DEVELOPMENT OF NANOFIBERS AND HYDROGEL FOR DELIVERY OF ANTICANCER AGENTS

Abstract

With time, remarkable progress has been achieved in our understanding of cancer progression and treatment. A great deal of data and information has been amassed regarding the aberrant biological processes responsible for the pathophysiology of cancer. Due to defects in various signalling pathways, regulation of cellular proliferation is lost in cancer cells. They exhibit abnormalities in intracellular, intercellular as well as extracellular modes of communication. The intercellular communication is mediated by gap junctions which ensure equilibrium of growth control signals for achieving cell-cell homeostasis. However, cancer cells display reduced gap junction mediated intercellular communication as well as downregulation of connexin (Cx) proteins which are subunit of gap junctions. The isoform Cx43 is expressed in various tissues and has been extensively studied. It is also reported to exert tumor- suppressive roles in many cancers. Thus, the present thesis aims to develop nanotechnology based approaches for delivery of agents to modulate connexins and gap junctions for anticancer application. With this perspective, we first developed a core-shell nanofibrous scaffold loaded with Cx43 gene and 4-phenylbutyrate drug. 4-phenylbutyrate (4-PB), a histone deacetylase inhibitor (HDACi), has antitumor potential that is also reported to increase Cx43 expression and gap junction communication. The nanofibrous scaffold was characterized by spectroscopic and electron microscopic techniques. The nanofibrous scaffold mediated transfection of the Cx43 gene into Cx43 deficient breast cancer cells (MCF-7), followed by controlled and sustained release of 4-PB, exhibited anti-cell proliferative activity. The anticancer effects were ascertained by cell staining, cell viability and flow cytometry-based assays. Overall, the novel core-shell nanofiber scaffold exhibited enormous therapeutic translation ability via Cx-based enhancement of anticancer potential of HDACi. Next, we developed a hydrogel for delivery of 4-PB alongwith an imaging modality. Therapy combined with diagnostics i.e. theranostics, is becoming an important facet of cancer management. Thus, considering these two critical aspects, we focussed on the synthesis, bio imaging and anti-proliferative effects of a multi-functional chitosan hydrogel incorporating highly fluorescent silver nanoclusters and 4-PB for enhancing Cx43 expression. While the remarkable fluorescence of silver nanoclusters enabled cellular uptake and imaging, 4-phenyl butyrate released from the hydrogel upregulated Cx43 expression and induced apoptosis in breast i cancer cells. Also, 4-phenyl butyrate successfully established gap junction communication between cancer cells as assessed by dye transfer assay. Thus, the current module not only holds potential in cancer theranostics but also for connexin based cancer therapeutics. In a nutshell, nanomaterial were employed to translate the anticancer potential of Cx43 into suitable therapeutics. The anticancer potential of these nanomaterials was studied in vitro in breast cancer cells.