POLY(AMIDOAMINE) DENDRIMER BASED NANOMATERIALS FOR DELIVERY OF ANTICANCER AGENTS

Abstract

Cancer is still notorious to create havoc in the modern society despite considerable advancements in field of medical technology. Though commendable efforts and improvements have been done to better the lives of cancer patients, still the ultimate goal to eradicate this dreadful disease demands inspection of new smart materials. In this fight towards cancer, nanotechnology based materials are certainly valuable. Lately, polymer based nanoscale drug delivery systems (DDS) as ‘nanomedicines’ have garnered much attention for the chemotherapeutic drug delivery in cancer treatment. With a suitable design and structural versatility, they provide biocompatibility, controlled drug release profiles, and increased drug circulation times. Such advantages suggest the pre-eminence of nanoscale drug carriers over traditional drugs. Among the available polymers, dendrimers especially poly(amido amine) (PAMAM) dendrimers offer numerous advantages such as distinct molecular architecture, monodispersity, enhanced solubility of hydrophobic drugs, reduced toxicity and tumor selectivity by enhanced permeability and retention (EPR) effects. Therefore, the present thesis is an endeavour to develop dendrimer based nanomaterials as delivery systems for anticancer agents. With this perspective, PAMAM dendrimer based multicomponent therapeutic agents have been developed for in vitro cancer therapy applications. Firstly, G5.0 PAMAM dendrimers stabilizing silver nanoparticle surface (DsAgNPs) were synthesized to encapsulate anticancer drug 5-fluorouracil (5-FU) to attain anticancer synergism. The formation of 5-FU loaded DsAg nanocomposites (5-FU@DsAgNCs) was confirmed by various characterization techniques. These NCs were taken up effectively by cells and elicited synergistic antiproliferative effects in A549 (human lung cancer) and MCF-7 (human breast cancer) cells at low doses. When the therapeutic outcomes were investigated in detail by different cell-based experiments, 5-FU@DsAgNCs induced apoptosis in cancer cells. The therapeutic effects of 5-FU@DsAgNCs were more pronounced in MCF-7, when compared to A549 cells. Another smart dendrimer nanoformulation i.e. chemically cross-linked nanogels of G5 PAMAM dendrimers and sodium alginate (AG) have been prepared as delivery systems. The integration of PAMAM dendrimer with alginate and formation of AG-G5 hybrid nanogels was confirmed by different microscopic and spectroscopic techniques. Chemo-drug epirubicin (EPI) was entrapped in the nanogels interiors. When evaluated in vitro, these nanogels released EPI slowly iv and steadily in tumor environment. Fluorescence imaging, study of nuclear and morphological deformations in EPI⊂AG-G5 nanogels treated MCF-7 indicated apoptosis induction and subsequently cell death. Subsequently, the impact of hydrophobic modification of G5 PAMAM dendrimer surface on delivery of anticancer agents has been studied. Lipid-like myristic acid (My) chains were introduced on the dendrimer surface, to augment the delivery profile of anti-estrogen tamoxifen (TAM) in MCF-7 (ER+) cells. The successful grafting of My chains on PAMAM dendrimers (My-g-G5) and formation of My-g-G5/TAM nanocomplexes was confirmed with several characterization experiments. This dendrimer nanoformulation of TAM demonstrated good water-solubility, stability and cell death inducing ability. Finally, the theranostic (therapeutic and diagnostic) applications of partially surface acetylated G5 PAMAM dendrimers towards cancer therapy have been elucidated. Luminescent carbon dots (CQDs) with anionic terminus and cationic acetylated G5 PAMAM dendrimers were combined to form self-assembled fluorescent hybrids. The fluorescence of CQDs in hybrids was enhanced in the vicinity of primary amine groups of dendrimers, making them suitable as cellular imaging probes. When EPI was entrapped in the dendritic architecture, CQDs@EPI⊂G5-Ac85 hybrids demonstrated anticancer potential. Moreover, these hybrids served as a dual-emission delivery system to track the intracellular distribution and cytotoxic effects of EPI. Further in vitro assays implicate apoptosis induction in hybrid treated MCF-cells. In a nutshell, different PAMAM dendrimer based nanomaterials are presented as nanomedicines to efficaciously deliver various anticancer agents especially to breast cancer cells to inhibit their proliferation and induce cell death.