There is an ever-increasing desire to develop novel materials that could control therelease of active compounds and increase their stability. Replacing petroleum-based synthetic polymers with sustainable materials has many advantages, such as reducing thedependence on fossil fuels, and diminishing environmental pollution. Recently, cellulosenanocrystal (CNC) obtained by acid hydrolysis of cellulosefibres has gained a lot of interest.The high mechanical strength, large and negatively charged surface area, and thepresence of several hydroxyl groups that allow for modification with different functionalitiesmake CNC an excellent candidate for various applications in the biomedicalfield. Thisthesis explores (i) the surface modification and characterization of modified CNC and (ii)the biomedical applications of these novel sustainable nanomaterials.In the first part, amine functionalized CNC was prepared. Ammonium hydroxide wasreacted with epichlorohydrin (EPH) to produce 2-hydroxy-3-chloro propylamine (HCPA),which was then grafted to CNC using an etherification reaction. A series of reactions werecarried out to determine the optimal conditions. Thefinal product (CNC-NH2(T)) wasdialyzed for one week. Further purification via centrifugation yielded the sediment (CNC-NH2(P)) and supernatant (POLY-NH2). The presence of amine groups was confirmed byFT-IR and the amine content was determined by potentiometric titration and elementalanalysis. A high amine content of 2.2 and 0.6 mmol amine/g was achieved for CNC-NH2(T) and CNC-NH2(P), respectively. Zeta potential measurements confirmed the chargereversal of amine CNC from negative to positive when the pH was decreased from 10to 3. TEM images showed similar structural properties of the nanocrystals along withsome minor aggregation. This simple, yet effective synthesis method can be used forfurther conjugation as required for various biomedical applications. Moreover, the surfaceof CNC was modified with chitosan oligosaccharide (CSos). First, the primary alcoholgroups of CNC were selectively oxidized to carboxyl groups using the catalyst, 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO), and were then reacted with the aminogroups of CSos via the carbodiimide reaction using N-hydroxysuccinimide (NHS) and1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC). The appearance of C=O peakin FT-IR spectrum of oxidized CNC (CNC-OX), accompanied by calculations based onpotentiometric titration revealed that CNC was successfully oxidized with a degree ofoxidation of 0.28. The grafting of CSos on oxidized CNC was confirmed by the followingobservations: (i) the reduction of the C=O peak in FT-IR of CNC-CSos and the appearanceof new amide peaks; (ii) the significant reduction of the carbonyl peak at 175 ppm in the13C NMR spectrum for CNC-CSos; (iii) a higher decomposition temperature in TGA ofCNC-CSos; (iv) a positive zeta potential of CNC-CSos at acidic pH; and (v) a degree of substitution of 0.26, which is close to the DO (0.28), indicating that 90% of COOHgroups on CNC-OX were involved in the formation of amide bonds with CSos. TEM andAFM studies also revealed a completely diff erent morphology for CNC-CSos.In the second part, the potential of exploiting CNCs as delivery carriers for two cationicmodel drugs, procaine hydrochloride (PrHy) and imipramine hydrochloride (IMI), wereinvestigated. IMI displayed a higher binding to CNC derivatives compared to PrHy.Isothermal titration calorimetry (ITC), transmittance and zeta potential measurementswere used to elucidate the complexation between model drugs and CNC samples. It wasobserved that the more dominant exothermic peak observed in the ITC isotherms leadingto the formation of larger particle-drug complexes could explain the increased bindingof IMI to CNC samples. Drug selective membranes were prepared for each model drugthat displayed adequate stability and rapid responses. Different in vitro release profilesat varying pH conditions were observed due to the pH responsive properties of the systems. Both drugs were released rapidly from CNC samples due to the ion-exchange e ffect, and CNC-CSos displayed a more sustained release profile. Furthermore, the antioxidant properties of CNC samples and the potential of CNC-CSos as a carrier for the delivery of vitamin C was investigated. CNC-CSos/vitamin C complexes (CNCS/VC) were formed between CNC-CSos and vitamin C via ionic complexation using sodium tripolyphosphate (TPP). The complexation was confirmed via DSC and UV-Vis absorbance measurements.TEM images showed complexes with a size of approximately 1 micron. The encapsulationefficiency of vitamin C was higher (91%) at pH 5 compared to pH 3 (72%). The invitro release of vitamin C from CNCS/VC complexes exhibited a sustained release of upto 3 weeks, with the released vitamin C displaying higher stability compared to a controlvitamin C solution. Antioxidant activity and kinetics of various CNC samples were studiedusing the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. CNC-CSos possessed a higherscavenging activity and faster antioxidant activity compared to its precursors, CNC-OXand CSos, and their physical mixture. Therefore, by loading vitamin C into CNC-CSosparticles, a dynamic antioxidant system was produced. Vitamin C can be released over aprolonged time period displaying enhanced and sustained antioxidant properties since thecarrier CNC-CSos also possesses antioxidant properties.As a result of this doctoral study, knowledge on the surface modification of CNC withamine groups and CSos have been advanced. The in vitro drug release and antioxidantstudies suggest that systems comprising of CNC could be further explored as potentialcarriers in biomedical applications.
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Surface Modification and Characterization of Cellulose Nanocrystal for Biomedical Applications
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