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Title: Pulmonary delivery of resveratrol-loaded nanocomposite microparticles to treat lung cancer
Author: Muller, A.
ISNI:       0000 0004 8507 1093
Awarding Body: Liverpool John Moores University
Current Institution: Liverpool John Moores University
Date of Award: 2020
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Lung cancer was a rare disease in the latter part of the 19th century, but grew into a full-scale epidemic in the 20th century, becoming the most common cause of cancer related death worldwide. Current cancer chemotherapy, involves the administration of cytotoxic drugs that kill all cells exhibiting a high rate of proliferation and regeneration, which is a characteristic of cancer cells, but also non-cancerous cells, such as hair follicles, bone marrow and gastrointestinal tract cells. Therefore, the systemic delivery of chemotherapy leads to adverse effects, such as chemotherapy induced alopecia (CIA) and chemotherapy-induced peripheral neuropathy (CIPN), which can range from life-altering to life-threatening. Moreover, the economic impact of current cancer chemotherapy is unsustainable and, thus, an alternative therapy for lung cancer need to be investigated. Towards this goal, resveratrol loaded polymeric nanoparticles (NPs) formulated into nanocomposite microparticles (NCMPs) using L-leucine and chitosan were developed for the pulmonary delivery via dry powder inhalation. Resveratrol was loaded into NPs of poly(glycerol adipate-co-ω-pentadecalactone) (PGA-co-PDL) with sizes ranging between 220-230 nm, which are ideal for uptake into cells. The 5%- and 10% resveratrol-loaded NPs (5% RNP and 10% RNP) had a high encapsulation efficiency of 39 ± 0.12 and 70 ± 0.89% and a drug loading of 78 ± 0.24 µg and 70 ± 0.89 µg (w/w), respectively. The PGA-co-PDL blank NPs (BNP) at 1 mg/mL showed good cytocompatibility in Calu 3 cells with a cell viability of 87.5±4.7% after 24-hour exposure. Meanwhile, the 5% RNP and 10% RNP decreased the IC50 of resveratrol in Calu 3 cells after 24 hours from 213 ± 63 µM to 47 ± 30 µM and 48 ± 12 µM, respectively. This is a reduction in IC50 of up to 78%. The PGA-co-PDL NPs were spray-dried in NCMPs with mass median aerodynamic xxvi diameters (MMADs) between 3.1-4 µm, which is within the ideal range of 1-5 µm for particles to be able to deposit in the deep regions of the lung. Furthermore, the NCMPs showed a slow release profile, with only 25% of resveratrol being released over 24 hours. Lastly, a novel polymer was synthesised which possessed an alkyne that can allow for the attachment of various ligands, including a fluorescent probe to visualise uptake of the NPs. Overall, the obtained results demonstrate that these NPs/NCMPs show promise as pulmonary drug delivery systems for lung cancer.
Supervisor: Hutcheon, G. ; Fatokun, A. ; Sarker, S. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: RM Therapeutics. Pharmacology