Investigation of chitosan nanoparticles as a carrier of therapeutic agents: Bio-mechanical effects on cancer cell line, applications in delivery of gene and chemotherapeutic agents

Abstract

Chitosan derivatives are used in drug and gene delivery applications due to their outstanding biological features. Chitosan, owing to its unique chemical structure, can fabricate nanoparticles through simple nanofabrication methods using various crosslinkers. There are several exclusive characteristics including the ability of forming conjugates with negatively charged materials such as DNA, siRNA and alginate, anticancer characteristics, relatively long blood circulation period as well as low uptake through reticulo endothelial system (RES) and mucoadhesion that make chitosan derivatives as a promising class of carriers for therapeutic delivery applications. Despite the increasing trend of applications for chitosan nanoparticles, in different research works these nanoparticles mainly were studied only from one or two particular perspectives. there are a limited number of comprehensive studies from different perspectives regarding pharmaceutical applications of the chitosan nanoparticles for cancer treatment. In addition, there is lack of study on biomechanical effects of the chitosan-anti cancer drug conjugates on cancerous cells. The aim of this PhD research program is to in-depth investigation of chitosan nanoparticles from different perspectives for pharmaceutical applications especially in cancer therapy (e.g. method of fabrication, physiological-responsive derivatives, biomechanical effects and development its prolonged release characteristics). In the first part of this project, a new redox responsive nanostructure based on chitosan derivative was designed, synthesized and employed for gene delivery application. In the second part, we demonstrated an efficient tumor targeting chitosan-based nanoparticulate drug delivery system, designed for the oral administration of cancer therapeutic agents. For the first time, a dual microfluidic platform was employed to synthesize nanocarriers with highly pH-tunable core-shell structure. In the third part, we investigated the effects of albendazole encapsulated chitosan nanoparticles on the mechanical behaviour of the cytoskeleton of SW48 (Human colon adenocarcinoma cell line. The anticancer efficacy of the chitosan-drug conjugates as well as its selectivity towards the cancer cells were examined. In the final part of this project, a recently-developed gel aspiration-ejection fabrication technique of dense collagen hydrogel (DNS CG) and chitosan-sulfated cyclodextrin (CS-SCD) conjugation was used to design hierarchical drug delivery system for prolonged controlled release of therapeutic agents.