applications with the help of advanced polymerization techniques and organic synthesis to create well-defined and novel polymeric structures. Various polymeric nanostructures are produced for different applications and the influence of the chemical structure on the biologic performances of the systems are investigated.
Le nanoparticelle polimeriche rapresentano una promettente strategia per il miglioramento delle modalità di somministrazione di diversi farmaci in molte applicazioni terapeutiche, grazie alla possibilità di modificare, attraverso di loro, il tempo di circolazione nel flusso sanguigno e il rilascio temporale del principio attivo. Lo scopo di questi sistemi è di modificare la distribuzione spaziale e temporale di farmaci noti in modo da poter migliorare la loro efficacia sui tessuti malati e diminuire gli effetti collaterali sui tessuti sani. I sistemi polimerici hanno molti vantaggi rispetto a altri tipi di materiali usati per applicazioni di drug delivery. Sono sicuri, biocompatibili e possono essere biodegradabili. Inoltre, grazie alla scoperta di nuove tecnologie per la polimerizzazione controllata quasi ogni parte della loro struttura può essere ingegnerizzata. Per questa ragione, le loro proprietà farmacologiche, come l'efficienza di binding, il tempo di circolazione, la velocità di degrado e di rilascio di farmaci possono essere controllate in modo da ottimizzare le loro prestazioni terapeutiche. L'applicazione più investigata nel campo del drug delivery è il trattamento dei tumori tramite chemioterapia. Una delle principali strategie adottate per migliorare la biodistribuzione dei nanovettori è il cosiddetto effetto di permeabilità e ritenzione aumentate (effetto EPR). Purtroppo, le recenti sperimentazioni cliniche di formulazioni basati su questo concetto hanno mostrato una diminuzione della tossicità ma non un aumento dell'efficacia terapeutica. Per superare questa limitazione, occorre sfruttare una strategia di targeting attivo, basata su interazioni ligando-recettore. Il targeting attivo di un nanovettore è influenzato non solo dalla natura della coppia ligando-recettore, ma dalla struttura molecolare dell'intero carrier. In particolare, l'accessibilità superficiale del ligando, la lunghezza e la natura dello spacer che lo lega, l'effetto di avidità dovuta all'eventuale multivalenza, il tempo di circolazione e la presenza di polimeri idrofili neutri che diminuiscono l'uptake da parte del sistema reticolo-endoteliale sono fattori che devono essere tenuti in considerazione. Inoltre, altre malattie associate a altre cellule o altri processi di infiammazione sono caratterizzati da specifici recettori che possono essere sfruttati grazie a nanovettori funzionalizzati con specifici ligandi.
Polymer conjugates and nanoparticles for drug delivery applications
GATTI, SIMONE
Abstract
Polymeric nanoparticles (NPs) represent a promising strategy for the delivery of different kinds of drugs in many therapeutic applications, due to their ability to modify the circulation time in the body and the temporal release of the active compounds. The goal of these systems is to modify the temporal and spatial biodistribution of a known drug in order to increase its efficacy against the diseased tissue and decrease its side effects against the healthy tissues. Polymeric carriers have many advantages over other kinds of materials used for drug delivery applications. They are safe, biocompatible and can be biodegradable. Moreover, due to the discovery of new controlled polymerization techniques almost every part of their structure can be handled. For this reason, their biological properties, such as binding efficiency, circulation time, rate of degradation and release, can be tuned in order to optimize their therapeutic performances. The most investigated application in drug delivery is cancer chemotherapy. One the main strategies adopted to improve the biodistribution of a nanocarrier in this case is the exploitation of the so-called enhanced permeability and retention effect (EPR). However, the recent clinical trials of drug formulations based on this concept have shown reduced toxicity but not improved therapeutic efficacy. To overcome this major limitation, an active targeting strategy based on a ligand-receptor interaction has to be exploited. The active targeting of a nanocarrier is not influenced just by the nature of the ligand-receptor pair. The overall structure of the carrier plays a rule in the in vivo performance of the targeting system. In particular, the surface accessibility of the ligand, the length and nature of the spacer, the avidity behavior for multivalent ligands, the circulation time of the carrier and the presence of hydrophilic neutral polymers able to decrease the reticuloendothelial system uptake are factors that have to be taken into account. Moreover, other disease associated to other cells and inflammation processes are characterized by specific receptors that could be exploited by ligand-functionalized polymeric carriers. The aim of this thesis is to explore new strategies for the production polymeric nanocarriers for different drug delivery applications with the help of advanced polymerization techniques and organic synthesis to create well-defined and novel polymeric structures. Various polymeric nanostructures are produced for different applications and the influence of the chemical structure on the biologic performances of the systems are investigated.File | Dimensione | Formato | |
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https://hdl.handle.net/10589/136895