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Title: Designing a safe dendronised polymeric nanocarrier for hydrophobic drugs or gene delivery in cancer therapy
Author: Wali, Aisha Roshan Mohamed
ISNI:       0000 0004 7972 4553
Awarding Body: University of Wolverhampton
Current Institution: University of Wolverhampton
Date of Award: 2018
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The hardship of cancer is continuously increasing and is rapidly spreading globally. At present, almost one-third of newly discovered potential therapeutics have poor pharmacokinetics and biopharmaceutical properties. Chemotherapeutic agents known to be the most effective treatment, lack tumour specificity and suffers from poor solubility. The lack of specificity results in severe side effects in off-target tissues, whereas poor soluble drugs exhibit short half-life in the bloodstream and high overall clearance rate. Amphiphilic block copolymers based on hydrophobic dendrons have shown to be a promising strategy to enhance the solubility of hydrophobic drugs, prolong circulation time, minimise non-specific uptake, and allow for specific tumour-targeting through the EPR effect. Herein, we have proposed the development of a new safe and more specific non-viral vector system based on peptide dendronised polymeric micelles to enhance the delivery of hydrophobic drugs into liver cancer cells. G3(PLLA and OGPLLL) arginine dendron of third generation bearing eight peripheral hydrophobic or cationic groups (PBF and BOC or guanidine groups) were synthesised in high yield, identified and tested for purity using NMR, MS and TLC. A series of three amphiphilic system characterised by different hydrophilic pullulan derivatives segments were then synthesised using Huisgen azide-alkyne 1,3-dipolar cycloaddition between pullulan (P), lactosylated pullulan (P(Lac)) and pullulan bearing disulphide linkage (PSS) with the G3 dendron to lead amphiphilic block copolymers P-PLLA, P(Lac)-PLLA and PSS-PLLA, respectively. Hydrophilic pullulan and lactobionic acid were selected for amphiphilic modification, aiming at specific asialoglycoprotein receptors recognition onto hepatocytes cells in the liver. Macromolecular structures of amphiphilic P-PLLA, P(Lac)-PLLA and PSS-PLLA were able to self-assemble spontaneously into spherical nanoarchitectures of sizes less than 90nm with low polydispersity in the aqueous media, which was confirmed by CAC, DLS and TEM. Furthermore, the polyaromatic anticancer drug Doxorubicin (Dox) was selectively encapsulated in the hydrophobic core through multiple interactions with the dendron, including π-π interactions, hydrogen bonding and hydrophobic interactions. Such multiple interactions had the merits of enhanced drug loading capacity (>16%), excellent stability against dilution, and excellent sustained release property. Results showed that a high number of hydrophobic segments within a micellar core enhance higher loading efficiency of hydrophobic drugs, whereas, an increase of surface hydrophilicity or an increase in the length of the hydrophobic segment, both have an effect in reducing the micellar size and CAC value. The disulfide-containing PSS-PLLA micelles were able to co-encapsulate both hydrophobic drugs Dox and Curcumin (Cur) which could simultaneously be co-released in high rate from the carrier (>80wt% in 60hours) in response to the high redox potential environment. Most importantly, the release of Dox from the carrier at pH 5 enhanced the release of curcumin, whereas curcumin, in turn, would improve the efficiency of Dox anticancer activity by overcoming Dox MDR. Such a delivery system provides a promising approach for combination therapy in cancer. The cell viability assay presented that the blank micelles had excellent biocompatibility both in the normal and tumour cells. Moreover, loaded drugs nanoparticles could be effectively internalised into the hepatoma carcinoma cells, and Dox-Cur-PSS-PLLA dramatically inhibited cell proliferation. Also, cationic dendron conjugated pullulan (P-OGPLLL) could efficiently condense DNA with excellent hemocompatibility and high gene transfection in Hela and Hek293T cells. Thus, this work offers an effective strategy of designing a non-viral system and the P-PLLA, P(Lac)-PLLA, PSS-PLLA and P-OGPLLL nanocarriers serve as a reliable drug/gene delivery nanoplatform to enable the improvement of the bioavailability, targetability, efficacy and overcome MDR of therapeutic agents.
Supervisor: Tang, James Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: cancer ; targeted drug delivery ; nanoparticles ; micelles ; dendrons ; amphiphilic polysaccharide ; doxorubicin ; curcumin