Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.755774
Title: Development of Afatinib lipid nanoparticles targeting non small cell lung cancer
Author: Almurshedi, A.
ISNI:       0000 0004 7428 7606
Awarding Body: Liverpool John Moores University
Current Institution: Liverpool John Moores University
Date of Award: 2018
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Abstract:
Lung cancer is the most common cause of cancer-associated mortality in males and females globally. Widespread research is currently focused on the development of novel approaches for targeting non small cell lung cancer with different therapeutic nanotechnologies. In this study, a sensitive and selective HPLC method was developed for the quantification of afatinib (AFT) in formulations. Novel drug delivery systems based on cationic (CL) and pH-sensitive liposomes (PSL) for AFT were developed, with different ratios of lipid to AFT, using a film hydration method. The obtained liposomes had a small particle size of less than 50 nm with a low polydispersibilty index and acceptable zeta potential. The highest Encapsulation Efficiency (EE%) of AFT reached 43.20%, 50.20%, and 52.01% for NL (Non targeting liposomes), PSL, CL, respectively at the 1:0.5 ratio of AFT: lipids. The in vitro release study confirmed that all formulations had sustained release profiles in pH 7.4. However, in acidic pH values, PSL exhibited fast release. The stability study, conducted at 4°C and 25°C for 1 month, showed that the characteristics of liposomes in liquid form did not change significantly over this period. In vitro cytotoxicity studies revealed high antitumor activity of PSL on all cell lines at 0.75 μM concentration after 24 h exposure, based on using the Annexin V assay. A proteomics study identified 12 proteins which can be used as biomarkers capable of prediction of treatment response and choice of therapy for two different types of human NSCLC cells (H-1975 and H-1650). Spray drying was used to produce nanocomposite microparticles (NCMPs) using L-leucine and coated using different ratios of chitosan for the optimized PSL NPs. The particles had a corrugated surface except at high CH ratios, where more homogenous and smooth particles with some small indentations were obtained. The powder properties showed good flow properties and reproducible size. Coated NCMPs showed a delayed drug release profile compared to PSL NPs and the best correlation with the Higuchi model. A stability study at 40°C/ 75% ± 5% relative humidity (RH) showed large changes in the drug content for all coated NCMPs powders. Analysis of the in vitro aerosolization performance demonstrated a mass median aerodynamic diameter (MMAD) of 3.24 – 5.85 μm and fine particle fraction (FPF%) of 54.20-33.66%. The particle size of the reconstituted powders was ˂ 100 nm, which is within the size range to be effectively taken up by tumor cells. Assessment of the stability of spray dried liposomes after 3 months of storage at 40 °C/75% RH, showed that fusion and aggregation of the liposomes occurred in all samples tested. The C1NCMPs (lipid: LEU: CH ratio of 1:1.5:0.5) exhibited the highest FPF (51.2%) and fine particle dose (FPD) (40.0 μg of AFT) indicating deep lung deposition. Further cell viability studies of C1 NCMP, at a concentration of 0.75 μM on H-1975 NSCLC cell line showed a good toxicity profile comparable to PSL nanoparticles (NPs). The obtained data indicates that pulmonary delivery of PSL NCMPs is a potential new clinical strategy for better targetability and delivery of AFT for the treatment of lung cancer.
Supervisor: Hutcheon, G. ; Saleem, I. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.755774  DOI: Not available
Keywords: RC0254 Neoplasms. Tumors. Oncology (including Cancer) ; RM Therapeutics. Pharmacology
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