Ovarian cancer is the most lethal gynecological malignancy worldwide due to its high mortality rates, elusive early symptoms, and limited diagnostic methods. Abnormal cells can rapidly spread to adjacent regions of ovaries and surrounding abdominal organs, contributing to rapid disease progression and complicating treatment. Metastasis, especially into the peritoneal cavity, often leads to relapse, reducing patient life expectation and life quality. Current treatments include surgery, radiotherapy, intravenous (IV) and intraperitoneal (IP) chemotherapy, where Paclitaxel (PTX) and Cisplatin (CPt) are the most employed drugs. This research work is focused on developing advanced drug delivery systems for IP administration, specifically involving polymeric and lipidic carriers. The formulated systems comprise calcium alginate microbeads (CaAlg MBDs) encapsulating either CPt-loaded cholesterol/lecithin liposomes or PTX-loaded PLGA microparticles (MPs). This strategy aims at enhancing drug efficacy, improving localized drug delivery with controlled release profile, and minimizing systemic toxic side effects. Particles morphology characterization, including size and shape evaluation, encapsulated drug quantification and drug release studies were performed for each system. By carefully designing the formulation composition, both delivery systems were optimized to increase their effectiveness and reliability, aligning with in vivo physiological conditions. The CaAlg MBDs encapsulating PTX-loaded PLGA MPs were also tested in 3D cell culture models to assess their therapeutic effect in vitro, showing promising results. In addition, improvements in the outer shell of the MBDs was obtained through a multilayering process involving the addition of an intermediate chitosan film. This modification increased the MBDs structural integrity, which may improve their resistance to swelling and degradation.
Il cancro ovarico è la neoplasia ginecologica più letale a livello mondiale, a causa dell'elevato tasso di mortalità, dei sintomi iniziali difficilmente identificabili e della scarsità di metodi diagnostici. Le cellule anomale possono diffondersi rapidamente alle regioni adiacenti delle ovaie e agli organi addominali circostanti, contribuendo a una rapida progressione della malattia e complicando il trattamento. La metastasi, soprattutto nella cavità peritoneale, porta a frequenti ricadute riducendo l’aspettativa e la qualità di vita dei pazienti. I trattamenti attuali comprendono chirurgia, radioterapia, chemioterapia per via endovenosa (IV) e intraperitoneale (IP), dove il Paclitaxel (PTX) e il Cisplatino (CPt) sono i farmaci più utilizzati. Questo lavoro di ricerca è focalizzato sullo sviluppo di sistemi avanzati di somministrazione e rilascio di farmaci per via IP, coinvolgendo in particolare vettori polimerici e lipidici. I sistemi formulati comprendono microbiglie di alginato di calcio (CaAlg MBDs) che incapsulano liposomi di colesterolo e lecitina caricati con CPt o microparticelle di PLGA (MPs) caricate con PTX. Questa strategia mira a migliorare l'efficacia del farmaco, ottimizzando la somministrazione localizzata con un profilo di rilascio controllato e minimizzando gli effetti collaterali tossici sistemici. Per ogni sistema, è stata eseguita la caratterizzazione morfologica delle particelle, inclusa la valutazione di dimensioni e forma, la quantificazione del farmaco incapsulato e gli studi di rilascio del farmaco. Progettando attentamente la composizione della formulazione, entrambi i sistemi di rilascio sono stati ottimizzati per aumentare la loro efficacia e affidabilità, allineandosi alle condizioni fisiologiche in vivo. Le CaAlg MBDs che incapsulano microparticelle di PLGA caricate con PTX sono state inoltre testate in modelli di coltura cellulare 3D per valutarne l'effetto terapeutico in vitro, mostrando risultati promettenti. Inoltre, sono stati ottenuti miglioramenti nel rivestimento esterno delle biglie tramite un processo multistrato che prevedere l’aggiunta di un film intermedio di chitosano. Questa modifica ha aumentato l'integrità strutturale delle MBDs, potenzialmente aumentando la loro resistenza al rigonfiamento e alla degradazione.
Polymeric and lipidic drug-loaded microparticles for ovarian cancer treatment
BRAMBILLA, LAURA
2023/2024
Abstract
Ovarian cancer is the most lethal gynecological malignancy worldwide due to its high mortality rates, elusive early symptoms, and limited diagnostic methods. Abnormal cells can rapidly spread to adjacent regions of ovaries and surrounding abdominal organs, contributing to rapid disease progression and complicating treatment. Metastasis, especially into the peritoneal cavity, often leads to relapse, reducing patient life expectation and life quality. Current treatments include surgery, radiotherapy, intravenous (IV) and intraperitoneal (IP) chemotherapy, where Paclitaxel (PTX) and Cisplatin (CPt) are the most employed drugs. This research work is focused on developing advanced drug delivery systems for IP administration, specifically involving polymeric and lipidic carriers. The formulated systems comprise calcium alginate microbeads (CaAlg MBDs) encapsulating either CPt-loaded cholesterol/lecithin liposomes or PTX-loaded PLGA microparticles (MPs). This strategy aims at enhancing drug efficacy, improving localized drug delivery with controlled release profile, and minimizing systemic toxic side effects. Particles morphology characterization, including size and shape evaluation, encapsulated drug quantification and drug release studies were performed for each system. By carefully designing the formulation composition, both delivery systems were optimized to increase their effectiveness and reliability, aligning with in vivo physiological conditions. The CaAlg MBDs encapsulating PTX-loaded PLGA MPs were also tested in 3D cell culture models to assess their therapeutic effect in vitro, showing promising results. In addition, improvements in the outer shell of the MBDs was obtained through a multilayering process involving the addition of an intermediate chitosan film. This modification increased the MBDs structural integrity, which may improve their resistance to swelling and degradation.File | Dimensione | Formato | |
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2024_12_Brambilla_Tesi_01.pdf
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2024_12_Brambilla_Executive_Summary_01.pdf
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https://hdl.handle.net/10589/231511