Polymers are a class of materials largely used in biomedical field thanks to their properties of biocompatibility and biodegradability. Natural and synthetic polymers play an integral role in nanomedicine, in particular for drug delivery technology by providing controlled release of therapeutic agents such as chemotherapeutic agents, vaccines, gene, antibiotics, anti-inflammatory agents, hormones and anesthetics.. The most studied natural polymers for drug delivery are chitosan, alginate and pectin. The last one is especially investigated for its intrinsic anticancer activity induce from its characteristic to bind and inhibit the protein galectin-3 (GAL3), a multifaceted and prometastatic protein expressed in many tumors. On the other hand the most common synthetic polymers are poly-lactic acid (PLA), poly-glycolic acid (PGA), poly-lactic-co-glycolic acid (PLGA), poly-ɛ-caprolattone (PCL), poly-ethylene-glycol (PEG) and poly(N-isopropylacrylamide) (PNIPAAm). In particular, PLGA is one of the most investigated polymer for its characteristic to be hydrolyzed in two metabolite monomers, lactic acid and glycolic acid, easily metabolized by the body from the Krebs cycle. This polymer is approved by the US Food and Drug Administration and European Medicine Agency for human used and nanomedicine. Among the different drugs, there are the Local Anesthetics (Las). LAs are used for acute and chronic pain treatment, principally after surgery, but LA systemic administration could present severe drawbacks (allergies and stroke). There are very few examples of implantable device loaded with LAs, usually they are used in external systems or directly injected in blood vassels. Procaine and chloroprocaine demonstrate to be less cardiotoxic than the majority of the other LAs but they have an extremely short half-life. For this reason drug delivery systems have been developed to minimize severe side effects and prolong anesthetic actions. Up to now many LAs delivery systems have been developed (microparticles, liposome, nanoparticles and nanogel) but no one is either commercially available or perfectly suitable for pre-peritoneal LA administration following abdominal surgery. The aim of this project is to develop nanostructured materials for drug release. The work has been divided in three parts: in the first chapter pectin nanoparticles for drug release were produced and characterized, in particular for cancer therapy. In the second part were produced PLGA nanoparticles loaded with procaine and chloroprocaine using the water in oil in water (W/O/W) emulsion solvent evaporation technique. In the last part the attention was focused on the production of an ad hoc implantable device for LAs administration in pre-peritoneal, degradable into non-toxic products and sterilizable, as sterility is a basic requirement for any implantable device. Natural materials are suitable for this application for their capability of producing hydrogel, which are interesting for their anatomical compatibility with soft tissues. The final aim is to insert the pectin and PLGA nanoparticles in the alginate device to decrease the release rate and prolong the effect of the drugs.
I polimeri sono una classe di materiali largamente usata in campo biomedico grazie alle loro proprietà di biocompatibilità e biodegradabilità. I polimeri naturali e sintetici assumono un ruolo fondamentale in nanomedicina, in particolare per tecnologie di rilascio di farmaco, provvedendo a un rilascio controllato di agenti terapeutici come farmaci chemioterapici, vaccini, geni, antibiotici, farmaci antinfiammatori, ormoni e anestetici. I polimeri naturali più studiati per il rilascio di farmaco sono chitosano, alginato e pectina. L’ultimo è particolarmente investigato per la sua intrinseca attività anticancro indotta dalla capacità di legare e inibire la proteina galectin-3 (GAL3), una proteina prometastatica espressa in molti tumori. Riguardo i polimeri sintetici, i più comuni sono l’acido polilattico (PLA), L’acido poliglicolico (PGA), il poli(acido lattico-co-glicolico) (PLGA), il policaprolattone (PCL), il glicole polietilenico (PEG) e il Poli(N-isopropilacrilammide). In particolare il PLGA è uno dei più studiati per la sua caratteristica di essere idrolizzato in due monomeri metaboliti, acido lattico e acido glicolico, facilmente metabolizzati dal corpo umano nel Ciclo di Krebs. Questo polimero è approvato dalla US Food and Drug Administration (FDA)e dall’ European Medicine Agency (EMA) per l’uso nel corpo umano e in nanomedicina. Tra i diversi farmaci, ci sono gli anestetici locali (LAs). LAs sono usati nei trattamenti del dolore acuto e cronico, principalmente nel periodo post-operatorio, ma la loro somministrazione può provocare gravi effetti secondari (allergie e ictus). Ci sono pochi esempi di dispositivi impiantabili caricati con LAs, solitamente sono usati in sistemi esterni o iniettati direttamente via venosa. La procaina e la cloroprocaina hanno dimostrato di essere meno cardiotossiche della maggioranza degli