Design and Development of Novel Biocompatible Nanosystems for Drug Delivery

In recent years, pharmaceutical research has focused on the development on nanotechnology systems applicable in different fields of medicine, especially in the field of drug delivery. Nanotechnology is an emerging branch of sciences for designing tools and devices of nanoscale size with specific function at the cellular, atomic and molecular levels. Nanocarriers, owing to their high surface area volume ratio, have the ability to alter basic properties and bioactivity of drugs. Improved the pharmacokinetics and biodistribution, decreased toxicities, improved solubility and stability, controlled release and site-specific delivery of therapeutic agents are some of the features that nanocarriers can incorporate in drug delivery system. The composition of the nanocarriers, (e. g. organic, inorganic, and hybrid materials) and the form in which drugs are associated with them, such as core-shell system or matrix system, are also fundamental for understanding their drug delivery profile. Considering the above facts, this dissertation aims to design novel nano-based drug delivery systems and to develop new control process strategies, such as modified the shape, chemical composition, internal structure and morphology of the nanocarriers so as to obtain new levels of product performance in the targeted drug delivery system. Firstly, we designed a new nano-formulations to enhance the therapeutic efficacy and bioavailability of ocular drugs, for glaucoma therapy. An amphiphilic di-block copolymer, composed of methoxy poly(ethylene glycol) (mPEG) and poly(-caprolactone) (PLC), that can self-assemble into polymeric micelles (PMs), was synthesized. mPEG-PLC PMs bearing the hydrophobic drug, Methazolamide (MTZ) were formulated and fully characterized. In vitro and in vivo studies were carried out to verify ocular tolerability and to evaluate anti-glaucoma activity in a glucocorticoidinduced glaucoma model. The results showed that, a better in vivo inhibitory effect of MTZ-PMs was achieved, compared to MTZ solution on glaucoma induction in experimental rabbits. Hence, these newly developed nano formulations have characteristics which are appropriate for ocular nanodelivery. Secondly, in effort to develop improved nano-liposomal carriers for in vivo application on Zebrafish embryo models, in collaboration with Leiden University, we focused on preparation of new glicoliposome formulations, obtained by combining the advantages of synthetic sugar fatty acid esters and liposomes, in order to use this nano drug delivery system to target the Mannose receptor (mrc1) and to study their receptor specificity and potential for intracellular delivery in Liver sinusoidal endothelial cells (LSECs). We have successfully generated a LSECs-targeted glycol-liposomal drug delivery system with precise and in vivo confirmed specificity towards LSECs through interaction with the mrc1 receptor. Another work carried out, was based on the formulation and characterization of a novel mixed/chimeric liposomal system. The bock copolymer methoxy polytylene glycol-co-poly (ddecalactone) (mPEGx-PDLy) was incorporated into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-diasteroyl-sn-glycero-3phosphocholine (DSPC) lipid bilayers. The chimeric liposomes were studied in regards with their physicochemical properties, their colloidal stability and their in vitro toxicity. As a result, depending on their thermodynamic, physicochemical and toxicity profiles, these chimeric polymer-grafted liposomes could be promising candidates for further in vitro and in vivo investigation for future nano drug delivery applications.