AbstractThis thesis focuses on the formulation of polymersomes (Ps) capable of delivering drug payloads to the posterior of the eye. Drug delivery through the ocular layers has faced significant challenges due to the anatomical and physiological barriers in the eye, discussed in detail in chapter one. To overcome these barriers, researchers have formulated various delivery methods to deliver drugs to the posterior of the eye, the most popular being intravitreal injections (IVIs). IVIs are effective in delivering drugs because they mechanically overcome the eye’s physical barrier by injecting the drugs directly to the posterior of the eye. As would be expected, this comes with substantial side effects, discussed in detail in chapter one. To overcome the ocular barriers and avoid side effects, researchers have employed the use of nanoparticles to aid in drug delivery. Ps are attractive nanocarriers due to their tuneability, stability, ability to carry both hydrophobic and hydrophilic drug cargo, among others, hence their application in delivering drug payloads in this thesis.
Chapter two discusses formulation of a neutral Ps capable of delivering drug surrogate , FITC-CM-dextran (FCD), to the posterior of the eye and its ability compared with free FCD. The neutral Ps was formulated from an amphiphilic polymer formed from the random polymerisation of two copolymers, decyl methacrylate and PEG methacrylate Mn500. The neutral Ps was then characterised using various analysis methods such as DLS to confirm their formulation and experiments were carried out to examine their superiority, if any, to free FCD. These experiments included and was not limited to cell uptake and viability studies and permeation through ocular layers. The results demonstrated that the neutral Ps was taken up by Human Corneal Epithelial (HCE) cells with minimal toxicity and demonstrated enhanced permeation through ocular layers and vitreous humour (VH) when compared to free FCD.
Chapter three focuses on the effect of charge on Ps efficiency. Cationic, neutral and anionic Ps were formulated and loaded with FCD, and their effect on cell uptake, viability and permeation compared against each other and free drug. The cationic compound was a novel compound formulated in house and was anchored into the Ps bilayer using a decyl chain and the anionic compound was bought in and similarly anchored into the Ps bilayer using a decyl chain. The polymersomes demonstrated superiority over free drug however with varied advantages. The positively charged Ps demonstrated the highest cell uptake, probably due to electrostatic attraction on the ocular surface. The negatively charged Ps demonstrated the most efficient movement through the VH and finally the neutral Ps demonstrated both attractive cell uptake and VH permeation, in addition to this, they were the most biocompatible.
Chapter four involved preliminary work into the effect of charge on Ps, with the charge originating from the fabrication of charged peptides on the Ps. Seven peptides were formulated from three amino acids conjugated to decanoic acid. Of these formulated seven peptides, two were positive peptides, three were neutral peptides and two were negatively charged. Of these, six peptides were carried forward formulating one neutral Ps, two cationic Ps and three anionic Ps. What followed was a series of experiments to investigate their effects on cell uptake and viability. The result was the most effective uptake came from the anionic and cationic Ps as was demonstrated in chapter three, however, cell toxicity was significant in these Ps. Once the cytotoxicity of these Ps is combated, these peptide Ps would be a promising drug delivery system.
It was concluded in Chapter 5 that Ps demonstrated great benefit when compared with free drug, with the charged Ps demonstrating various advantages to the Ps as they cross the ocular barriers. These amphiphilic Ps show great potential in their use as drug delivery systems for ocular applications. All methods used within this research are described in chapter 6.
|Date of Award||Sept 2023|
|Supervisor||Bridgeen Callan (Supervisor), John Callan (Supervisor), Andrew Nesbit (Supervisor) & Tara Moore (Supervisor)|
- Macular degeneration
- Diabetic retinopathy
- Intravitreal injections