Natural and synthetic nanoparticles for delivery of biologics

Abstract

Nano is a prefix derives from the Greek word ‘νᾶνος’, which means ‘drawf’. Nanomedicine is the healthcare application of nanoscale or nanostructure materials. It is an inter-disciplinary field involving chemistry, biology, physics, materials sciences and clinical medicine.Nanomedicines can be used for both the diagnosis and therapy of diseases. There are several attractive features of nanomedicines as drug delivery systems when compared with traditional small molecular weight drugs. For example, 1) they can increase the solubility of hydrophobic drugs; 2) effectively deliver drugs intracellularly and across barriers such as the blood-brain barrier; 3) be ‘smart’ by active targeting the site of disease, thus increase therapeutic outcome and simultaneously reduce side effects of drugs caused by accumulation in healthy tissues; 4) prolong circulation time by surface decoration drug-loaded nanoparticles with polyethylene glycol (PEG) that prevent aggregation, opsonization, and phagocytosis; 5) overcome drug resistance as drug-loaded nanoparticles are uptake in a stealth endocytosis process that drugs become ‘invisible’ to drug efflux pumps.

Nanomedicine can be mainly divided into two categories, i.e. synthetic nanomedicine system and natural nanomedicine system. Synthetic systems are mainly obtained by chemical synthesis methods, which can be further divided into 1) polymer-based nanocarriers such as micelles, nanogels and dendrimers; and 2) liposomes and lipidbased nanocarriers. Natural nanomedicine systems include, viruses, lipoproteins and extracellular vesicles (EVs). EVs can be released by different domains of life including eukaryotes, bacteria and fungi. (Deatherage and Cookson 2012, Brown, Wolf et al. 2015)

In this thesis, two nanomedicine systems are investigated. One is a synthetic system: i.e. a nanogel. The characterization of this novel nanogel is presented, and we also investigated the possibility of using this nanogel for nucleic acid delivery in chapter 2 in both in vitro and in vivo models. EVs have shown to be an interesting emerging nanomedicine system over the past decade. They can be released by all domains of life which includes eukaryotes, bacteria, fungi and archaea. EVs released by mammalian cells and bacteria are studied in this thesis. We discuss the potential application of mammalian EVs as drug carriers for gene delivery purposes in chapter 3, and discuss the application of bacterial EVs as vaccine candidates in chapter 4. In addition, we investigated the possibility of using bacterial EVs as ‘nano-weapons’ for combating bacterial infections. As EVs from Gram-positive bacteria have received less attention than their counterpart from Gram-negative bacteria, in chapter 5, we studied the isolation, characterization and immuno-modulatory aspects of membrane vesicles (MVs) from Gram-positive bacteria Enterococcus faecium E1162 and its isogenic mutants. To improve the targeting and immunogenicity properties of EVs from both mammalian cells and bacteria, we investigated a post-insertion approach for EVs modification in chapter 6. Finally, a co-culture system which mimic the intestinal environment was set up to evaluate the immunogenicity of OMVs in chapter 7 with the aim to develop an in-vitro platform to study the oral vaccination evaluation of OMVs. In chapter 8 the main results of this thesis are summarized and future research directions are discussed.