Mucoadhesive Nanocomposite Derived from Cellulose Nanocrystal and Chitosan for the Delivery of Hydrophobic Compounds

The sea lice are a major ectoparasite of salmon aquaculture that anchor to host fish’s mucus membrane, epidermis, and vascular system, thereby compromising the fish immunity. The surging amount of sea lice has caused enormous financial damage to the global salmon farming industries. Current sea lice treatment has relied on conventional drug delivery system that reduces drug efficacy that poses an environmental risk due to the excessive use of toxic chemical compounds. Nanomedicine and nano delivery system are rapidly developing to serve as therapeutic agents for targeting specific sites in a controlled manner, thereby enhancing the therapeutic effects at lower drug dosages. The objective of this research is to develop novel mucoadhesive nano drug delivery platforms that can encapsulate hydrophobic compounds, thereby enhancing the pharmaceutical effects of various applications including biomedical and agricultural fields. The thesis describes various mucoadhesive drug delivery platforms comprising of cellulose nanocrystals (CNC) and chitosan (CS) with different moieties. The scope of the research focuses on the development of mucoadhesive nanocomposite using green chemistry and facile synthesis methods through electrostatic gelation. To improve the functionality of the nanocomposite, colloidal behavior and mucoadhesive properties, various chemical modification techniques were employed to modify the functional groups and to decorate different moieties using nano-polysaccharide based materials. \nThrough this study, we found that the particle size CNC/CS nanoparticles was in the range of 200 nm to 2 μm, depending on the mass ratio of CNC and CS. The optimal mass ratio was 10:1 (CNC:CS w/w) yielding the smallest average particle size (~200 nm), highest zeta potentials (+40 mV), and highest drug loading efficiency. It was confirmed that polyvinylpyrrolidone (PVP) enhanced the colloidal stability of hydrophobic compounds by making the system hydrophilic. Chitosan coating enhanced colloidal stability and drug encapsulation efficiency via electrostatic repulsion. The loading and encapsulation efficiency of CNC/CS nanocomposite was 11.6 and 65.6 %, respectively. CNC/CS nanoparticle exhibited good antifungal properties against S. cerevisiae and mucoadhesive studies confirmed that nanoparticles could bind to mucus surface of zebrafish. CNC/CS modified with quaternary ammonium groups (Gch) exhibited permanent positive charge at all pH values, resulting in enhanced solubility of CS. The optimal mass ratio was 1:4 (CNC:Gch w/w), and the shape of CNC/CS based nanocomposite depended on the synthesis order, reaction time, and sonication power. To produce nanocomplexes with a homogenous structure, polymeric CS solution should be added to the CNC to coat the surface. Finally, the optimal mass ratio of CNC/CS nanoparticles modified with catechol groups (cat) was 7:1 (CNC:CS-cat w/w). After functionalizing with poly(diallyldimethylammonium chloride) (PDADMAC), the colloidal stability was enhanced yielding a particle size of ~150 nm and a zeta potential of +50 mV. Mucoadhesive studies using confocal microscopy confirmed that CNC/CS nanoparticles modified catechol groups could bind to the zebrafish mucus after 30 mins exposure, as the fluorescence signals were significantly enhanced compared to control study without modification. \nThe significant discovery of this research are: (1) a facile and reproducible method to prepare CNC/CS based nanocomposite that encapsulate large amount of hydrophobic drugs via electrostatic gelation was developed, (2) the colloidal behavior and stabilization effect of CNC/CS based nanocomposites were elucidated, (3) mucoadhesive nano-drug delivery systems by incorporating bio-inspired active compounds were produced, and (4) the potentials of mucoadhesive CNC/CS based nanocomposite for the treatment of livestock’s parasitic \ndiseases by demonstrating mucoadhesive capabilities of prepared nanoparticles on zebrafish was demonstrated. \nWith these findings, it is expected that CNC/CS based nanoparticles can serve as targeted drug delivery agents for the delivery of hydrophobic molecules, increasing colloidal stability, drug efficacy, and bioavailability. Furthermore, CNC/CS based nanocomposite will be applied for the treatment of various mucosal infections in agricultural and biomedical fields. This research establishes the foundation for the design and development of mucoadhesive delivery systems for the treatment of sea lice and other parasites found in fish farms in Canada.

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