Stimuli-Responsive Multi-layered Nanocarriers for Oral Drug Delivery to Treat Colon Cancer



Elbaz Elmotayem, Nancy Mohamed
(2020) Stimuli-Responsive Multi-layered Nanocarriers for Oral Drug Delivery to Treat Colon Cancer. Doctor of Philosophy thesis, University of Liverpool.

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Abstract

Colorectal cancer is one of the most common cancers worldwide. Chemotherapy is among the conventional treatment of colorectal cancer and most of the anticancer agents are parenterally administrated. An oral route of administration is typically the most preferred among patients. While several potential drugs have a potent anticancer activity, they suffer from poor oral bioavailability due to their inadequate physicochemical such as poor aqueous solubility, stability, and poor permeability. In order for medicines to reach the colon, the administrated drug should safely across the stomach, avoid absorption in the small intestine. The colon is an ideal site for drug delivery because it has a long retention time and colonic mucosa that facilities the drug absorption. Despite the unique traits of the colon, the oral administration to the colon is challenging because the colon is located in the distal part of the gastrointestinal tract, therefore the orally administered drug has to traverse the entire alimentary canal without being degraded or absorbed until reaching the colon. The main aim of this research was to enhance the physicochemical properties of a natural anticancer agent (curcumin) and synthesise stimuli-responsive multi-layered nanocarriers for oral delivery system and oral colon-targeted delivery system. The layer-by-layer self-assembly technique was used to prepare and optimise LbL nanocapsules made of four layers of poly-L-arginine and sodium alginate. Solid dispersion was used to enhance the dissolution rate of curcumin and allow its encapsulation into calcium carbonate cores with drug loading of 5.1 wt%. Afterward, two stimuli-responsive multilayered nanocapsules were formed made of six layers including poly-L-arginine, sodium alginate, chitosan, and Eudragit L100 as an outermost layer. Two stimuli-responsive multi-layered nanocapsules showed delay release in the stomach pH (1.2) due to the presence of the outermost pH-responsive layer. At the small intestine pH (7.4), the two nanocapsules showed a different behaviour depending on the fifth layer. The nanocapsules have poly-L-arginine as a fifth layer showed around 96 % release in the pH of small intestine, while nanocapsules have chitosan as a fifth layer showed around 46 % curcumin release over 24 hours. To increase the drug loading, the curcumin was formulated as solid drug nanoparticles (SDNs) with drug loading of 10 % wt. The SDNs samples were prepared in screening process using different excipients. Among several samples, one SDN sample made of curcumin and polyethylene glycol (PEG) as the excipient was chosen for further studies. This SDN sample showed higher chemical stability at all pH values studied that mimics the stomach, small intestine and colon. The SDNs also demonstrated an enhanced in-vitro bioaccessibility and a decreased in-vitro cytotoxicity profile compared to solubilised curcumin on colon cancer cell lines. To modify the SDNs’ colloidal stability, dissolution rate, and provide a sustained drug release, the chosen SDNs were coated with multiple layers of polyelectrolytes using titration method, a simple wash less approach. Two stimuli-responsive SDNs formulations were formed that were similar to the stimuli-responsive multi-layered nanocapsules. The in-vitro release and bioaccessibility model studies revealed that the presence of Eudragit L100 as an outermost shell in the two formulations resulted in protection of curcumin SDNs in stomach pH and a sustained drug release in intestine pH, which proposed to formulate a promising oral delivery system for curcumin SDNs. Furthermore, the presence of chitosan as a fifth layer demonstrated a delayed and sustained drug release at stomach and small intestine offering a promising nanoformulation for oral colon-targeted drug delivery.

Item Type: Thesis (Doctor of Philosophy)
Divisions: Faculty of Science and Engineering > School of Physical Sciences > Chemistry
Depositing User: Symplectic Admin
Date Deposited: 03 Sep 2021 10:51
Last Modified: 01 Aug 2023 01:30
DOI: 10.17638/03114646
Supervisors:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3114646