Bombesin receptor-targeted liposomes for enhanced delivery to lung cancer cells

Akbar, Mohammad (2021) Bombesin receptor-targeted liposomes for enhanced delivery to lung cancer cells. Doctoral thesis, University of East Anglia.

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Abstract

Targeted nanotherapeutics have been used in cancer to overcome the limitations of conventional chemotherapeutics. Liposomes are versatile carriers which can be tuned for targeting specific type of cancer. Small cell lung cancer (SCLC) represents about 15% of all lung cancers and is characterized by rapid proliferation, metastasis, recurrence and poor prognosis. It is strongly associated with tobacco smoking and patients usually present with metastatic disease. It is also categorized as a neuroendocrine type of cancer. This means that it produces neuropeptides such as GRP. GRP act as a mitogen and highly express its receptor (GRP-R) which creates autocrine loop. This loop of GRP/GRP-R drives the SCLC growth which makes the system appealing for targeting therapy. There are almost no novel treatments have been approved or introduced into the standard SCLC regimen in the last few decades. Therefore, this study offers an insight into utilizing GRP/GRP-R growth loop to target SCLC using targeted liposomes that features antagonistic peptide to enhance safe delivery, accumulation, and internalization into GRP-R overexpressing SCLC via receptor-mediated approach.

The aim of this project was to synthesize targeted liposomes for SCLC that enhances accumulation to GRP-R overexpressing cells. This was performed by functionalizing pegylated liposomes with a GRP-R antagonist peptide. To achieve this aim, we studied GRP-R expression and functionality in a number of selected SCLC cell lines (H510, H345, H209, H82 and N417). In addition to that, we manipulated GRP-R expression in selected SCLC cell lines (H510 and H345) as well as A549 in order to develop an in vitro cell line model to test the capability of the targeting formulation. an N-terminally cysteine modified GRP-R antagonist (termed cystabn) was synthesised and shown to inhibit cell growth in vitro. Cystabn was used to prepare a targeted DSPE-PEG2000 lipid conjugate that was formulated into liposomes. The liposomes were colloidally stable with favourable properties in terms of size and surface charge and good stability under storage conditions. Flow cytometric and microscopic studies showed that fluorescently labelled cystabn-functionalized liposomes are preferentially internalised by receptor-mediated approach into GRP-R overexpressing cells more extensively than plain pegylated liposomes that contained no cystabn targeting motif. In conclusion, the finding of this work offer promising targeted liposomal delivery system, which can be delivered safely (without triggering receptor-mediated growth signalling), in a targeted manner, and actively via receptor mediated approach, into SCLC or any other GRP-R overexpressing cancer using small antagonistic ligand formulated into the liposomes.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Chris White
Date Deposited: 01 Aug 2022 08:51
Last Modified: 01 Aug 2022 08:51
URI: https://ueaeprints.uea.ac.uk/id/eprint/87007
DOI:

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