Tailorable nanocarrier emulsion for drug delivery

Abstract

Close to 40-percent of new pharmaceuticals and over 30-percent of pipeline drugs exhibit poor water solubility which provides challenges in drug delivery, such as the delivery of therapeutic levels of drugs to specific biological targets to achieve a desired therapeutic outcome. The challenge of increasing drug therapeutic efficacy, with a concurrent minimization of side effects, can be tackled through proper design and engineering of a suitable drug delivery system (DDS). There is a high demand for DDS that are easy to prepare in the absence of non-pharmaceutical solvents, can carry a variety of drugs, have appropriate pharmacokinetic properties including stability under biological conditions and/or can deliver a drug to a particular tissue or receptor. The development of nanotechnology and bioengineered nanomaterials has greatly increased the potential of nanocarriers for drug delivery. Motivated by the challenges experienced with modular design of effective nanocarrier, this PhD project aims to develop a platform tailorable nanocarrier emulsion (TNE) with combined long circulating and target specific properties, using only biological components and facile processes.Nanoemulsions are a promising nanocarrier class for enhancement of solubility and bioavailability of poorly soluble drugs. They are emulsions that have extremely small droplet size ranging from 10 nm to 200 nm with narrow size distribution. The enormous interfacial area formed by nano-sized droplets provides further engineering opportunities for sustained and controlled drug delivery. Peptide surfactant AM1 was shown to have good emulsification properties and can stabilize oil-in-water emulsions prepared from a range of oils. Recent works from our laboratory have shown that AM1 stabilized emulsion can be used to deliver a hydrophobic molecule to knock down an intracellular protein target in vitro. In this PhD work, we tested our hypotheses that a recently-reported biosurfactant protein DAMP4, which comprises four repeating sequences closely related to AM1, could be used to functionalize the interface of AM1 stabilized oil-in-water emulsion through non-covalent self-assembly by addressing the following: (1) Utilization of DAMP4 modified with polyethylene glycol (PEG) to investigate whether DAMP4 can display PEG at the interface and impart altered cell association to the nanoemulsion; (2) Utilization of DAMP4 modified with monoclonal antibody (mAb) against the CD8 + dendritic cells (DCs) specific receptor Clec9A to design a nanocarrier emulsion that is able to target Clec9A + DCs; (3) Encapsulation of a model antigen within the immune evading and Clec9A + DCs targeting emulsion to investigate the immune function in a relevant animal model. This work, to our best knowledge, introduces the first DC targeting and immune-evading tailorable nanocarrier emulsion (TNE) made using only biological components and assembled in a bottom-up fashion. Simple topii down sequential addition of immune evading and receptor-specific Ab elements conjugated to DAM...