Design, Construction And Application Of Functionalized Cellulose Nanocrystals In Controlled Drug Delivery System

As an ideal drug carrier, cellulose nanocrystals (CNCs) are interesting nanoscalebiomacromolecular building blocks due to their biological activity, biocompatibility,biodegradability and low toxicity. Much work has been considered as an ideal drug carriers.An extensive number of works have been devoted to isolation and modification of cellulosenanocrystals, but these methods have drawbacks such as harsh conditions,environmentally-unfriendly, low crystallinity, multiple reaction steps and low yield. Toovercome these boundaries, the design and construction of functionalized cellulosenanocrystals and their applications in controlled drug release were studied in this dissertation.The cellulose nanocrystals were manufactured by exchange resin-catalyzed hydrolysis in anenvironmentally-friendly way. To utilize the mechanical, chemical and thermal effects ofmechanochemistry, we developed two approaches to manufacture functionalized CNCs. Asimple and environmentally benign approach was developed for manufacturing maleicanhydride functionalized cellulose nanocrystals (MA-CNCs) via one-pot tandem reactionsunder solvent-free conditions. On the other hand, by utilizing of the mechanism of Fischeresterification, the acetic acid esterified cellulose nanocrystals (E-CNCs) were manufactured insynchronous reaction in which the degradation and esterification of cellulose took placealmost simultaneously. This work will provide a new route to design functionalized CNCs. Inaddition, the functionalized CNCs drug carriers were designed and their feasibility on colonicdrug delivery and mucoadhesive buccal films drug delivery systems were evaluated. The mainachievements and innovative points obtained in this dissertation are as follows.1. Exchange resin-catalyzed hydrolysis of cellulose can be an excellent method formanufacturing of cellulose nanocrystals (CNCs) in a simple and environmentally-friendlyway. The regular short rod-like CNCs with a high crystallinity of84.26%was obtained byexchange resin hydrolysis. The esterified cellulose nanocrystals (E-CNCs) were prepared withthe aid of ultrasonication in synchronous reaction, in which the degradation of cellulose pulpand esterification took place simultaneously. The results show ultrasonication treatment iseffective in the degradation of cellulose amorphous regions and esterification of hydroxylgroups. As the crystalline structures of E-CNCs by XRD and NMR revealed the degree ofsubstitute (DS) reaches0.47and E-CNCs still have high crystallinity of80.16%, indicatingthe maintenance of crystalline region of cellulose.2. We disclose a simple and versatile method to manufacture maleated cellulose nanocrystals (MA-CNCs) by conjunction of ball milling and ultrasonication in tandem mode,in which the nanocrystallization and maleation of cellulose take place simultaneously undersolvent-free conditions. In order to investigate the mechanochemical effects induced by ballmilling and ultrasonication on the yields and DS, some factors, such as the ball-milling time,ultrasonication temperature and ultrasonication time, were taken into consideration. The highyield and crystallinity, solvent-free conditions, as well as relative mild conditions make thisprocess a valuable and environmentally friendly alternative to the currently available methodsfor the preparation of functionalized cellulose nanocrystals in industry. The rheologicalbehaviors of CNCs, E-CNCs and MA-CNCs dispersions were tested. The results show that alldispersions are pseudoplastic fluid. The viscosity can be influenced by the concentration,temperature, pH values and the salt concentration.3. For the potential practical applications as drug delivery carriers for the fluorescentdetection of the drug release process, the amino modified cellulose nanocrystals (A-CNCs)and fluorescent labled nanoparticles (F-A-CNCs) were designed and constructed. Thesuccessful modifications of CNCs and photo responsive of F-A-CNCs were detected by FTIR,NMR, XPS, fluorescence spectrophotometer and CLSM. The functional mechanism of aminoand fluorescent modification of CNCs was explored.4. With exquisite biological physical and chemical properties of CNCs, a novel prodrugwas prepared by the covalent attachment of the tosufloxacin tosylate (TFLX) onto the surfaceof MA-CNCs with L-leucine as a spacer. The fluorescent labeled prodrug(F-TFLX-A-MA-CNCs) was designed for monitoring the process of drug release. The releasebehaviors of TFLX-A-MA-CNCs and F-TFLX-A-MA-CNCs in simulated gastric fluid (SGF),simulated intestinal fluid (SIF) and simulated colonic fluid (SCF) were investigated. Therelationship between the accumulative drug release and the fluorescence responsive has beenevaluated. The results show that the drug was efficiently entrapped by MA-CNCs carrier andpresents excellent behavior for colon specificity and may be considered as a potential materialfor a colon-specific drug delivery system.5. The new mucoadhesive films for topical administration in the oral cavity have beendeveloped, using a natural resin shellac as backing layer for preventing liquid permeation. TheE-CNCs, PEG and shellac composites were used as the drug carrier. The films were evaluated for their weight, thickness, swelling, drug content uniformity, mechanical property, vitro drugrelease and mucoadhesive properties. The films exhibit good swelling, mucoadhesiveproperties and promising controlled drug release, thus it can be selected to develop the buccalfilm for effective therapeutic uses. E-CNCs may be considered as a potential candidate for themucoadhesive film drug carrier.