altri anestetici locali, ma hanno un emivita molto corta. Per questa ragione sono stati sviluppati sistemi di rilascio controllato di farmaco, sia per minimizzare gli effetti secondari sia per prolungare l’effetto degli anestetici. Fino ad ora sono stati sviluppati diversi sistemi di rilascio di LAs (microparticelle, liposomi, nanoparticelle, nanogeli) ma nessuno è ancora disponibile sul mercato o perfettamente adeguato per l’uso in zona pre-peritoneale dopo chirurgia addominale.Lo scopo di questo progetto è di sviluppare materiali nanostrutturati per il rilascio di farmaci. Il lavoro è stato diviso in tre parti : nel primo capitolo sono state prodotte nanoparticelle di pectina per il rilascio di farmaco, in particolare per la terapia anticancro. Nella seconda parte sono state prodotte nanoparticelle di PLGA caricate con procaina e cloroprocaina usando la tecnica della doppia emulsione acqua in olio in acqua (W/O/W) e evaporazione del solvente. Nell’ultima parte l’attenzione è stata focalizzata sulla produzione di un dispositivo impiantabile per la somministrazione di LAs in zona pre-peritoneale. Il dispositivo deve essere degradabile in prodotti non tossici e sterilizzabile visto che la sterilità è un requisito fondamentale per ogni dispositivo impiantabile. I polimeri naturali sono adatti per questa applicazione per la loro capacità di produrre idrogeli, i quali sono molto interessanti per la loro compatibilità anatomica con i tessuti molli. Lo scopo finale del lavoro è l’inserimento delle nanoparticelle di pectina e di PLGA nella matrice di alginato per diminuire la velocità di rilascio e prolungare l’effetto dei farmaci.
Nanostructured materials for drug release
BRAMBILLA, PAOLA
2014/2015
Abstract
Polymers are a class of materials largely used in biomedical field thanks to their properties of biocompatibility and biodegradability. Natural and synthetic polymers play an integral role in nanomedicine, in particular for drug delivery technology by providing controlled release of therapeutic agents such as chemotherapeutic agents, vaccines, gene, antibiotics, anti-inflammatory agents, hormones and anesthetics.. The most studied natural polymers for drug delivery are chitosan, alginate and pectin. The last one is especially investigated for its intrinsic anticancer activity induce from its characteristic to bind and inhibit the protein galectin-3 (GAL3), a multifaceted and prometastatic protein expressed in many tumors. On the other hand the most common synthetic polymers are poly-lactic acid (PLA), poly-glycolic acid (PGA), poly-lactic-co-glycolic acid (PLGA), poly-ɛ-caprolattone (PCL), poly-ethylene-glycol (PEG) and poly(N-isopropylacrylamide) (PNIPAAm). In particular, PLGA is one of the most investigated polymer for its characteristic to be hydrolyzed in two metabolite monomers, lactic acid and glycolic acid, easily metabolized by the body from the Krebs cycle. This polymer is approved by the US Food and Drug Administration and European Medicine Agency for human used and nanomedicine. Among the different drugs, there are the Local Anesthetics (Las). LAs are used for acute and chronic pain treatment, principally after surgery, but LA systemic administration could present severe drawbacks (allergies and stroke). There are very few examples of implantable device loaded with LAs, usually they are used in external systems or directly injected in blood vassels. Procaine and chloroprocaine demonstrate to be less cardiotoxic than the majority of the other LAs but they have an extremely short half-life. For this reason drug delivery systems have been developed to minimize severe side effects and prolong anesthetic actions. Up to now many LAs delivery systems have been developed (microparticles, liposome, nanoparticles and nanogel) but no one is either commercially available or perfectly suitable for pre-peritoneal LA administration following abdominal surgery. The aim of this project is to develop nanostructured materials for drug release. The work has been divided in three parts: in the first chapter pectin nanoparticles for drug release were produced and characterized, in particular for cancer therapy. In the second part were produced PLGA nanoparticles loaded with procaine and chloroprocaine using the water in oil in water (W/O/W) emulsion solvent evaporation technique. In the last part the attention was focused on the production of an ad hoc implantable device for LAs administration in pre-peritoneal, degradable into non-toxic products and sterilizable, as sterility is a basic requirement for any implantable device. Natural materials are suitable for this application for their capability of producing hydrogel, which are interesting for their anatomical compatibility with soft tissues. The final aim is to insert the pectin and PLGA nanoparticles in the alginate device to decrease the release rate and prolong the effect of the drugs.| File | Dimensione | Formato | |
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https://hdl.handle.net/10589/108863