Nanofabrication and characterisation of targeted drug delivery systems for liver cancer therapy

Hamdallah, Sherif (2023) Nanofabrication and characterisation of targeted drug delivery systems for liver cancer therapy. Doctoral thesis, University of East Anglia.

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Abstract

Liver cancer (primarily hepatocellular carcinoma, HCC) is a leading cause of cancer-related mortality and morbidity worldwide, with a poor prognosis and limited treatment options. Sorafenib (Sf) is a multikinase inhibitor that is FDA-approved as the first line of treatment for advanced hepatocellular carcinoma (HCC). Despite its promising therapeutic outcomes, its low solubility, and oral bioavailability have limited its clinical application. Therefore, there is an urgent need for innovative and effective therapeutic strategies for liver cancer.

Nanotechnology-based drug delivery systems have emerged as promising platforms for the elective and controlled delivery of cytotoxic agents to cancer cells, minimising systemic toxicity and enhancing therapeutic efficacy. These nanocarriers can encapsulate, protect, and release drugs in a controlled manner and can be functionalised with ligands for targeted delivery to cancer cells. Among these, galactosylation of nanoparticles represents a potential strategy for liver-specific drug delivery.

The presented work herein involves the preparation, optimisation and characterisation of different galactosylated nanodrug delivery systems, including solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), lipid nanocapsules (LNC), and polymeric micelles (PMs), for liver-targeted delivery of sorafenib to overcome its limited bioavailability and systemic side effects. The developed lipid-based delivery systems (SLN, NLC, and LNC) showed excellent colloidal properties with high drug entrapment efficiency (> 85%). Galactosylated LNC exhibited higher cytotoxicity and cellular uptake by HepG2 cells than untargeted LNC.

On the other hand, the developed Soluplus® based-polymeric micelles for oral administration have shown a tremendous enhancement of Sf solubility (>1100 times), translated into a 27-fold improvement in dissolution efficiency. Furthermore, these micelles exhibited an 8-fold increase in the cellular transport in the Caco-2 cell model compared to drug suspension. Lastly, galactosylated polymeric mixed micelles were formulated, exhibiting good colloidal properties and high Sf loading capacity (~15.5%). They demonstrated enhanced cellular cytotoxicity and receptor-mediated cellular uptake compared to untargeted counterparts.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Pharmacy
Depositing User:	Chris White
Date Deposited:	23 Aug 2023 08:49
Last Modified:	23 Aug 2023 08:49
URI:	https://ueaeprints.uea.ac.uk/id/eprint/92913
DOI:

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